Brain mitochondrial iron accumulates in Huntington's disease, mediates mitochondrial dysfunction, and can be removed pharmacologically.

PubMed

Agrawal, Sonal; Fox, Julia; Thyagarajan, Baskaran; Fox, Jonathan H

2018-05-20

Mitochondrial bioenergetic dysfunction is involved in neurodegeneration in Huntington's disease (HD). Iron is critical for normal mitochondrial bioenergetics but can also contribute to pathogenic oxidation. The accumulation of iron in the brain occurs in mouse models and in human HD. Yet the role of mitochondria-related iron dysregulation as a contributor to bioenergetic pathophysiology in HD is unclear. We demonstrate here that human HD and mouse model HD (12-week R6/2 and 12-month YAC128) brains accumulated mitochondrial iron and showed increased expression of iron uptake protein mitoferrin 2 and decreased iron-sulfur cluster synthesis protein frataxin. Mitochondria-enriched fractions from mouse HD brains had deficits in membrane potential and oxygen uptake and increased lipid peroxidation. In addition, the membrane-permeable iron-selective chelator deferiprone (1 μM) rescued these effects ex-vivo, whereas hydrophilic iron and copper chelators did not. A 10-day oral deferiprone treatment in 9-week R6/2 HD mice indicated that deferiprone removed mitochondrial iron, restored mitochondrial potentials, decreased lipid peroxidation, and improved motor endurance. Neonatal iron supplementation potentiates neurodegeneration in mouse models of HD by unknown mechanisms. We found that neonatal iron supplementation increased brain mitochondrial iron accumulation and potentiated markers of mitochondrial dysfunction in HD mice. Therefore, bi-directional manipulation of mitochondrial iron can potentiate and protect against markers of mouse HD. Our findings thus demonstrate the significance of iron as a mediator of mitochondrial dysfunction and injury in mouse models of human HD and suggest that targeting the iron-mitochondrial pathway may be protective. Copyright © 2018 Elsevier Inc. All rights reserved.

First principles design of a core bioenergetic transmembrane electron-transfer protein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goparaju, Geetha; Fry, Bryan A.; Chobot, Sarah E.

Here we describe the design, Escherichia coli expression and characterization of a simplified, adaptable and functionally transparent single chain 4-α-helix transmembrane protein frame that binds multiple heme and light activatable porphyrins. Such man-made cofactor-binding oxidoreductases, designed from first principles with minimal reference to natural protein sequences, are known as maquettes. This design is an adaptable frame aiming to uncover core engineering principles governing bioenergetic transmembrane electron-transfer function and recapitulate protein archetypes proposed to represent the origins of photosynthesis. This article is part of a Special Issue entitled Biodesign for Bioenergetics — the design and engineering of electronic transfer cofactors, proteinsmore » and protein networks, edited by Ronald L. Koder and J.L. Ross Anderson.« less

Understanding Muscle Dysfunction in Chronic Fatigue Syndrome

PubMed Central

Rutherford, Gina; Manning, Philip; Newton, Julia L.

2016-01-01

Introduction. Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a debilitating disorder of unknown aetiology, characterised by severe disabling fatigue in the absence of alternative diagnosis. Historically, there has been a tendency to draw psychological explanations for the origin of fatigue; however, this model is at odds with findings that fatigue and accompanying symptoms may be explained by central and peripheral pathophysiological mechanisms, including effects of the immune, oxidative, mitochondrial, and neuronal pathways. For example, patient descriptions of their fatigue regularly cite difficulty in maintaining muscle activity due to perceived lack of energy. This narrative review examined the literature for evidence of biochemical dysfunction in CFS/ME at the skeletal muscle level. Methods. Literature was examined following searches of PUB MED, MEDLINE, and Google Scholar, using key words such as CFS/ME, immune, autoimmune, mitochondria, muscle, and acidosis. Results. Studies show evidence for skeletal muscle biochemical abnormality in CFS/ME patients, particularly in relation to bioenergetic dysfunction. Discussion. Bioenergetic muscle dysfunction is evident in CFS/ME, with a tendency towards an overutilisation of the lactate dehydrogenase pathway following low-level exercise, in addition to slowed acid clearance after exercise. Potentially, these abnormalities may lead to the perception of severe fatigue in CFS/ME. PMID:26998359

Genetic ablation of calcium-independent phospholipase A2gamma leads to alterations in mitochondrial lipid metabolism and function resulting in a deficient mitochondrial bioenergetic phenotype.

PubMed

Mancuso, David J; Sims, Harold F; Han, Xianlin; Jenkins, Christopher M; Guan, Shao Ping; Yang, Kui; Moon, Sung Ho; Pietka, Terri; Abumrad, Nada A; Schlesinger, Paul H; Gross, Richard W

2007-11-30

Previously, we identified a novel calcium-independent phospholipase, designated calcium-independent phospholipase A(2) gamma (iPLA(2)gamma), which possesses dual mitochondrial and peroxisomal subcellular localization signals. To identify the roles of iPLA(2)gamma in cellular bioenergetics, we generated mice null for the iPLA(2)gamma gene by eliminating the active site of the enzyme through homologous recombination. Mice null for iPLA(2)gamma display multiple bioenergetic dysfunctional phenotypes, including 1) growth retardation, 2) cold intolerance, 3) reduced exercise endurance, 4) greatly increased mortality from cardiac stress after transverse aortic constriction, 5) abnormal mitochondrial function with a 65% decrease in ascorbate-induced Complex IV-mediated oxygen consumption, and 6) a reduction in myocardial cardiolipin content accompanied by an altered cardiolipin molecular species composition. We conclude that iPLA(2)gamma is essential for maintaining efficient bioenergetic mitochondrial function through tailoring mitochondrial membrane lipid metabolism and composition.

Zebrafish: a model animal for analyzing the impact of environmental pollutants on muscle and brain mitochondrial bioenergetics.

PubMed

Bourdineaud, Jean-Paul; Rossignol, R; Brèthes, D

2013-01-01

Mercury, anthropogenic release of uranium (U), and nanoparticles constitute hazardous environmental pollutants able to accumulate along the aquatic food chain with severe risk for animal and human health. The impact of such pollutants on living organisms has been up to now approached by classical toxicology in which huge doses of toxic compounds, environmentally irrelevant, are displayed through routes that never occur in the lifespan of organisms (for instance injecting a bolus of mercury to an animal although the main route is through prey and fish eating). We wanted to address the effect of such pollutants on the muscle and brain mitochondrial bioenergetics under realistic conditions, at unprecedented low doses, using an aquatic model animal, the zebrafish Danio rerio. We developed an original method to measure brain mitochondrial respiration: a single brain was put in 1.5 mL conical tube containing a respiratory buffer. Brains were gently homogenized by 13 strokes with a conical plastic pestle, and the homogenates were immediately used for respiration measurements. Skinned muscle fibers were prepared by saponin permeabilization. Zebrafish were contaminated with food containing 13 μg of methylmercury (MeHg)/g, an environmentally relevant dose. In permeabilized muscle fibers, we observed a strong inhibition of both state 3 mitochondrial respiration and cytochrome c oxidase activity after 49 days of MeHg exposure. We measured a dramatic decrease in the rate of ATP release by skinned muscle fibers. Contrarily to muscles, brain mitochondrial respiration was not modified by MeHg exposure although brain accumulated twice as much MeHg than muscles. When zebrafish were exposed to 30 μg/L of waterborne U, the basal mitochondrial respiratory control ratio was decreased in muscles after 28 days of exposure. This was due to an increase of the inner mitochondrial membrane permeability. The impact of a daily ration of food containing gold nanoparticles of two sizes (12 and 50 nm) was investigated at a very low dose for 60 days (40 ng gold/fish/day). Mitochondrial dysfunctions appeared in brain and muscle for both tested sizes. In conclusion, at low environmental doses, dietary or waterborne heavy metals impinged on zebrafish tissue mitochondrial respiration. Due to its incredible simplicity avoiding tedious and time-consuming mitochondria isolation, our one-pot method allowing brain respiratory analysis should give colleagues the incentive to use zebrafish brain as a model in bioenergetics. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy. Copyright © 2012 Elsevier Ltd. All rights reserved.

Insulin Resistance and Alzheimer’s Disease: Bioenergetic Linkages

PubMed Central

Neth, Bryan J.; Craft, Suzanne

2017-01-01

Metabolic dysfunction is a well-established feature of Alzheimer’s disease (AD), evidenced by brain glucose hypometabolism that can be observed potentially decades prior to the development of AD symptoms. Furthermore, there is mounting support for an association between metabolic disease and the development of AD and related dementias. Individuals with insulin resistance, type 2 diabetes mellitus (T2D), hyperlipidemia, obesity, or other metabolic disease may have increased risk for the development of AD and similar conditions, such as vascular dementia. This association may in part be due to the systemic mitochondrial dysfunction that is common to these pathologies. Accumulating evidence suggests that mitochondrial dysfunction is a significant feature of AD and may play a fundamental role in its pathogenesis. In fact, aging itself presents a unique challenge due to inherent mitochondrial dysfunction and prevalence of chronic metabolic disease. Despite the progress made in understanding the pathogenesis of AD and in the development of potential therapies, at present we remain without a disease-modifying treatment. In this review, we will discuss insulin resistance as a contributing factor to the pathogenesis of AD, as well as the metabolic and bioenergetic disruptions linking insulin resistance and AD. We will also focus on potential neuroimaging tools for the study of the metabolic dysfunction commonly seen in AD with hopes of developing therapeutic and preventative targets. PMID:29163128

The impact of cryopreservation on human peripheral blood leucocyte bioenergetics.

PubMed

Keane, Kevin N; Calton, Emily K; Cruzat, Vinicius F; Soares, Mario J; Newsholme, Philip

2015-05-01

Circulating immune cells are considered a source for biomarkers in health and disease, since they are exposed to nutritional, metabolic and immunological stimuli in the vasculature. Cryopreservation of leucocytes is routinely used for long-term storage and determination of phenotypic/functional changes at a later date. Exploring the role of bioenergetics and mitochondrial (dys)function in leucocytes is often examined by using freshly isolated cells. The aim of the pilot study described herein was to assess leucocyte bioenergetics in cryopreserved cells. Leucocytes were isolated from whole blood, counted and frozen in liquid nitrogen (LN2) for a period of 3 months. Cells were thawed at regular intervals and bioenergetic analysis performed using the Seahorse XFe96 flux analyser. Cryogenic storage reduced cell viability by 20%, but cell bioenergetic responses were largely intact for up to 1 month storage in LN2. However, after 1 month storage, mitochondrial function was impaired as reflected by decreasing basal respiration, ATP production, maximum (MAX) respiration, reserve capacity and coupling efficiency. Conversely, glycolytic activity was increased after 1 month, most notably the enhanced glycolytic response to 25 mM glucose without any change in glycolytic capacity. Finally, calculation of bioenergetic health index (BHI) demonstrated that this potential diagnostic parameter was sensitive to cryopreservation. The present study has demonstrated for the first time that cryopreservation of primary immune cells modified their metabolism in a time-dependent fashion, indicated by attenuated aerobic respiration and enhanced glycolytic activity. Taken together, we recommend caution in the interpretation of bioenergetic responses or BHI in cryopreserved samples.

Estrogen: A master regulator of bioenergetic systems in the brain and body

PubMed Central

Rettberg, Jamaica R; Yao, Jia; Brinton, Roberta Diaz

2014-01-01

Estrogen is a fundamental regulator of the metabolic system of the female brain and body. Within the brain, estrogen regulates glucose transport, aerobic glycolysis, and mitochondrial function to generate ATP. In the body, estrogen protects against adiposity, insulin resistance, and type II diabetes, and regulates energy intake and expenditure. During menopause, decline in circulating estrogen is coincident with decline in brain bioenergetics and shift towards a metabolically compromised phenotype. Compensatory bioenergetic adaptations, or lack thereof, to estrogen loss could determine risk of late-onset Alzheimer’s disease. Estrogen coordinates brain and body metabolism, such that peripheral metabolic state can indicate bioenergetic status of the brain. By generating biomarker profiles that encompass peripheral metabolic changes occurring with menopause, individual risk profiles for decreased brain bioenergetics and cognitive decline can be created. Biomarker profiles could identify women at risk while also serving as indicators of efficacy of hormone therapy or other preventative interventions. PMID:23994581

Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion.

PubMed

Bengsch, Bertram; Johnson, Andy L; Kurachi, Makoto; Odorizzi, Pamela M; Pauken, Kristen E; Attanasio, John; Stelekati, Erietta; McLane, Laura M; Paley, Michael A; Delgoffe, Greg M; Wherry, E John

2016-08-16

Dynamic reprogramming of metabolism is essential for T cell effector function and memory formation. However, the regulation of metabolism in exhausted CD8(+) T (Tex) cells is poorly understood. We found that during the first week of chronic lymphocytic choriomeningitis virus (LCMV) infection, before severe dysfunction develops, virus-specific CD8(+) T cells were already unable to match the bioenergetics of effector T cells generated during acute infection. Suppression of T cell bioenergetics involved restricted glucose uptake and use, despite persisting mechanistic target of rapamycin (mTOR) signaling and upregulation of many anabolic pathways. PD-1 regulated early glycolytic and mitochondrial alterations and repressed transcriptional coactivator PGC-1α. Improving bioenergetics by overexpression of PGC-1α enhanced function in developing Tex cells. Therapeutic reinvigoration by anti-PD-L1 reprogrammed metabolism in a subset of Tex cells. These data highlight a key metabolic control event early in exhaustion and suggest that manipulating glycolytic and mitochondrial metabolism might enhance checkpoint blockade outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

Regulation of mitochondrial bioenergetics by the non-canonical roles of mitochondrial dynamics proteins in the heart.

PubMed

Wang, Wang; Fernandez-Sanz, Celia; Sheu, Shey-Shing

2018-05-01

Recent advancement in mitochondrial research has significantly extended our knowledge on the role and regulation of mitochondria in health and disease. One important breakthrough is the delineation of how mitochondrial morphological changes, termed mitochondrial dynamics, are coupled to the bioenergetics and signaling functions of mitochondria. In general, it is believed that fusion leads to an increased mitochondrial respiration efficiency and resistance to stress-induced dysfunction while fission does the contrary. This concept seems not applicable to adult cardiomyocytes. The mitochondria in adult cardiomyocytes exhibit fragmented morphology (tilted towards fission) and show less networking and movement as compared to other cell types. However, being the most energy-demanding cells, cardiomyocytes in the adult heart possess vast number of mitochondria, high level of energy flow, and abundant mitochondrial dynamics proteins. This apparent discrepancy could be explained by recently identified new functions of the mitochondrial dynamics proteins. These "non-canonical" roles of mitochondrial dynamics proteins range from controlling inter-organelle communication to regulating cell viability and survival under metabolic stresses. Here, we summarize the newly identified non-canonical roles of mitochondrial dynamics proteins. We focus on how these fission and fusion independent roles of dynamics proteins regulate mitochondrial bioenergetics. We also discuss potential molecular mechanisms, unique intracellular location, and the cardiovascular disease relevance of these non-canonical roles of the dynamics proteins. We propose that future studies are warranted to differentiate the canonical and non-canonical roles of dynamics proteins and to identify new approaches for the treatment of heart diseases. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers. Copyright © 2017 Elsevier B.V. All rights reserved.

Sequential Actions of SIRT1-RELB-SIRT3 Coordinate Nuclear-Mitochondrial Communication during Immunometabolic Adaptation to Acute Inflammation and Sepsis*

PubMed Central

Liu, Tie Fu; Vachharajani, Vidula; Millet, Patrick; Bharadwaj, Manish S.; Molina, Anthony J.; McCall, Charles E.

2015-01-01

We reported that NAD+-dependent SIRT1, RELB, and SIRT6 nuclear proteins in monocytes regulate a switch from the glycolysis-dependent acute inflammatory response to fatty acid oxidation-dependent sepsis adaptation. We also found that disrupting SIRT1 activity during adaptation restores immunometabolic homeostasis and rescues septic mice from death. Here, we show that nuclear SIRT1 guides RELB to differentially induce SIRT3 expression and also increases mitochondrial biogenesis, which alters bioenergetics during sepsis adaptation. We constructed this concept using TLR4-stimulated THP1 human promonocytes, a model that mimics the initiation and adaptation stages of sepsis. Following increased expression, mitochondrial SIRT3 deacetylase activates the rate-limiting tricarboxylic acid cycle (TCA) isocitrate dehydrogenase 2 and superoxide dismutase 2, concomitant with increases in citrate synthase activity. Mitochondrial oxygen consumption rate increases early and decreases during adaptation, parallel with modifications to membrane depolarization, ATP generation, and production of mitochondrial superoxide and whole cell hydrogen peroxide. Evidence of SIRT1-RELB induction of mitochondrial biogenesis included increases in mitochondrial mass, mitochondrial-to-nuclear DNA ratios, and both nuclear and mitochondrial encoded proteins. We confirmed the SIRT-RELB-SIRT3 adaptation link to mitochondrial bioenergetics in both TLR4-stimulated normal and sepsis-adapted human blood monocytes and mouse splenocytes. We also found that SIRT1 inhibition ex vivo reversed the sepsis-induced changes in bioenergetics. PMID:25404738

Arts, Science, Engineering and Medicine Collaborate to Educate Public on Bioenergetics.

PubMed

Tompkins, Emily; Faris, Sarah; Hughes, Laura; Maurakis, Eugene; Lesnefsky, Edward Joseph; Rao, Raj Raghavendra; Iyer, Shilpa

2017-01-01

Mitochondrial dysfunction has correlated with a rise in energy deficiency disorders (EDD). The EDDs include mitochondrial disorders, obesity, metabolic disorders, cardiovascular and neurodegenerative disorders. Many individuals in our communities are at high risk of developing these disorders, yet are unaware of it. Our goal was to increase public awareness of mitochondrial health, whilst providing students with an innovative educational experience. We designed a 'Bioenergetics exhibition' by introducing Arts into traditional STEM (Science, Technology, Engineering & Mathematics) disciplines to create a new STEAM-(Health) initiative. Results indicated ~120,000 guests visited the exhibition, including many school-aged children, teachers and families. Comparative analysis of random first-time vs. repeat visitor surveys demonstrated a statistically significant (8.25% at p-value = 0.006) increase in knowledge of mitochondrial disease and bioenergetics. Our findings clearly support the power of the STEAM-H initiative in creatively communicating the complex science to a broader community.

Mitochondrial dysfunction in alveolar and white matter developmental failure in premature infants

PubMed Central

Ten, Vadim S.

2017-01-01

At birth, some organs in premature infants are not developed enough to meet challenges of the extra-uterine life. Although growth and maturation continues after premature birth, postnatal organ development may become sluggish or even arrested, leading to organ dysfunction. There is no clear mechanistic concept of this postnatal organ developmental failure in premature neonates. This review introduces a concept-forming hypothesis: Mitochondrial bioenergetic dysfunction is a fundamental mechanism of organs maturation failure in premature infants. Data collected in support of this hypothesis are relevant to two major diseases of prematurity: white matter injury and broncho-pulmonary dysplasia. In these diseases, totally different clinical manifestations are defined by the same biological process, developmental failure of the main functional units—alveoli in the lungs and axonal myelination in the brain. Although molecular pathways regulating alveolar and white matter maturation differ, proper bioenergetic support of growth and maturation remains critical biological requirement for any actively developing organ. Literature analysis suggests that successful postnatal pulmonary and white matter development highly depends on mitochondrial function which can be inhibited by sublethal postnatal stress. In premature infants, sublethal stress results mostly in organ maturation failure without excessive cellular demise. PMID:27901512

Mitochondrial dysfunction in alveolar and white matter developmental failure in premature infants.

PubMed

Ten, Vadim S

2017-02-01

At birth, some organs in premature infants are not developed enough to meet challenges of the extra-uterine life. Although growth and maturation continues after premature birth, postnatal organ development may become sluggish or even arrested, leading to organ dysfunction. There is no clear mechanistic concept of this postnatal organ developmental failure in premature neonates. This review introduces a concept-forming hypothesis: Mitochondrial bioenergetic dysfunction is a fundamental mechanism of organs maturation failure in premature infants. Data collected in support of this hypothesis are relevant to two major diseases of prematurity: white matter injury and broncho-pulmonary dysplasia. In these diseases, totally different clinical manifestations are defined by the same biological process, developmental failure of the main functional units-alveoli in the lungs and axonal myelination in the brain. Although molecular pathways regulating alveolar and white matter maturation differ, proper bioenergetic support of growth and maturation remains critical biological requirement for any actively developing organ. Literature analysis suggests that successful postnatal pulmonary and white matter development highly depends on mitochondrial function which can be inhibited by sublethal postnatal stress. In premature infants, sublethal stress results mostly in organ maturation failure without excessive cellular demise.

Altered mitochondrial acetylation profiles in a kainic acid model of temporal lobe epilepsy.

PubMed

Gano, Lindsey B; Liang, Li-Ping; Ryan, Kristen; Michel, Cole R; Gomez, Joe; Vassilopoulos, Athanassios; Reisdorph, Nichole; Fritz, Kristofer S; Patel, Manisha

2018-08-01

Impaired bioenergetics and oxidative damage in the mitochondria are implicated in the etiology of temporal lobe epilepsy, and hyperacetylation of mitochondrial proteins has recently emerged as a critical negative regulator of mitochondrial functions. However, the roles of mitochondrial acetylation and activity of the primary mitochondrial deacetylase, SIRT3, have not been explored in acquired epilepsy. We investigated changes in mitochondrial acetylation and SIRT3 activity in the development of chronic epilepsy in the kainic acid rat model of TLE. Hippocampal measurements were made at 48 h, 1 week and 12 weeks corresponding to the acute, latent and chronic stages of epileptogenesis. Assessment of hippocampal bioenergetics demonstrated a ≥ 27% decrease in the ATP/ADP ratio at all phases of epileptogenesis (p < 0.05), whereas cellular NAD+ levels were decreased by ≥ 41% in the acute and latent time points (p < 0.05), but not in chronically epileptic rats. In spontaneously epileptic rats, we found decreased protein expression of SIRT3 and a 60% increase in global mitochondrial acetylation, as well as enhanced acetylation of the known SIRT3 substrates MnSOD, Ndufa9 of Complex I and IDH2 (all p < 0.05), suggesting SIRT3 dysfunction in chronic epilepsy. Mass spectrometry-based acetylomics investigation of hippocampal mitochondria demonstrated a 79% increase in unique acetylated proteins from rats in the chronic phase vs. controls. Pathway analysis identified numerous mitochondrial bioenergetic pathways affected by mitochondrial acetylation. These results suggest SIRT3 dysfunction and aberrant protein acetylation may contribute to mitochondrial dysfunction in chronic epilepsy. Copyright © 2018 Elsevier Inc. All rights reserved.

Regulation of Vascular Tone, Angiogenesis and Cellular Bioenergetics by the 3-Mercaptopyruvate Sulfurtransferase/H2S Pathway: Functional Impairment by Hyperglycemia and Restoration by DL-α-Lipoic Acid.

PubMed

Coletta, Ciro; Módis, Katalin; Szczesny, Bartosz; Brunyánszki, Attila; Oláh, Gábor; Rios, Ester C S; Yanagi, Kazunori; Ahmad, Akbar; Papapetropoulos, Andreas; Szabo, Csaba

2015-02-18

Hydrogen sulfide (H2S), as a reducing agent and an antioxidant molecule, exerts protective effects against hyperglycemic stress in the vascular endothelium. The mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is an important biological source of H2S. We have recently demonstrated that 3-MST activity is inhibited by oxidative stress in vitro and speculated that this may have an adverse effect on cellular homeostasis. In the current study, given the importance of H2S as a vasorelaxant, angiogenesis stimulator and cellular bioenergetic mediator, we first determined whether the 3-MST/H2S system plays a physiological regulatory role in endothelial cells. Next, we tested whether a dysfunction of this pathway develops during the development of hyperglycemia and μmol/L to diabetes-associated vascular complications. Intraperitoneal (IP) 3-MP (1 mg/kg) raised plasma H2S levels in rats. 3-MP (10 1 mmol/L) promoted angiogenesis in vitro in bEnd3 microvascular endothelial cells and in vivo in a Matrigel assay in mice (0.3-1 mg/kg). In vitro studies with bEnd3 cell homogenates demonstrated that the 3-MP-induced increases in H2S production depended on enzymatic activity, although at higher concentrations (1-3 mmol/L) there was also evidence for an additional nonenzymatic H2S production by 3-MP. In vivo, 3-MP facilitated wound healing in rats, induced the relaxation of dermal microvessels and increased mitochondrial bioenergetic function. In vitro hyperglycemia or in vivo streptozotocin diabetes impaired angiogenesis, attenuated mitochondrial function and delayed wound healing; all of these responses were associated with an impairment of the proangiogenic and bioenergetic effects of 3-MP. The antioxidants DL-α-lipoic acid (LA) in vivo, or dihydrolipoic acid (DHLA) in vitro restored the ability of 3-MP to stimulate angiogenesis, cellular bioenergetics and wound healing in hyperglycemia and diabetes. We conclude that diabetes leads to an impairment of the 3-MST/H2S pathway, and speculate that this may contribute to the pathogenesis of hyperglycemic endothelial cell dysfunction. We also suggest that therapy with H2S donors, or treatment with the combination of 3-MP and lipoic acid may be beneficial in improving angiogenesis and bioenergetics in hyperglycemia.

Regulation of Vascular Tone, Angiogenesis and Cellular Bioenergetics by the 3-Mercaptopyruvate Sulfurtransferase/H2S Pathway: Functional Impairment by Hyperglycemia and Restoration by dl-α-Lipoic Acid

PubMed Central

Coletta, Ciro; Módis, Katalin; Szczesny, Bartosz; Brunyánszki, Attila; Oláh, Gábor; Rios, Ester CS; Yanagi, Kazunori; Ahmad, Akbar; Papapetropoulos, Andreas; Szabo, Csaba

2015-01-01

Hydrogen sulfide (H2S), as a reducing agent and an antioxidant molecule, exerts protective effects against hyperglycemic stress in the vascular endothelium. The mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is an important biological source of H2S. We have recently demonstrated that 3-MST activity is inhibited by oxidative stress in vitro and speculated that this may have an adverse effect on cellular homeostasis. In the current study, given the importance of H2S as a vasorelaxant, angiogenesis stimulator and cellular bioenergetic mediator, we first determined whether the 3-MST/H2S system plays a physiological regulatory role in endothelial cells. Next, we tested whether a dysfunction of this pathway develops during the development of hyperglycemia and μmol/L to diabetes-associated vascular complications. Intraperitoneal (IP) 3-MP (1 mg/kg) raised plasma H2S levels in rats. 3-MP (10 1 mmol/L) promoted angiogenesis in vitro in bEnd3 microvascular endothelial cells and in vivo in a Matrigel assay in mice (0.3–1 mg/kg). In vitro studies with bEnd3 cell homogenates demonstrated that the 3-MP-induced increases in H2S production depended on enzymatic activity, although at higher concentrations (1–3 mmol/L) there was also evidence for an additional nonenzymatic H2S production by 3-MP. In vivo, 3-MP facilitated wound healing in rats, induced the relaxation of dermal microvessels and increased mitochondrial bioenergetic function. In vitro hyperglycemia or in vivo streptozotocin diabetes impaired angiogenesis, attenuated mitochondrial function and delayed wound healing; all of these responses were associated with an impairment of the proangiogenic and bioenergetic effects of 3-MP. The antioxidants dl-α-lipoic acid (LA) in vivo, or dihydrolipoic acid (DHLA) in vitro restored the ability of 3-MP to stimulate angiogenesis, cellular bioenergetics and wound healing in hyperglycemia and diabetes. We conclude that diabetes leads to an impairment of the 3-MST/H2S pathway, and speculate that this may contribute to the pathogenesis of hyperglycemic endothelial cell dysfunction. We also suggest that therapy with H2S donors, or treatment with the combination of 3-MP and lipoic acid may be beneficial in improving angiogenesis and bioenergetics in hyperglycemia. PMID:25715337

Skeletal muscle mitochondrial energetics in obesity and type 2 diabetes mellitus: endocrine aspects.

PubMed

Aguer, Céline; Harper, Mary-Ellen

2012-12-01

During the development of type 2 diabetes mellitus, skeletal muscle is a major site of insulin resistance. The latter has been linked to mitochondrial dysfunction and impaired fatty acid oxidation. Some hormones like insulin, thyroid hormones and adipokines (e.g., leptin, adiponectin) have positive effects on muscle mitochondrial bioenergetics through their direct or indirect effects on mitochondrial biogenesis, mitochondrial protein expression, mitochondrial enzyme activities and/or AMPK pathway activation--all of which can improve fatty acid oxidation. It is therefore not surprising that treatment with these hormones has been proposed to improve muscle and whole body insulin sensitivity. However, treatment of diabetic patients with leptin and adiponectin has no effect on muscle mitochondrial bioenergetics showing resistance to these hormones during type 2 diabetes. Furthermore, treatment with most thyroid hormones has unexpectedly revealed negative effects on muscle insulin sensitivity. Future research should focus on development of agents that improve metabolic dysfunction downstream of hormone receptors. Copyright © 2012 Elsevier Ltd. All rights reserved.

Estrogen: a master regulator of bioenergetic systems in the brain and body.

PubMed

Rettberg, Jamaica R; Yao, Jia; Brinton, Roberta Diaz

2014-01-01

Estrogen is a fundamental regulator of the metabolic system of the female brain and body. Within the brain, estrogen regulates glucose transport, aerobic glycolysis, and mitochondrial function to generate ATP. In the body, estrogen protects against adiposity, insulin resistance, and type II diabetes, and regulates energy intake and expenditure. During menopause, decline in circulating estrogen is coincident with decline in brain bioenergetics and shift towards a metabolically compromised phenotype. Compensatory bioenergetic adaptations, or lack thereof, to estrogen loss could determine risk of late-onset Alzheimer's disease. Estrogen coordinates brain and body metabolism, such that peripheral metabolic state can indicate bioenergetic status of the brain. By generating biomarker profiles that encompass peripheral metabolic changes occurring with menopause, individual risk profiles for decreased brain bioenergetics and cognitive decline can be created. Biomarker profiles could identify women at risk while also serving as indicators of efficacy of hormone therapy or other preventative interventions. Copyright © 2013 Elsevier Inc. All rights reserved.

Endothelial Cell Bioenergetics and Mitochondrial DNA Damage Differ in Humans Having African or West Eurasian Maternal Ancestry

PubMed Central

Krzywanski, David M.; Moellering, Douglas R.; Westbrook, David G.; Dunham-Snary, Kimberly J.; Brown, Jamelle; Bray, Alexander W.; Feeley, Kyle P.; Sammy, Melissa J.; Smith, Matthew R.; Schurr, Theodore G.; Vita, Joseph A.; Ambalavanan, Namasivayam; Calhoun, David; Dell’Italia, Louis; Ballinger, Scott W.

2016-01-01

Background We hypothesized that endothelial cells having distinct mitochondrial genetic backgrounds would show variation in mitochondrial function and oxidative stress markers concordant with known differential cardiovascular disease susceptibilities. To test this hypothesis, mitochondrial bioenergetics were determined in endothelial cells from healthy individuals with African versus European maternal ancestries. Methods and Results Bioenergetics and mitochondrial DNA (mtDNA) damage were assessed in single donor human umbilical vein endothelial cells (HUVECs) belonging to mtDNA haplogroups H and L, representing West Eurasian and African maternal ancestry, respectively. HUVECs from haplogroup L utilized less oxygen for ATP production and had increased levels of mtDNA damage compared to those in haplogroup H. Differences in bioenergetic capacity were also observed in that HUVECs belonging to haplogroup L had decreased maximal bioenergetic capacities compared to haplogroup H. Analysis of peripheral blood mononuclear cells from age-matched healthy controls with West Eurasian or African maternal ancestries showed that haplogroups sharing an A to G mtDNA mutation at nucleotide pair (np) 10,398 had increased mtDNA damage compared to those lacking this mutation. Further study of angiographically proven coronary artery disease patients and age-matched healthy controls revealed that mtDNA damage was associated with vascular function and remodeling, and that age of disease onset was later in individuals from haplogroups lacking the A to G mutation at np 10,398. Conclusions Differences in mitochondrial bioenergetics and mtDNA damage associated with maternal ancestry may contribute to endothelial dysfunction and vascular disease. PMID:26787433

Brain metabolism in health, aging, and neurodegeneration.

PubMed

Camandola, Simonetta; Mattson, Mark P

2017-06-01

Brain cells normally respond adaptively to bioenergetic challenges resulting from ongoing activity in neuronal circuits, and from environmental energetic stressors such as food deprivation and physical exertion. At the cellular level, such adaptive responses include the "strengthening" of existing synapses, the formation of new synapses, and the production of new neurons from stem cells. At the molecular level, bioenergetic challenges result in the activation of transcription factors that induce the expression of proteins that bolster the resistance of neurons to the kinds of metabolic, oxidative, excitotoxic, and proteotoxic stresses involved in the pathogenesis of brain disorders including stroke, and Alzheimer's and Parkinson's diseases. Emerging findings suggest that lifestyles that include intermittent bioenergetic challenges, most notably exercise and dietary energy restriction, can increase the likelihood that the brain will function optimally and in the absence of disease throughout life. Here, we provide an overview of cellular and molecular mechanisms that regulate brain energy metabolism, how such mechanisms are altered during aging and in neurodegenerative disorders, and the potential applications to brain health and disease of interventions that engage pathways involved in neuronal adaptations to metabolic stress. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Mitochondria: 3-bromopyruvate vs. mitochondria? A small molecule that attacks tumors by targeting their bioenergetic diversity.

PubMed

Galina, Antonio

2014-09-01

Enhanced glycolysis, the classic bioenergetic phenotype of cancer cells was described by Otto Warburg approximately 90 years ago. However, the Warburg hypothesis does not necessarily imply mitochondrial dysfunction. The alkyl-halogen, 3-bromopyruvate (3BP), would not be expected to have selective targets for cancer therapy due to its high potential reactivity toward many SH side groups. Contrary to predictions, 3BP interferes with glycolysis and oxidative phosphorylation in cancer cells without side effects in normal tissues. The mitochondrial hexokinase II has been claimed as the main target. This "Organelle in focus" article presents a historical view of the use of 3BP in biochemistry and its effects on ATP-producing pathways of cancer cells. I will discuss how the alkylated enzymes contribute to the cooperative collapse of mitochondria and apoptosis. Perspectives for targeting 3BP to bioenergetics enzymes for cancer treatment will be considered. Copyright © 2014 Elsevier Ltd. All rights reserved.

Rubella viruses shift cellular bioenergetics to a more oxidative and glycolytic phenotype with a strain-specific requirement for glutamine.

PubMed

Bilz, Nicole C; Jahn, Kristin; Lorenz, Mechthild; Lüdtke, Anja; Hübschen, Judith M; Geyer, Henriette; Mankertz, Annette; Hübner, Denise; Liebert, Uwe G; Claus, Claudia

2018-06-27

The flexible regulation of cellular metabolic pathways enables cellular adaptation to changes in energy demand under conditions of stress such as posed by a virus infection. To analyze such an impact on cellular metabolism, rubella virus (RV) was used in this study. RV replication under selected substrate supplementation with glucose, pyruvate, and glutamine as essential nutrients for mammalian cells revealed its requirement for glutamine. The assessment of the mitochondrial respiratory (based on oxygen consumption rate, OCR) and glycolytic (based on extracellular acidification rate, ECAR) rate and capacity by respective stress tests through Seahorse technology enabled determination of the bioenergetic phenotype of RV-infected cells. Irrespective of the cellular metabolic background, RV infection induced a shift of the bioenergetic state of epithelial (Vero and A549) and endothelial (HUVEC) cells to a higher oxidative and glycolytic level. Interestingly there was a RV strain-specific, but genotype-independent demand for glutamine to induce a significant increase in metabolic activity. While glutaminolysis appeared to be rather negligible for RV replication, glutamine could serve as donor of its amide nitrogen in biosynthesis pathways for important metabolites. This study suggests that the capacity of rubella viruses to induce metabolic alterations could evolve differently during natural infection. Thus, changes in cellular bioenergetics represent an important component of virus-host interactions and could complement our understanding of the viral preference for a distinct host cell population. Importance RV pathologies, especially during embryonal development, could be connected with its impact on mitochondrial metabolism. With bioenergetic phenotyping we pursued a rather novel approach in virology. For the first time it was shown that a virus infection could shift the bioenergetics of its infected host cell to a higher energetic state. Notably, the capacity to induce such alterations varied among different RV isolates. Thus, our data adds viral adaptation of cellular metabolic activity to its specific needs as a novel aspect to virus-host evolution. Additionally, this study emphasizes the implementation of different viral strains in the study of virus-host interactions and the use of bioenergetic phenotyping of infected cells as a biomarker for virus-induced pathological alterations. Copyright © 2018 American Society for Microbiology.

Long-term skeletal muscle mitochondrial dysfunction is associated with hypermetabolism in severely burned children

USDA-ARS?s Scientific Manuscript database

The long-term impact of burn trauma on skeletal muscle bioenergetics remains unknown. Here, we determined respiratory capacity and function of skeletal muscle mitochondria in healthy individuals and in burn victims for up to two years post-injury. Biopsies were collected from the m. vastus lateralis...

Mitochondrial Stress Tests Using Seahorse Respirometry on Intact Dictyostelium discoideum Cells.

PubMed

Lay, Sui; Sanislav, Oana; Annesley, Sarah J; Fisher, Paul R

2016-01-01

Mitochondria not only play a critical and central role in providing metabolic energy to the cell but are also integral to the other cellular processes such as modulation of various signaling pathways. These pathways affect many aspects of cell physiology, including cell movement, growth, division, differentiation, and death. Mitochondrial dysfunction which affects mitochondrial bioenergetics and causes oxidative phosphorylation defects can thus lead to altered cellular physiology and manifest in disease. The assessment of the mitochondrial bioenergetics can thus provide valuable insights into the physiological state, and the alterations to the state of the cells. Here, we describe a method to successfully use the Seahorse XF(e)24 Extracellular Flux Analyzer to assess the mitochondrial respirometry of the cellular slime mold Dictyostelium discoideum.

Mitophagy in Parkinson's Disease: Pathogenic and Therapeutic Implications.

PubMed

Gao, Fei; Yang, Jia; Wang, Dongdong; Li, Chao; Fu, Yi; Wang, Huaishan; He, Wei; Zhang, Jianmin

2017-01-01

Neurons affected in Parkinson's disease (PD) experience mitochondrial dysfunction and bioenergetic deficits that occur early and promote the disease-related α-synucleinopathy. Emerging findings suggest that the autophagy-lysosome pathway, which removes damaged mitochondria (mitophagy), is also compromised in PD and results in the accumulation of dysfunctional mitochondria. Studies using genetic-modulated or toxin-induced animal and cellular models as well as postmortem human tissue indicate that impaired mitophagy might be a critical factor in the pathogenesis of synaptic dysfunction and the aggregation of misfolded proteins, which in turn impairs mitochondrial homeostasis. Interventions that stimulate mitophagy to maintain mitochondrial health might, therefore, be used as an approach to delay the neurodegenerative processes in PD.

The role of the ATPase inhibitor factor 1 (IF1) in cancer cells adaptation to hypoxia and anoxia.

PubMed

Sgarbi, G; Barbato, S; Costanzini, A; Solaini, G; Baracca, A

2018-02-01

The physiological role of the mitochondrial ATP synthase complex is to generate ATP through oxidative phosphorylation. Indeed, the enzyme can reverse its activity and hydrolyze ATP under ischemic conditions, as shown in isolated mitochondria and in mammalian heart and liver. However, what occurs when cancer cells experience hypoxia or anoxia has not been well explored. In the present study, we investigated the bioenergetics of cancer cells under hypoxic/anoxic conditions with particular emphasis on ATP synthase, and the conditions driving it to work in reverse. In this context, we further examined the role exerted by its endogenous inhibitor factor, IF 1 , that it is overexpressed in cancer cells. Metabolic and bioenergetic analysis of cancer cells exposed to severe hypoxia (down to 0.1% O 2 ) unexpectedly showed that Δψ m is preserved independently of the presence of IF 1 and that ATP synthase still phosphorylates ADP though at a much lower rate than in normoxia. However, when we induced an anoxia-mimicking condition by collapsing Δμ Η + with the FCCP uncoupler, the IF 1 -silenced clones only reversed the ATP synthase activity hydrolyzing ATP in order to reconstitute the electrochemical proton gradient. Notably, in cancer cells IF 1 overexpression fully prevents ATP synthase hydrolytic activity activation under uncoupling conditions. Therefore, our results suggest that IF 1 overexpression promotes cancer cells survival under temporary anoxic conditions by preserving cellular ATP despite mitochondria dysfunction. Copyright © 2017 Elsevier B.V. All rights reserved.

Early Detection of Myocardial Bioenergetic Deficits: A 9.4 Tesla Complete Non Invasive 31P MR Spectroscopy Study in Mice with Muscular Dystrophy.

PubMed

Cui, Weina; Jang, Albert; Zhang, Pengyuan; Thompson, Brian; Townsend, DeWayne; Metzger, Joseph M; Zhang, Jianyi

2015-01-01

Duchenne muscular dystrophy (DMD) is the most common fatal form of muscular dystrophy characterized by striated muscle wasting and dysfunction. Patients with DMD have a very high incidence of heart failure, which is increasingly the cause of death in DMD patients. We hypothesize that in the in vivo system, the dystrophic cardiac muscle displays bioenergetic deficits prior to any functional or structural deficits. To address this we developed a complete non invasive 31P magnetic resonance spectroscopy (31P MRS) approach to measure myocardial bioenergetics in the heart in vivo. Six control and nine mdx mice at 5 months of age were used for the study. A standard 3D -Image Selected In vivo Spectroscopy (3D-ISIS) sequence was used to provide complete gradient controlled three-dimensional localization for heart 31P MRS. These studies demonstrated dystrophic hearts have a significant reduction in PCr/ATP ratio compare to normal (1.59±0.13 vs 2.37±0.25, p<0.05). Our present study provides the direct evidence of significant cardiac bioenergetic deficits in the in vivo dystrophic mouse. These data suggest that energetic defects precede the development of significant hemodynamic or structural changes. The methods provide a clinically relevant approach to use myocardial energetics as an early marker of disease in the dystrophic heart. The new method in detecting the in vivo bioenergetics abnormality as an early non-invasive marker of emerging dystrophic cardiomyopathy is critical in management of patients with DMD, and optimized therapies aimed at slowing or reversing the cardiomyopathy.

Oxidative stress alters mitochondrial bioenergetics and modifies pancreatic cell death independently of cyclophilin D, resulting in an apoptosis-to-necrosis shift

PubMed Central

Armstrong, Jane A.; Cash, Nicole J.; Ouyang, Yulin; Morton, Jack C.; Chvanov, Michael; Latawiec, Diane; Awais, Muhammad; Tepikin, Alexei V.; Sutton, Robert; Criddle, David N.

2018-01-01

Mitochondrial dysfunction lies at the core of acute pancreatitis (AP). Diverse AP stimuli induce Ca2+-dependent formation of the mitochondrial permeability transition pore (MPTP), a solute channel modulated by cyclophilin D (CypD), the formation of which causes ATP depletion and necrosis. Oxidative stress reportedly triggers MPTP formation and is elevated in clinical AP, but how reactive oxygen species influence cell death is unclear. Here, we assessed potential MPTP involvement in oxidant-induced effects on pancreatic acinar cell bioenergetics and fate. H2O2 application promoted acinar cell apoptosis at low concentrations (1–10 μm), whereas higher levels (0.5–1 mm) elicited rapid necrosis. H2O2 also decreased the mitochondrial NADH/FAD+ redox ratio and ΔΨm in a concentration-dependent manner (10 μm to 1 mm H2O2), with maximal effects at 500 μm H2O2. H2O2 decreased the basal O2 consumption rate of acinar cells, with no alteration of ATP turnover at <50 μm H2O2. However, higher H2O2 levels (≥50 μm) diminished spare respiratory capacity and ATP turnover, and bioenergetic collapse, ATP depletion, and cell death ensued. Menadione exerted detrimental bioenergetic effects similar to those of H2O2, which were inhibited by the antioxidant N-acetylcysteine. Oxidant-induced bioenergetic changes, loss of ΔΨm, and cell death were not ameliorated by genetic deletion of CypD or by its acute inhibition with cyclosporine A. These results indicate that oxidative stress alters mitochondrial bioenergetics and modifies pancreatic acinar cell death. A shift from apoptosis to necrosis appears to be associated with decreased mitochondrial spare respiratory capacity and ATP production, effects that are independent of CypD-sensitive MPTP formation. PMID:29626097

Alterations in bioenergetic function induced by Parkinson's disease mimetic compounds: Lack of correlation with superoxide generation

PubMed Central

Dranka, Brian P.; Zielonka, Jacek; Kanthasamy, Anumantha G.; Kalyanaraman, Balaraman

2012-01-01

In vitro and in vivo models of Parkinson's disease (PD) suggest that increased oxidant production leads to mitochondrial dysfunction in dopaminergic neurons and subsequent cell death. However, it remains unclear if cell death in these models is caused by inhibition of mitochondrial function or oxidant production. The objective of the present study was to determine the relationship between mitochondrial dysfunction and oxidant production in response to multiple PD neurotoxicant mimetics. MPP+ caused a dose-dependent decrease in the basal oxygen consumption rate (OCR) in dopaminergic N27 cells, indicating a loss of mitochondrial function. In parallel, we found that MPP+ only modestly increased oxidation of hydroethidine as a diagnostic marker of superoxide production in these cells. Similar results were found using rotenone as a mitochondrial inhibitor, or 6-hydroxydopamine as a mechanistically distinct PD neurotoxicant, but not with exposure to paraquat. Additionally, the Extracellular Acidification Rate, used as a marker of glycolysis, was stimulated to compensate for OCR inhibition after exposure to MPP+, rotenone, or 6-hydroxydopamine, but not paraquat. Together these data indicate that MPP+, rotenone and 6-hydroxydopamine dramatically shift bioenergetic function away from the mitochondria and towards glycolysis in N27 cells. PMID:22708893

Increased platelet mitochondrial respiration after cardiac arrest and resuscitation as a potential peripheral biosignature of cerebral bioenergetic dysfunction.

PubMed

Ferguson, Michael A; Sutton, Robert M; Karlsson, Michael; Sjövall, Fredrik; Becker, Lance B; Berg, Robert A; Margulies, Susan S; Kilbaugh, Todd J

2016-06-01

Cardiac arrest (CA) results in a sepsis-like syndrome with activation of the innate immune system and increased mitochondrial bioenergetics. To determine if platelet mitochondrial respiration increases following CA in a porcine pediatric model of asphyxia-associated ventricular fibrillation (VF) CA, and if this readily obtained biomarker is associated with decreased brain mitochondrial respiration. CA protocol: 7 min of asphyxia, followed by VF, protocolized titration of compression depth to systolic blood pressure of 90 mmHg and vasopressor administration to a coronary perfusion pressure greater than 20 mmHg. platelet integrated mitochondrial electron transport system (ETS) function evaluated pre- and post-CA/ROSC four hours after return of spontaneous circulation (ROSC). Secondary outcome: correlation of platelet mitochondrial bioenergetics to cerebral bioenergetic function. Platelet maximal oxidative phosphorylation (OXPHOSCI+CII), P < 0.02, and maximal respiratory capacity (ETSCI+CII), P < 0.04, were both significantly increased compared to pre-arrest values. This was primarily due to a significant increase in succinate-supported respiration through Complex II (OXPHOSCII, P < 0.02 and ETSCII, P < 0.03). Higher respiration was not due to uncoupling, as the LEAKCI + CII respiration (mitochondrial respiration independent of ATP-production) was unchanged after CA/ROSC. Larger increases in platelet mitochondrial respiratory control ratio (RCR) compared to pre-CA RCR were significantly correlated with lower RCRs in the cortex (P < 0.03) and hippocampus (P < 0.04) compared to sham respiration. Platelet mitochondrial respiration is significantly increased four hours after ROSC. Future studies will identify mechanistic relationships between this serum biomarker and altered cerebral bioenergetics function following cardiac arrest.

Paclitaxel-induced painful neuropathy is associated with changes in mitochondrial bioenergetics, glycolysis, and an energy deficit in dorsal root ganglia neurons

PubMed Central

Duggett, Natalie A.; Griffiths, Lisa A.; Flatters, Sarah J.L.

2017-01-01

Abstract Painful neuropathy is the major dose-limiting side effect of paclitaxel chemotherapy. Mitochondrial dysfunction and adenosine triphosphate (ATP) deficit have previously been shown in peripheral nerves of paclitaxel-treated rats, but the effects of paclitaxel in the dorsal root ganglia (DRGs) have not been explored. The aim of this study was to determine the bioenergetic status of DRG neurons following paclitaxel exposure in vitro and in vivo. Utilising isolated DRG neurons, we measured respiratory function under basal conditions and at maximal capacity, glycolytic function, and Adenosine diphosphate (ADP)/ATP levels at 3 key behavioural timepoints; prior to pain onset (day 7), peak pain severity and pain resolution. At day 7, maximal respiration and spare reserve capacity were significantly decreased in DRG neurons from paclitaxel-treated rats. This was accompanied by decreased basal ATP levels and unaltered ADP levels. At peak pain severity, respiratory function was unaltered, yet glycolytic function was significantly increased. Reduced ATP and unaltered ADP levels were also observed at the peak pain timepoint. All these effects in DRG neurons had dissipated by the pain resolution timepoint. None of these paclitaxel-evoked changes could be replicated from in vitro paclitaxel exposure to naive DRG neurons, demonstrating the impact of in vivo exposure and the importance of in vivo models. These data demonstrate the nature of mitochondrial dysfunction evoked by in vivo paclitaxel in the DRG for the first time. Furthermore, we have identified paclitaxel-evoked changes in the bioenergetics of DRG neurons, which result in a persistent energy deficit that is causal to the development and maintenance of paclitaxel-induced pain. PMID:28541258

Mitochondrial dysfunction: the missing link between aging and sporadic Alzheimer's disease.

PubMed

Grimm, Amandine; Friedland, Kristina; Eckert, Anne

2016-04-01

Alzheimer's disease (AD) is a progressive neurodegenerative disease that represents the most common form of dementia among the elderly. Despite the fact that AD was studied for decades, the underlying mechanisms that trigger this neuropathology remain unresolved. Since the onset of cognitive deficits occurs generally within the 6th decade of life, except in rare familial case, advancing age is the greatest known risk factor for AD. To unravel the pathogenesis of the disease, numerous studies use cellular and animal models based on genetic mutations found in rare early onset familial AD (FAD) cases that represent less than 1 % of AD patients. However, the underlying process that leads to FAD appears to be distinct from that which results in late-onset AD. As a genetic disorder, FAD clearly is a consequence of malfunctioning/mutated genes, while late-onset AD is more likely due to a gradual accumulation of age-related malfunction. Normal aging and AD are both marked by defects in brain metabolism and increased oxidative stress, albeit to varying degrees. Mitochondria are involved in these two phenomena by controlling cellular bioenergetics and redox homeostasis. In the present review, we compare the common features observed in both brain aging and AD, placing mitochondrial in the center of pathological events that separate normal and pathological aging. We emphasize a bioenergetic model for AD including the inverse Warburg hypothesis which postulates that AD is a consequence of mitochondrial deregulation leading to metabolic reprogramming as an initial attempt to maintain neuronal integrity. After the failure of this compensatory mechanism, bioenergetic deficits may lead to neuronal death and dementia. Thus, mitochondrial dysfunction may represent the missing link between aging and sporadic AD, and represent attractive targets against neurodegeneration.

Phosphorous magnetic resonance spectroscopy-based skeletal muscle bioenergetic studies in subclinical hypothyroidism.

PubMed

Rana, P; Sripathy, G; Varshney, A; Kumar, P; Devi, M Memita; Marwaha, R K; Tripathi, R P; Khushu, S

2012-02-01

Subclinical hypothyroidism (sHT) is considered to be a milder form of thyroid dysfunction. Few earlier studies have reported neuromuscular symptoms as well as impaired muscle metabolism in sHT patients. In this study we report our findings on muscle bioenergetics in sHT patients using phosphorous magnetic resonance spectroscopy (31P MRS) and look upon the possibility to use 31P MRS technique as a clinical marker for monitoring muscle function in subclinical thyroid dysfunction. Seventeen normal subjects, 15 patients with sHT, and 9 patients with hypothyroidism performed plantar flexion exercise while lying supine in 1.5 T magnetic resonance scanner using custom built exercise device. MR Spectroscopy measurements of inorganic phosphate (Pi), phosphocreatine (PCr), and ATP of the calf muscle were taken during rest, at the end of exercise and in the recovery phase. PCr recovery rate constant (kPCr) and oxidative capacity were calculated by monoexponential fit of PCr vs time (t) at the beginning of recovery. We observed that changes in some of the phosphometabolites (increased phosphodiester levels and Pi concentration) in sHT patients which were similar to those detected in patients with hypothyroidism. However, our results do not demonstrate impaired muscle oxidative metabolism in sHT patients based upon PCr dynamics as observed in hypothyroid patients. 31P MRS-based PCr recovery rate could be used as a marker for monitoring muscle oxidative metabolism in sub clinical thyroid dysfunction.

Mitochondrial remodeling in the liver following chronic alcohol feeding to rats.

PubMed

Han, Derick; Johnson, Heather S; Rao, Madhuri P; Martin, Gary; Sancheti, Harsh; Silkwood, Kai H; Decker, Carl W; Nguyen, Kim Tho; Casian, Joseph G; Cadenas, Enrique; Kaplowitz, Neil

2017-01-01

The feeding of alcohol orally (Lieber-DeCarli diet) to rats has been shown to cause declines in mitochondrial respiration (state III), decreased expression of respiratory complexes, and decreased respiratory control ratios (RCR) in liver mitochondria. These declines and other mitochondrial alterations have led to the hypothesis that alcohol feeding causes "mitochondrial dysfunction" in the liver. If oral alcohol feeding leads to mitochondrial dysfunction, one would predict that increasing alcohol delivery by intragastric (IG) alcohol feeding to rats would cause greater declines in mitochondrial bioenergetics in the liver. In this study, we examined the mitochondrial alterations that occur in rats fed alcohol both orally and intragastrically. Oral alcohol feeding decreased glutamate/malate-, acetaldehyde- and succinate-driven state III respiration, RCR, and expression of respiratory complexes (I, III, IV, V) in liver mitochondria, in agreement with previous results. IG alcohol feeding, on the other hand, caused a slight increase in glutamate/malate-driven respiration, and significantly increased acetaldehyde-driven respiration in liver mitochondria. IG feeding also caused liver mitochondria to experience a decline in succinate-driven respiration, but these decreases were smaller than those observed with oral alcohol feeding. Surprisingly, oral and IG alcohol feeding to rats increased mitochondrial respiration using other substrates, including glycerol-3-phosphate (which delivers electrons from cytoplasmic NADH to mitochondria) and octanoate (a substrate for beta-oxidation). The enhancement of glycerol-3-phosphate- and octanoate-driven respiration suggests that liver mitochondria remodeled in response to alcohol feeding. In support of this notion, we observed that IG alcohol feeding also increased expression of mitochondrial glycerol phosphate dehydrogenase-2 (GPD2), transcription factor A (TFAM), and increased mitochondrial NAD + -NADH and NADP + -NADPH levels in the liver. Our findings suggest that mitochondrial dysfunction represents an incomplete picture of mitochondrial dynamics that occur in the liver following alcohol feeding. While alcohol feeding causes some mitochondrial dysfunction (i.e. succinate-driven respiration), our work suggests that the major consequence of alcohol feeding is mitochondrial remodeling in the liver as an adaptation. This mitochondrial remodeling may play an important role in the enhanced alcohol metabolism and other adaptations in the liver that develop with alcohol intake. Copyright © 2016 Elsevier Inc. All rights reserved.

Mitochondrial control of cell bioenergetics in Parkinson’s disease

PubMed Central

Requejo-Aguilar, Raquel; Bolaños, Juan P.

2016-01-01

Parkinson disease (PD) is a neurodegenerative disorder characterized by a selective loss of dopaminergic neurons in the substantia nigra. The earliest biochemical signs of the disease involve failure in mitochondrial-endoplasmic reticulum cross talk and lysosomal function, mitochondrial electron chain impairment, mitochondrial dynamics alterations, and calcium and iron homeostasis abnormalities. These changes are associated with increased mitochondrial reactive oxygen species (mROS) and energy deficiency. Recently, it has been reported that, as an attempt to compensate for the mitochondrial dysfunction, neurons invoke glycolysis as a low-efficient mode of energy production in models of PD. Here, we review how mitochondria orchestrate the maintenance of cellular energetic status in PD, with special focus on the switch from oxidative phosphorylation to glycolysis, as well as the implication of endoplasmic reticulum and lysosomes in the control of bioenergetics. PMID:27091692

Mitochondrial Transfer from Wharton's Jelly Mesenchymal Stem Cell to MERRF Cybrid Reduces Oxidative Stress and Improves Mitochondrial Bioenergetics

PubMed Central

Liou, Chia-Wei; Chen, Shang-Der; Wang, Pei-Wen; Chuang, Jiin-Haur; Tiao, Mao-Meng; Hsu, Te-Yao

2017-01-01

Myoclonus epilepsy associated with ragged-red fibers (MERRF) is a maternally inherited mitochondrial disease affecting neuromuscular functions. Mt.8344A>G mutation in mitochondrial DNA (mtDNA) is the most common cause of MERRF syndrome and has been linked to an increase in reactive oxygen species (ROS) level and oxidative stress, as well as impaired mitochondrial bioenergetics. Here, we tested whether WJMSC has therapeutic potential for the treatment of MERRF syndrome through the transfer of mitochondria. The MERRF cybrid cells exhibited a high mt.8344A>G mutation ratio, enhanced ROS level and oxidative damage, impaired mitochondrial bioenergetics, defected mitochondria-dependent viability, exhibited an imbalance of mitochondrial dynamics, and are susceptible to apoptotic stress. Coculture experiments revealed that mitochondria were intercellularly conducted from the WJMSC to the MERRF cybrid. Furthermore, WJMSC transferred mitochondria exclusively to cells with defective mitochondria but not to cells with normal mitochondria. MERRF cybrid following WJMSC coculture (MF+WJ) demonstrated improvement of mt.8344A>G mutation ratio, ROS level, oxidative damage, mitochondrial bioenergetics, mitochondria-dependent viability, balance of mitochondrial dynamics, and resistance against apoptotic stress. WJMSC-derived mitochondrial transfer and its therapeutic effect were noted to be blocked by F-actin depolymerizing agent cytochalasin B. Collectively, the WJMSC ability to rescue cells with defective mitochondrial function through donating healthy mitochondria may lead to new insights into the development of more efficient strategies to treat diseases related to mitochondrial dysfunction. PMID:28607632

Telomeres and Mitochondria in the Aging Heart

PubMed Central

Moslehi, Javid; DePinho, Ronald A.; Sahin, Ergün

2013-01-01

Studies in humans and in mice have highlighted the importance of short telomeres and impaired mitochondrial function in driving age-related functional decline in the heart. Although telomere and mitochondrial dysfunction have been viewed mainly in isolation, recent studies in telomerase-deficient mice have provided evidence for an intimate link between these two processes. Telomere dysfunction induces a profound p53-dependent repression of the master regulators of mitochondrial biogenesis and function, peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and PGC-1β in the heart, which leads to bioenergetic compromise due to impaired oxidative phosphorylation and ATP generation. This telomere-p53-PGC mitochondrial/metabolic axis integrates many factors linked to heart aging including increased DNA damage, p53 activation, mitochondrial, and metabolic dysfunction and provides a molecular basis of how dysfunctional telomeres can compromise cardiomyocytes and stem cell compartments in the heart to precipitate cardiac aging. PMID:22539756

Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: implication for bioenergetic intervention.

PubMed

Ding, Fan; Yao, Jia; Rettberg, Jamaica R; Chen, Shuhua; Brinton, Roberta Diaz

2013-01-01

We previously demonstrated that mitochondrial bioenergetic deficits in the female brain accompanied reproductive senescence and was accompanied by a shift from an aerobic glycolytic to a ketogenic phenotype. Herein, we investigated the relationship between systems of fuel supply, transport and mitochondrial metabolic enzyme expression/activity during aging (3-15 months) in the hippocampus of nontransgenic (nonTg) background and 3xTgAD female mice. Results indicate that during female brain aging, both nonTg and 3xTgAD brains undergo significant decline in glucose transport, as detected by FDG-microPET, between 6-9 months of age just prior to the transition into reproductive senescence. The deficit in brain metabolism was sustained thereafter. Decline in glucose transport coincided with significant decline in neuronal glucose transporter expression and hexokinase activity with a concomitant rise in phosphorylated/inactivated pyruvate dehydrogenase. Lactate utilization declined in parallel to the decline in glucose transport suggesting lactate did not serve as an alternative fuel. An adaptive response in the nonTg hippocampus was a shift to transport and utilization of ketone bodies as an alternative fuel. In the 3xTgAD brain, utilization of ketone bodies as an alternative fuel was evident at the earliest age investigated and declined thereafter. The 3xTgAD adaptive response was to substantially increase monocarboxylate transporters in neurons while decreasing their expression at the BBB and in astrocytes. Collectively, these data indicate that the earliest change in the metabolic system of the aging female brain is the decline in neuronal glucose transport and metabolism followed by decline in mitochondrial function. The adaptive shift to the ketogenic system as an alternative fuel coincided with decline in mitochondrial function. Translationally, these data provide insights into the earliest events in bioenergetic aging of the female brain and provide potential targets for preventing shifts to less efficient bioenergetic fuels and transition to the ketogenic phenotype of the Alzheimer's brain.

Colloquium paper: bioenergetics, the origins of complexity, and the ascent of man.

PubMed

Wallace, Douglas C

2010-05-11

Complex structures are generated and maintained through energy flux. Structures embody information, and biological information is stored in nucleic acids. The progressive increase in biological complexity over geologic time is thus the consequence of the information-generating power of energy flow plus the information-accumulating capacity of DNA, winnowed by natural selection. Consequently, the most important component of the biological environment is energy flow: the availability of calories and their use for growth, survival, and reproduction. Animals can exploit and adapt to available energy resources at three levels. They can evolve different anatomical forms through nuclear DNA (nDNA) mutations permitting exploitation of alternative energy reservoirs, resulting in new species. They can evolve modified bioenergetic physiologies within a species, primarily through the high mutation rate of mitochondrial DNA (mtDNA)-encoded bioenergetic genes, permitting adjustment to regional energetic environments. They can alter the epigenomic regulation of the thousands of dispersed bioenergetic genes via mitochondrially generated high-energy intermediates permitting individual accommodation to short-term environmental energetic fluctuations. Because medicine pertains to a single species, Homo sapiens, functional human variation often involves sequence changes in bioenergetic genes, most commonly mtDNA mutations, plus changes in the expression of bioenergetic genes mediated by the epigenome. Consequently, common nDNA polymorphisms in anatomical genes may represent only a fraction of the genetic variation associated with the common "complex" diseases, and the ascent of man has been the product of 3.5 billion years of information generation by energy flow, accumulated and preserved in DNA and edited by natural selection.

Rethinking energy in parkinsonian motor symptoms: a potential role for neural metabolic deficits

PubMed Central

Amano, Shinichi; Kegelmeyer, Deborah; Hong, S. Lee

2015-01-01

Parkinson’s disease (PD) is characterized as a chronic and progressive neurodegenerative disorder that results in a variety of debilitating symptoms, including bradykinesia, resting tremor, rigidity, and postural instability. Research spanning several decades has emphasized basal ganglia dysfunction, predominantly resulting from dopaminergic (DA) cell loss, as the primarily cause of the aforementioned parkinsonian features. But, why those particular features manifest themselves remains an enigma. The goal of this paper is to develop a theoretical framework that parkinsonian motor features are behavioral consequence of a long-term adaptation to their inability (inflexibility or lack of capacity) to meet energetic demands, due to neural metabolic deficits arising from mitochondrial dysfunction associated with PD. Here, we discuss neurophysiological changes that are generally associated with PD, such as selective degeneration of DA neurons in the substantia nigra pars compacta (SNc), in conjunction with metabolic and mitochondrial dysfunction. We then characterize the cardinal motor symptoms of PD, bradykinesia, resting tremor, rigidity and gait disturbance, reviewing literature to demonstrate how these motor patterns are actually energy efficient from a metabolic perspective. We will also develop three testable hypotheses: (1) neural metabolic deficits precede the increased rate of neurodegeneration and onset of behavioral symptoms in PD; (2) motor behavior of persons with PD are more sensitive to changes in metabolic/bioenergetic state; and (3) improvement of metabolic function could lead to better motor performance in persons with PD. These hypotheses are designed to introduce a novel viewpoint that can elucidate the connections between metabolic, neural and motor function in PD. PMID:25610377

Energy Metabolism and Inflammation in Brain Aging and Alzheimer’s Disease

PubMed Central

Yin, Fei; Sancheti, Harsh; Patil, Ishan; Cadenas, Enrique

2016-01-01

The high energy demand of the brain renders it sensitive to changes in energy fuel supply and mitochondrial function. Deficits in glucose availability and mitochondrial function are well-known hallmarks of brain aging and are particularly accentuated in neurodegenerative disorders such as Alzheimer’s disease. As important cellular sources of H2O2, mitochondrial dysfunction is usually associated with altered redox status. Bioenergetic deficits and chronic oxidative stress are both major contributors to cognitive decline associated with brain aging and Alzheimer’s disease. Neuroinflammatory changes, including microglial activation and production of inflammatory cytokines, are observed in neurodegenerative diseases and normal aging. The bioenergetic hypothesis advocates for sequential events from metabolic deficits to propagation of neuronal dysfunction, to aging, and to neurodegeneration, while the inflammatory hypothesis supports microglia activation as the driving force for neuroinflammation. Nevertheless, growing evidence suggests that these diverse mechanisms have redox dysregulation as a common denominator and connector. An independent view of the mechanisms underlying brain aging and neurodegeneration is being replaced by one that entails multiple mechanisms coordinating and interacting with each other. This review focuses on the alterations in energy metabolism and inflammatory responses and their connection via redox regulation in normal brain aging and Alzheimer’s disease. Interactions of these systems is reviewed based on basic research and clinical studies. PMID:27154981

Loss of thymidine kinase 2 alters neuronal bioenergetics and leads to neurodegeneration

PubMed Central

Bartesaghi, Stefano; Betts-Henderson, Joanne; Cain, Kelvin; Dinsdale, David; Zhou, Xiaoshan; Karlsson, Anna; Salomoni, Paolo; Nicotera, Pierluigi

2010-01-01

Mutations of thymidine kinase 2 (TK2), an essential component of the mitochondrial nucleotide salvage pathway, can give rise to mitochondrial DNA (mtDNA) depletion syndromes (MDS). These clinically heterogeneous disorders are characterized by severe reduction in mtDNA copy number in affected tissues and are associated with progressive myopathy, hepatopathy and/or encephalopathy, depending in part on the underlying nuclear genetic defect. Mutations of TK2 have previously been associated with an isolated myopathic form of MDS (OMIM 609560). However, more recently, neurological phenotypes have been demonstrated in patients carrying TK2 mutations, thus suggesting that loss of TK2 results in neuronal dysfunction. Here, we directly address the role of TK2 in neuronal homeostasis using a knockout mouse model. We demonstrate that in vivo loss of TK2 activity leads to a severe ataxic phenotype, accompanied by reduced mtDNA copy number and decreased steady-state levels of electron transport chain proteins in the brain. In TK2-deficient cerebellar neurons, these abnormalities are associated with impaired mitochondrial bioenergetic function, aberrant mitochondrial ultrastructure and degeneration of selected neuronal types. Overall, our findings demonstrate that TK2 deficiency leads to neuronal dysfunction in vivo, and have important implications for understanding the mechanisms of neurological impairment in MDS. PMID:20123860

Loss of thymidine kinase 2 alters neuronal bioenergetics and leads to neurodegeneration.

PubMed

Bartesaghi, Stefano; Betts-Henderson, Joanne; Cain, Kelvin; Dinsdale, David; Zhou, Xiaoshan; Karlsson, Anna; Salomoni, Paolo; Nicotera, Pierluigi

2010-05-01

Mutations of thymidine kinase 2 (TK2), an essential component of the mitochondrial nucleotide salvage pathway, can give rise to mitochondrial DNA (mtDNA) depletion syndromes (MDS). These clinically heterogeneous disorders are characterized by severe reduction in mtDNA copy number in affected tissues and are associated with progressive myopathy, hepatopathy and/or encephalopathy, depending in part on the underlying nuclear genetic defect. Mutations of TK2 have previously been associated with an isolated myopathic form of MDS (OMIM 609560). However, more recently, neurological phenotypes have been demonstrated in patients carrying TK2 mutations, thus suggesting that loss of TK2 results in neuronal dysfunction. Here, we directly address the role of TK2 in neuronal homeostasis using a knockout mouse model. We demonstrate that in vivo loss of TK2 activity leads to a severe ataxic phenotype, accompanied by reduced mtDNA copy number and decreased steady-state levels of electron transport chain proteins in the brain. In TK2-deficient cerebellar neurons, these abnormalities are associated with impaired mitochondrial bioenergetic function, aberrant mitochondrial ultrastructure and degeneration of selected neuronal types. Overall, our findings demonstrate that TK2 deficiency leads to neuronal dysfunction in vivo, and have important implications for understanding the mechanisms of neurological impairment in MDS.

Brown Adipose Tissue Bioenergetics: A New Methodological Approach

PubMed Central

Calderon‐Dominguez, María; Alcalá, Martín; Sebastián, David; Zorzano, Antonio; Viana, Marta; Serra, Dolors

2017-01-01

The rediscovery of brown adipose tissue (BAT) in humans and its capacity to oxidize fat and dissipate energy as heat has put the spotlight on its potential as a therapeutic target in the treatment of several metabolic conditions including obesity and diabetes. To date the measurement of bioenergetics parameters has required the use of cultured cells or extracted mitochondria with the corresponding loss of information in the tissue context. Herein, we present a method to quantify mitochondrial bioenergetics directly in BAT. Based on XF Seahorse Technology, we assessed the appropriate weight of the explants, the exact concentration of each inhibitor in the reaction, and the specific incubation time to optimize bioenergetics measurements. Our results show that BAT basal oxygen consumption is mostly due to proton leak. In addition, BAT presents higher basal oxygen consumption than white adipose tissue and a positive response to b‐adrenergic stimulation. Considering the whole tissue and not just subcellular populations is a direct approach that provides a realistic view of physiological respiration. In addition, it can be adapted to analyze the effect of potential activators of thermogenesis, or to assess the use of fatty acids or glucose as a source of energy. PMID:28435771

Melatonin, mitochondria, and the skin.

PubMed

Slominski, Andrzej T; Zmijewski, Michal A; Semak, Igor; Kim, Tae-Kang; Janjetovic, Zorica; Slominski, Radomir M; Zmijewski, Jaroslaw W

2017-11-01

The skin being a protective barrier between external and internal (body) environments has the sensory and adaptive capacity to maintain local and global body homeostasis in response to noxious factors. An important part of the skin response to stress is its ability for melatonin synthesis and subsequent metabolism through the indolic and kynuric pathways. Indeed, melatonin and its metabolites have emerged as indispensable for physiological skin functions and for effective protection of a cutaneous homeostasis from hostile environmental factors. Moreover, they attenuate the pathological processes including carcinogenesis and other hyperproliferative/inflammatory conditions. Interestingly, mitochondria appear to be a central hub of melatonin metabolism in the skin cells. Furthermore, substantial evidence has accumulated on the protective role of the melatonin against ultraviolet radiation and the attendant mitochondrial dysfunction. Melatonin and its metabolites appear to have a modulatory impact on mitochondrion redox and bioenergetic homeostasis, as well as the anti-apoptotic effects. Of note, some metabolites exhibit even greater impact than melatonin alone. Herein, we emphasize that melatonin-mitochondria axis would control integumental functions designed to protect local and perhaps global homeostasis. Given the phylogenetic origin and primordial actions of melatonin, we propose that the melatonin-related mitochondrial functions represent an evolutionary conserved mechanism involved in cellular adaptive response to skin injury and repair.

Hybrid incompatibility arises in a sequence-based bioenergetic model of transcription factor binding.

PubMed

Tulchinsky, Alexander Y; Johnson, Norman A; Watt, Ward B; Porter, Adam H

2014-11-01

Postzygotic isolation between incipient species results from the accumulation of incompatibilities that arise as a consequence of genetic divergence. When phenotypes are determined by regulatory interactions, hybrid incompatibility can evolve even as a consequence of parallel adaptation in parental populations because interacting genes can produce the same phenotype through incompatible allelic combinations. We explore the evolutionary conditions that promote and constrain hybrid incompatibility in regulatory networks using a bioenergetic model (combining thermodynamics and kinetics) of transcriptional regulation, considering the bioenergetic basis of molecular interactions between transcription factors (TFs) and their binding sites. The bioenergetic parameters consider the free energy of formation of the bond between the TF and its binding site and the availability of TFs in the intracellular environment. Together these determine fractional occupancy of the TF on the promoter site, the degree of subsequent gene expression and in diploids, and the degree of dominance among allelic interactions. This results in a sigmoid genotype-phenotype map and fitness landscape, with the details of the shape determining the degree of bioenergetic evolutionary constraint on hybrid incompatibility. Using individual-based simulations, we subjected two allopatric populations to parallel directional or stabilizing selection. Misregulation of hybrid gene expression occurred under either type of selection, although it evolved faster under directional selection. Under directional selection, the extent of hybrid incompatibility increased with the slope of the genotype-phenotype map near the derived parental expression level. Under stabilizing selection, hybrid incompatibility arose from compensatory mutations and was greater when the bioenergetic properties of the interaction caused the space of nearly neutral genotypes around the stable expression level to be wide. F2's showed higher hybrid incompatibility than F1's to the extent that the bioenergetic properties favored dominant regulatory interactions. The present model is a mechanistically explicit case of the Bateson-Dobzhansky-Muller model, connecting environmental selective pressure to hybrid incompatibility through the molecular mechanism of regulatory divergence. The bioenergetic parameters that determine expression represent measurable properties of transcriptional regulation, providing a predictive framework for empirical studies of how phenotypic evolution results in epistatic incompatibility at the molecular level in hybrids. Copyright © 2014 by the Genetics Society of America.

Bioenergetical and Cardiac Adaptations of Pilots to a 24-Hour Team Kart Race.

PubMed

Durand, Sylvain; Ripamonti, Michael; Rahmani, Abderrahmane; Beaune, Bruno

2015-11-01

This study aimed to evaluate energy expenditure (EE) and heart rate (HR) response in kart pilots to successive driving bouts during a 24-hour team race. Eight adult male pilots (22.8 ± 4.1 years) participated to a team 24-hour speedway kart race in Le Mans (France). They alternatively piloted a 390 cm kart. Each relay was 45 minutes long and each pilot performed 4 relays. For each pilot, mean speeds were calculated from lap-to-lap duration recordings using a telemetric infrared timing device. Heart rate values were recorded continuously on 5-second intervals using a portable cardiometric device. Total energy expenditure (EET) and physical activity ratio (PAR) were determined by accelerometry. To pilot a kart during 45 minutes at a mean speed around 62 km·h induces a 300-kcal EET, corresponding to a 5.6-Mets PAR. This effort is responsive for a 73 b·min increase in HR, from 84.1 ± 7.6 to 157.4 ± 11.0 b·min (82% maximal heart rate intensity). However, during this relay period, HR values seemed independent to mean speed performance and bioenergetical values. Thus, in the context of the 24-hour team race, the variability in effort made during each relay and relay succession did not alter bioenergetical adaptation of pilots to kart driving. The high EE and HR values would be better explained by both emotional stress and environmental constraints such as speedway configuration and vibrations. The way how these factors specifically influence bioenergetical demand, and their relative importance, has to be specified to optimize training procedure and recommendations.

Mitochondrial bioenergetics decay in aging: beneficial effect of melatonin.

PubMed

Paradies, Giuseppe; Paradies, Valeria; Ruggiero, Francesca M; Petrosillo, Giuseppe

2017-11-01

Aging is a biological process characterized by progressive decline in physiological functions, increased oxidative stress, reduced capacity to respond to stresses, and increased risk of contracting age-associated disorders. Mitochondria are referred to as the powerhouse of the cell through their role in the oxidative phosphorylation to generate ATP. These organelles contribute to the aging process, mainly through impairment of electron transport chain activity, opening of the mitochondrial permeability transition pore and increased oxidative stress. These events lead to damage to proteins, lipids and mitochondrial DNA. Cardiolipin, a phospholipid of the inner mitochondrial membrane, plays a pivotal role in several mitochondrial bioenergetic processes as well as in mitochondrial-dependent steps of apoptosis and in mitochondrial membrane stability and dynamics. Cardiolipin alterations are associated with mitochondrial bienergetics decline in multiple tissues in a variety of physiopathological conditions, as well as in the aging process. Melatonin, the major product of the pineal gland, is considered an effective protector of mitochondrial bioenergetic function. Melatonin preserves mitochondrial function by preventing cardiolipin oxidation and this may explain, at least in part, the protective role of this compound in mitochondrial physiopathology and aging. Here, mechanisms through which melatonin exerts its protective role against mitochondrial dysfunction associated with aging and age-associated disorders are discussed.

Decreasing mitochondrial fission alleviates hepatic steatosis in a murine model of nonalcoholic fatty liver disease.

PubMed

Galloway, Chad A; Lee, Hakjoo; Brookes, Paul S; Yoon, Yisang

2014-09-15

Mitochondria produce the majority of cellular ATP through oxidative phosphorylation, and their capacity to do so is influenced by many factors. Mitochondrial morphology is recently suggested as an important contributor in controlling mitochondrial bioenergetics. Mitochondria divide and fuse continuously, which is affected by environmental factors, including metabolic alterations. Underscoring its bioenergetic influence, altered mitochondrial morphology is reported in tissues of patients and in animal models of metabolic dysfunction. In this study, we found that mitochondrial fission plays a vital role in the progression of nonalcoholic fatty liver disease (NAFLD). The development of hepatic steatosis, oxidative/nitrative stress, and hepatic tissue damage, induced by a high-fat diet, were alleviated in genetically manipulated mice suppressing mitochondrial fission. The alleviation of steatosis was recapitulated in primary hepatocytes with the inhibition of mitochondrial fission. Mechanistically, our study indicates that fission inhibition enhances proton leak under conditions of free fatty acid incubation, implicating bioenergetic change through manipulating mitochondrial fission. Taken together, our results suggest a mechanistic role for mitochondrial fission in the etiology of NAFLD. The efficacy of decreasing mitochondrial fission in the suppression of NAFLD suggests that mitochondrial fission represents a novel target for therapeutic treatment of NAFLD. Copyright © 2014 the American Physiological Society.

Early Decline in Glucose Transport and Metabolism Precedes Shift to Ketogenic System in Female Aging and Alzheimer's Mouse Brain: Implication for Bioenergetic Intervention

PubMed Central

Ding, Fan; Yao, Jia; Rettberg, Jamaica R.; Chen, Shuhua; Brinton, Roberta Diaz

2013-01-01

We previously demonstrated that mitochondrial bioenergetic deficits in the female brain accompanied reproductive senescence and was accompanied by a shift from an aerobic glycolytic to a ketogenic phenotype. Herein, we investigated the relationship between systems of fuel supply, transport and mitochondrial metabolic enzyme expression/activity during aging (3–15 months) in the hippocampus of nontransgenic (nonTg) background and 3xTgAD female mice. Results indicate that during female brain aging, both nonTg and 3xTgAD brains undergo significant decline in glucose transport, as detected by FDG-microPET, between 6–9 months of age just prior to the transition into reproductive senescence. The deficit in brain metabolism was sustained thereafter. Decline in glucose transport coincided with significant decline in neuronal glucose transporter expression and hexokinase activity with a concomitant rise in phosphorylated/inactivated pyruvate dehydrogenase. Lactate utilization declined in parallel to the decline in glucose transport suggesting lactate did not serve as an alternative fuel. An adaptive response in the nonTg hippocampus was a shift to transport and utilization of ketone bodies as an alternative fuel. In the 3xTgAD brain, utilization of ketone bodies as an alternative fuel was evident at the earliest age investigated and declined thereafter. The 3xTgAD adaptive response was to substantially increase monocarboxylate transporters in neurons while decreasing their expression at the BBB and in astrocytes. Collectively, these data indicate that the earliest change in the metabolic system of the aging female brain is the decline in neuronal glucose transport and metabolism followed by decline in mitochondrial function. The adaptive shift to the ketogenic system as an alternative fuel coincided with decline in mitochondrial function. Translationally, these data provide insights into the earliest events in bioenergetic aging of the female brain and provide potential targets for preventing shifts to less efficient bioenergetic fuels and transition to the ketogenic phenotype of the Alzheimer's brain. PMID:24244584

Functional Mitochondria in Health and Disease.

PubMed

Herst, Patries M; Rowe, Matthew R; Carson, Georgia M; Berridge, Michael V

2017-01-01

The ability to rapidly adapt cellular bioenergetic capabilities to meet rapidly changing environmental conditions is mandatory for normal cellular function and for cancer progression. Any loss of this adaptive response has the potential to compromise cellular function and render the cell more susceptible to external stressors such as oxidative stress, radiation, chemotherapeutic drugs, and hypoxia. Mitochondria play a vital role in bioenergetic and biosynthetic pathways and can rapidly adjust to meet the metabolic needs of the cell. Increased demand is met by mitochondrial biogenesis and fusion of individual mitochondria into dynamic networks, whereas a decrease in demand results in the removal of superfluous mitochondria through fission and mitophagy. Effective communication between nucleus and mitochondria (mito-nuclear cross talk), involving the generation of different mitochondrial stress signals as well as the nuclear stress response pathways to deal with these stressors, maintains bioenergetic homeostasis under most conditions. However, when mitochondrial DNA (mtDNA) mutations accumulate and mito-nuclear cross talk falters, mitochondria fail to deliver critical functional outputs. Mutations in mtDNA have been implicated in neuromuscular and neurodegenerative mitochondriopathies and complex diseases such as diabetes, cardiovascular diseases, gastrointestinal disorders, skin disorders, aging, and cancer. In some cases, drastic measures such as acquisition of new mitochondria from donor cells occurs to ensure cell survival. This review starts with a brief discussion of the evolutionary origin of mitochondria and summarizes how mutations in mtDNA lead to mitochondriopathies and other degenerative diseases. Mito-nuclear cross talk, including various stress signals generated by mitochondria and corresponding stress response pathways activated by the nucleus are summarized. We also introduce and discuss a small family of recently discovered hormone-like mitopeptides that modulate body metabolism. Under conditions of severe mitochondrial stress, mitochondria have been shown to traffic between cells, replacing mitochondria in cells with damaged and malfunctional mtDNA. Understanding the processes involved in cellular bioenergetics and metabolic adaptation has the potential to generate new knowledge that will lead to improved treatment of many of the metabolic, degenerative, and age-related inflammatory diseases that characterize modern societies.

Streptococcus agalactiae impairs cerebral bioenergetics in experimentally infected silver catfish.

PubMed

Baldissera, Matheus D; Souza, Carine F; Parmeggiani, Belisa S; Santos, Roberto C V; Leipnitz, Guilhian; Moreira, Karen L S; da Rocha, Maria Izabel U M; da Veiga, Marcelo L; Baldisserotto, Bernardo

2017-10-01

It is becoming evident that bacterial infectious diseases affect brain energy metabolism, where alterations of enzymatic complexes of the mitochondrial respiratory chain and creatine kinase (CK) lead to an impairment of cerebral bioenergetics which contribute to disease pathogenesis in the central nervous system (CNS). Based on this evidence, the aim of this study was to evaluate whether alterations in the activity of complex IV of the respiratory chain and CK contribute to impairment of cerebral bioenergetics during Streptococcus agalactiae infection in silver catfish (Rhamdia quelen). The activity of complex IV of the respiratory chain in brain increased, while the CK activity decreased in infected animals compared to uninfected animals. Brain histopathology revealed inflammatory demyelination, gliosis of the brain and intercellular edema in infected animals. Based on this evidence, S. agalactiae infection causes an impairment in cerebral bioenergetics through the augmentation of complex IV activity, which may be considered an adaptive response to maintain proper functioning of the electron respiratory chain, as well as to ensure ongoing electron flow through the electron transport chain. Moreover, inhibition of cerebral CK activity contributes to lower availability of ATP, contributing to impairment of cerebral energy homeostasis. In summary, these alterations contribute to disease pathogenesis linked to the CNS. Copyright © 2017 Elsevier Ltd. All rights reserved.

A comparison of maximal bioenergetic enzyme activities obtained with commonly used homogenization techniques.

PubMed

Grace, M; Fletcher, L; Powers, S K; Hughes, M; Coombes, J

1996-12-01

Homogenization of tissue for analysis of bioenergetic enzyme activities is a common practice in studies examining metabolic properties of skeletal muscle adaptation to disease, aging, inactivity or exercise. While numerous homogenization techniques are in use today, limited information exists concerning the efficacy of specific homogenization protocols. Therefore, the purpose of this study was to compare the efficacy of four commonly used approaches to homogenizing skeletal muscle for analysis of bioenergetic enzyme activity. The maximal enzyme activity (Vmax) of citrate synthase (CS) and lactate dehydrogenase (LDH) were measured from homogenous muscle samples (N = 48 per homogenization technique) and used as indicators to determine which protocol had the highest efficacy. The homogenization techniques were: (1) glass-on-glass pestle; (2) a combination of a mechanical blender and a teflon pestle (Potter-Elvehjem); (3) a combination of the mechanical blender and a biological detergent; and (4) the combined use of a mechanical blender and a sonicator. The glass-on-glass pestle homogenization protocol produced significantly higher (P < 0.05) enzyme activities compared to all other protocols for both enzymes. Of the four protocols examined, the data demonstrate that the glass-on-glass pestle homogenization protocol is the technique of choice for studying bioenergetic enzyme activity in skeletal muscle.

Insulin Resistance and Mitochondrial Dysfunction.

PubMed

Gonzalez-Franquesa, Alba; Patti, Mary-Elizabeth

2017-01-01

Insulin resistance precedes and predicts the onset of type 2 diabetes (T2D) in susceptible humans, underscoring its important role in the complex pathogenesis of this disease. Insulin resistance contributes to multiple tissue defects characteristic of T2D, including reduced insulin-stimulated glucose uptake in insulin-sensitive tissues, increased hepatic glucose production, increased lipolysis in adipose tissue, and altered insulin secretion. Studies of individuals with insulin resistance, both with established T2D and high-risk individuals, have consistently demonstrated a diverse array of defects in mitochondrial function (i.e., bioenergetics, biogenesis and dynamics). However, it remains uncertain whether mitochondrial dysfunction is primary (critical initiating defect) or secondary to the subtle derangements in glucose metabolism, insulin resistance, and defective insulin secretion present early in the course of disease development. In this chapter, we will present the evidence linking mitochondrial dysfunction and insulin resistance, and review the potential for mitochondrial targets as a therapeutic approach for T2D.

Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases

PubMed Central

DeBalsi, Karen L.; Hoff, Kirsten E.; Copeland, William C.

2016-01-01

As regulators of bioenergetics in the cell and the primary source of endogenous reactive oxygen species (ROS), dysfunctional mitochondria have been implicated for decades in the process of aging and age-related diseases. Mitochondrial DNA (mtDNA) is replicated and repaired by nuclear-encoded mtDNA polymerase γ (Pol γ) and several other associated proteins, which compose the mtDNA replication machinery. Here, we review evidence that errors caused by this replication machinery and failure to repair these mtDNA errors results in mtDNA mutations. Clonal expansion of mtDNA mutations results in mitochondrial dysfunction, such as decreased electron transport chain (ETC) enzyme activity and impaired cellular respiration. We address the literature that mitochondrial dysfunction, in conjunction with altered mitochondrial dynamics, is a major driving force behind aging and age-related diseases. Additionally, interventions to improve mitochondrial function and attenuate the symptoms of aging are examined. PMID:27143693

Energy metabolism and inflammation in brain aging and Alzheimer's disease.

PubMed

Yin, Fei; Sancheti, Harsh; Patil, Ishan; Cadenas, Enrique

2016-11-01

The high energy demand of the brain renders it sensitive to changes in energy fuel supply and mitochondrial function. Deficits in glucose availability and mitochondrial function are well-known hallmarks of brain aging and are particularly accentuated in neurodegenerative disorders such as Alzheimer's disease. As important cellular sources of H 2 O 2 , mitochondrial dysfunction is usually associated with altered redox status. Bioenergetic deficits and chronic oxidative stress are both major contributors to cognitive decline associated with brain aging and Alzheimer's disease. Neuroinflammatory changes, including microglial activation and production of inflammatory cytokines, are observed in neurodegenerative diseases and normal aging. The bioenergetic hypothesis advocates for sequential events from metabolic deficits to propagation of neuronal dysfunction, to aging, and to neurodegeneration, while the inflammatory hypothesis supports microglia activation as the driving force for neuroinflammation. Nevertheless, growing evidence suggests that these diverse mechanisms have redox dysregulation as a common denominator and connector. An independent view of the mechanisms underlying brain aging and neurodegeneration is being replaced by one that entails multiple mechanisms coordinating and interacting with each other. This review focuses on the alterations in energy metabolism and inflammatory responses and their connection via redox regulation in normal brain aging and Alzheimer's disease. Interaction of these systems is reviewed based on basic research and clinical studies. Copyright © 2016 Elsevier Inc. All rights reserved.

TRPM2 Channels Protect against Cardiac Ischemia-Reperfusion Injury

PubMed Central

Miller, Barbara A.; Hoffman, Nicholas E.; Merali, Salim; Zhang, Xue-Qian; Wang, JuFang; Rajan, Sudarsan; Shanmughapriya, Santhanam; Gao, Erhe; Barrero, Carlos A.; Mallilankaraman, Karthik; Song, Jianliang; Gu, Tongda; Hirschler-Laszkiewicz, Iwona; Koch, Walter J.; Feldman, Arthur M.; Madesh, Muniswamy; Cheung, Joseph Y.

2014-01-01

Cardiac TRPM2 channels were activated by intracellular adenosine diphosphate-ribose and blocked by flufenamic acid. In adult cardiac myocytes the ratio of GCa to GNa of TRPM2 channels was 0.56 ± 0.02. To explore the cellular mechanisms by which TRPM2 channels protect against cardiac ischemia/reperfusion (I/R) injury, we analyzed proteomes from WT and TRPM2 KO hearts subjected to I/R. The canonical pathways that exhibited the largest difference between WT-I/R and KO-I/R hearts were mitochondrial dysfunction and the tricarboxylic acid cycle. Complexes I, III, and IV were down-regulated, whereas complexes II and V were up-regulated in KO-I/R compared with WT-I/R hearts. Western blots confirmed reduced expression of the Complex I subunit and other mitochondria-associated proteins in KO-I/R hearts. Bioenergetic analyses revealed that KO myocytes had a lower mitochondrial membrane potential, mitochondrial Ca2+ uptake, ATP levels, and O2 consumption but higher mitochondrial superoxide levels. Additionally, mitochondrial Ca2+ uniporter (MCU) currents were lower in KO myocytes, indicating reduced mitochondrial Ca2+ uptake was likely due to both lower ψm and MCU activity. Similar to isolated myocytes, O2 consumption and ATP levels were also reduced in KO hearts. Under a simulated I/R model, aberrant mitochondrial bioenergetics was exacerbated in KO myocytes. Reactive oxygen species levels were also significantly higher in KO-I/R compared with WT-I/R heart slices, consistent with mitochondrial dysfunction in KO-I/R hearts. We conclude that TRPM2 channels protect the heart from I/R injury by ameliorating mitochondrial dysfunction and reducing reactive oxygen species levels. PMID:24492610

Human immune cells' behavior and survival under bioenergetically restricted conditions in an in vitro fracture hematoma model

PubMed Central

Hoff, Paula; Maschmeyer, Patrick; Gaber, Timo; Schütze, Tabea; Raue, Tobias; Schmidt-Bleek, Katharina; Dziurla, René; Schellmann, Saskia; Lohanatha, Ferenz Leonard; Röhner, Eric; Ode, Andrea; Burmester, Gerd-Rüdiger; Duda, Georg N; Perka, Carsten; Buttgereit, Frank

2013-01-01

The initial inflammatory phase of bone fracture healing represents a critical step for the outcome of the healing process. However, both the mechanisms initiating this inflammatory phase and the function of immune cells present at the fracture site are poorly understood. In order to study the early events within a fracture hematoma, we established an in vitro fracture hematoma model: we cultured hematomas forming during an osteotomy (artificial bone fracture) of the femur during total hip arthroplasty (THA) in vitro under bioenergetically controlled conditions. This model allowed us to monitor immune cell populations, cell survival and cytokine expression during the early phase following a fracture. Moreover, this model enabled us to change the bioenergetical conditions in order to mimic the in vivo situation, which is assumed to be characterized by hypoxia and restricted amounts of nutrients. Using this model, we found that immune cells adapt to hypoxia via the expression of angiogenic factors, chemoattractants and pro-inflammatory molecules. In addition, combined restriction of oxygen and nutrient supply enhanced the selective survival of lymphocytes in comparison with that of myeloid derived cells (i.e., neutrophils). Of note, non-restricted bioenergetical conditions did not show any similar effects regarding cytokine expression and/or different survival rates of immune cell subsets. In conclusion, we found that the bioenergetical conditions are among the crucial factors inducing the initial inflammatory phase of fracture healing and are thus a critical step for influencing survival and function of immune cells in the early fracture hematoma. PMID:23396474

Skeletal Muscle and Lymphocyte Mitochondrial Dysfunctions in Septic Shock Trigger ICU-Acquired Weakness and Sepsis-Induced Immunoparalysis.

PubMed

Maestraggi, Quentin; Lebas, Benjamin; Clere-Jehl, Raphaël; Ludes, Pierre-Olivier; Chamaraux-Tran, Thiên-Nga; Schneider, Francis; Diemunsch, Pierre; Geny, Bernard; Pottecher, Julien

2017-01-01

Fundamental events driving the pathological processes of septic shock-induced multiorgan failure (MOF) at the cellular and subcellular levels remain debated. Emerging data implicate mitochondrial dysfunction as a critical factor in the pathogenesis of sepsis-associated MOF. If macrocirculatory and microcirculatory dysfunctions undoubtedly participate in organ dysfunction at the early stage of septic shock, an intrinsic bioenergetic failure, sometimes called "cytopathic hypoxia," perpetuates cellular dysfunction. Short-term failure of vital organs immediately threatens patient survival but long-term recovery is also severely hindered by persistent dysfunction of organs traditionally described as nonvital, such as skeletal muscle and peripheral blood mononuclear cells (PBMCs). In this review, we will stress how and why a persistent mitochondrial dysfunction in skeletal muscles and PBMC could impair survival in patients who overcome the first acute phase of their septic episode. First, muscle wasting protracts weaning from mechanical ventilation, increases the risk of mechanical ventilator-associated pneumonia, and creates a state of ICU-acquired muscle weakness, compelling the patient to bed. Second, failure of the immune system ("immunoparalysis") translates into its inability to clear infectious foci and predisposes the patient to recurrent nosocomial infections. We will finally emphasize how mitochondrial-targeted therapies could represent a realistic strategy to promote long-term recovery after sepsis.

p53/CEP-1 Increases or Decreases Lifespan, Depending on Level of Mitochondrial Bioenergetic Stress

PubMed Central

Ventura, Natascia; Rea, Shane L.; Schiavi, Alfonso; Torgovnick, Alessandro; Testi, Roberto; Johnson, Thomas E.

2009-01-01

SUMMARY Mitochondrial pathologies underlie a number of life-shortening diseases in humans. In the nematode Caenorhabditis elegans, severely reduced expression of mitochondrial proteins involved in electron transport chain-mediated energy production also leads to pathological phenotypes, including arrested development and/or shorter life; in sharp contrast, mild suppression of these same proteins extends lifespan. Here we show that the C. elegans p53 ortholog cep-1 mediates these opposite effects. We find that cep-1 is required to extend longevity in response to mild suppression of several bioenergetically relevant mitochondrial proteins, including frataxin - the protein defective in patients with Friedreich’s Ataxia. Importantly we show that cep-1 also mediates both the developmental arrest and life shortening induced by severe mitochondrial stress. Our findings support an evolutionarily conserved function for p53 in modulating organismal responses to mitochondrial dysfunction and suggest that metabolic checkpoint responses may play a role in longevity control and in human mitochondrial-associated diseases. PMID:19416129

Endosymbiosis and the design of eukaryotic electron transport.

PubMed

Berry, Stephan

2003-09-30

The bioenergetic organelles of eukaryotic cells, mitochondria and chloroplasts, are derived from endosymbiotic bacteria. Their electron transport chains (ETCs) resemble those of free-living bacteria, but were tailored for energy transformation within the host cell. Parallel evolutionary processes in mitochondria and chloroplasts include reductive as well as expansive events: On one hand, bacterial complexes were lost in eukaryotes with a concomitant loss of metabolic flexibility. On the other hand, new subunits have been added to the remaining bacterial complexes, new complexes have been introduced, and elaborate folding patterns of the thylakoid and mitochondrial inner membranes have emerged. Some bacterial pathways were reinvented independently by eukaryotes, such as parallel routes for quinol oxidation or the use of various anaerobic electron acceptors. Multicellular organization and ontogenetic cycles in eukaryotes gave rise to further modifications of the bioenergetic organelles. Besides mitochondria and chloroplasts, eukaryotes have ETCs in other membranes, such as the plasma membrane (PM) redox system, or the cytochrome P450 (CYP) system. These systems have fewer complexes and simpler branching patterns than those in energy-transforming organelles, and they are often adapted to non-bioenergetic functions such as detoxification or cellular defense.

Single-cell imaging of bioenergetic responses to neuronal excitotoxicity and oxygen and glucose deprivation.

PubMed

Connolly, Niamh M C; Düssmann, Heiko; Anilkumar, Ujval; Huber, Heinrich J; Prehn, Jochen H M

2014-07-30

Excitotoxicity is a condition occurring during cerebral ischemia, seizures, and chronic neurodegeneration. It is characterized by overactivation of glutamate receptors, leading to excessive Ca(2+)/Na(+) influx into neurons, energetic stress, and subsequent neuronal injury. We and others have previously investigated neuronal populations to study how bioenergetic parameters determine neuronal injury; however, such experiments are often confounded by population-based heterogeneity and the contribution of effects of non-neuronal cells. Hence, we here characterized bioenergetics during transient excitotoxicity in rat and mouse primary neurons at the single-cell level using fluorescent sensors for intracellular glucose, ATP, and activation of the energy sensor AMP-activated protein kinase (AMPK). We identified ATP depletion and recovery to energetic homeostasis, along with AMPK activation, as surprisingly rapid and plastic responses in two excitotoxic injury paradigms. We observed rapid recovery of neuronal ATP levels also in the absence of extracellular glucose, or when glycolytic ATP production was inhibited, but found mitochondria to be critical for fast and complete energetic recovery. Using an injury model of oxygen and glucose deprivation, we identified a similarly rapid bioenergetics response, yet with incomplete ATP recovery and decreased AMPK activity. Interestingly, excitotoxicity also induced an accumulation of intracellular glucose, providing an additional source of energy during and after excitotoxicity-induced energy depletion. We identified this to originate from extracellular, AMPK-dependent glucose uptake and from intracellular glucose mobilization. Surprisingly, cells recovering their elevated glucose levels faster to baseline survived longer, indicating that the plasticity of neurons to adapt to bioenergetic challenges is a key indicator of neuronal viability. Copyright © 2014 the authors 0270-6474/14/3410192-14$15.00/0.

Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics

PubMed Central

Marzetti, Emanuele; Csiszar, Anna; Dutta, Debapriya; Balagopal, Gauthami; Calvani, Riccardo

2013-01-01

Advanced age is associated with a disproportionate prevalence of cardiovascular disease (CVD). Intrinsic alterations in the heart and the vasculature occurring over the life course render the cardiovascular system more vulnerable to various stressors in late life, ultimately favoring the development of CVD. Several lines of evidence indicate mitochondrial dysfunction as a major contributor to cardiovascular senescence. Besides being less bioenergetically efficient, damaged mitochondria also produce increased amounts of reactive oxygen species, with detrimental structural and functional consequences for the cardiovascular system. The age-related accumulation of dysfunctional mitochondrial likely results from the combination of impaired clearance of damaged organelles by autophagy and inadequate replenishment of the cellular mitochondrial pool by mitochondriogenesis. In this review, we summarize the current knowledge about relevant mechanisms and consequences of age-related mitochondrial decay and alterations in mitochondrial quality control in the cardiovascular system. The involvement of mitochondrial dysfunction in the pathogenesis of cardiovascular conditions especially prevalent in late life and the emerging connections with neurodegeneration are also illustrated. Special emphasis is placed on recent discoveries on the role played by alterations in mitochondrial dynamics (fusion and fission), mitophagy, and their interconnections in the context of age-related CVD and endothelial dysfunction. Finally, we discuss pharmacological interventions targeting mitochondrial dysfunction to delay cardiovascular aging and manage CVD. PMID:23748424

Bioenergetics, Trophic Ecology, and Niche Separation of Tunas.

PubMed

Olson, R J; Young, J W; Ménard, F; Potier, M; Allain, V; Goñi, N; Logan, J M; Galván-Magaña, F

Tunas are highly specialized predators that have evolved numerous adaptations for a lifestyle that requires large amounts of energy consumption. Here we review our understanding of the bioenergetics and feeding dynamics of tunas on a global scale, with an emphasis on yellowfin, bigeye, skipjack, albacore, and Atlantic bluefin tunas. Food consumption balances bioenergetics expenditures for respiration, growth (including gonad production), specific dynamic action, egestion, and excretion. Tunas feed across the micronekton and some large zooplankton. Some tunas appear to time their life history to take advantage of ephemeral aggregations of crustacean, fish, and molluscan prey. Ontogenetic and spatial diet differences are substantial, and significant interdecadal changes in prey composition have been observed. Diet shifts from larger to smaller prey taxa highlight ecosystem-wide changes in prey availability and diversity and provide implications for changing bioenergetics requirements into the future. Where tunas overlap, we show evidence of niche separation between them; resources are divided largely by differences in diet percentages and size ranges of prey taxa. The lack of long-term data limits the ability to predict impacts of climate change on tuna feeding behaviour. We note the need for systematic collection of feeding data as part of routine monitoring of these species, and we highlight the advantages of using biochemical techniques for broad-scale analyses of trophic relations. We support the continued development of ecosystem models, which all too often lack the regional-specific trophic data needed to adequately investigate climate and fishing impacts. © 2016 Elsevier Ltd. All rights reserved.

Levothyroxine improves abnormal cardiac bioenergetics in subclinical hypothyroidism: a cardiac magnetic resonance spectroscopic study.

PubMed

Madathil, Asgar; Hollingsworth, Kieren G; Blamire, Andrew M; Razvi, Salman; Newton, Julia L; Taylor, Roy; Weaver, Jolanta U

2015-04-01

It is well established that subclinical hypothyroidism (SCH) is associated with mild cardiac dysfunction, but it is unknown whether there is an underlying impairment of cardiac bioenergetic function. The objective of the study was to quantify the cardiac phosphocreatine to adenosine triphosphate ratio (PCr to ATP) in SCH, compared with healthy controls, and to measure the effect of 6 months of levothyroxine treatment. This was a 6-month, prospective, case-controlled interventional study. The PCr to ATP ratio was measured using phosphorus-31 magnetic resonance spectroscopy in subjects with SCH at baseline and after levothyroxine therapy (1.6 μg/kg · d) and compared with age- and gender-matched euthyroid controls. All subjects were free of overt heart disease. Twenty-one subjects with SCH (normal free T4 and serum TSH between 4.1 and 10 mIU/L) and 17 controls were matched for age (mean age 40.5 vs 43.3 y) and sex (females 81% vs 82%) but differed in mean TSH (6.5 vs 2.1 mIU/L, P < .001). At baseline the mean (± SD) PCr to ATP ratio in SCH was lower than in controls (1.80 ± 0.26 vs 2.07 ± 0.20, P = .001). In the 16 subjects studied after levothyroxine treatment, the PCr to ATP ratio improved (from 1.74 ± 0.24 to 1.91 ± 0.26, P = .004) and approached controls (borderline loss of significance, P = .051). On multivariate analysis, SCH was independently associated with a reduced PCr to ATP ratio, even after adjusting for confounding variables (body mass index and fasting glucose) (P = .001). Our results demonstrate early cardiac bioenergetic impairment in SCH, which is reversible with levothyroxine therapy. This mechanistic insight provides justification for longitudinal trials to determine whether improvement in bioenergetic function improves cardiovascular outcome.

Rituximab is Ineffective for Treatment of Fatigue in Primary Biliary Cholangitis: A phase-2 Randomised Controlled Trial.

PubMed

Khanna, Amardeep; Jopson, Laura; Howel, Denise; Bryant, Andrew; Blamire, Andrew; Newton, Julia L; Jones, David E

2018-05-23

Primary Biliary Cholangitis (PBC) is a chronic cholestatic liver disease. Half of patients experience debilitating fatigue which is currently untreatable. Previous studies have shown muscle bioenergetic abnormalities in PBC, including increased muscle acidosis with exercise linked to the anti-mitochondrial antibody (AMA) diagnostic of the disease, and reduced anaerobic threshold. In this study we addressed the hypothesis that fatigue in PBC is driven by muscle bioenergetic abnormality related to AMA, and that AMA reduction with B-cell depletion therapy will improve fatigue. In our single-centred Phase II randomised controlled trial (RCT) 57 participants aged ≥18 years with PBC and moderate or severe fatigue were randomized to receive 2 doses of either rituximab (1000mg) or saline (placebo). The primary outcome measure was fatigue severity assessed using the PBC-40 fatigue domain at 3 months. Secondary outcomes measures included patient-reported outcomes, immunological and bioenergetics disease parameters. Experimental outcomes included biochemical markers of disease severity. Improvement in fatigue score at 3 months was seen in both arms, with no significant difference (adjusted mean difference -0.9 95%CI -4.6 to 3.1). Little difference was observed in other patient reported outcomes or physical activity. Significant anaerobic threshold improvement was seen in the Rituximab group only but this was not associated with fatigue improvement. No treatment-emergent SAEs were seen. Rituximab was safe over the 12 month study period but showed no evidence of effectiveness for the treatment of fatigue in PBC. Anaerobic threshold improvement was seen; potentially linking AMA with muscle bioenergetics dysfunction, however, this was not related to improvement in fatigue. Rituximab had some evidence of a beneficial effect on alkaline phosphatase levels in this largely UDCA-responding, early disease stage cohort. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the Study of Liver Diseases.

Metabolic Reprogramming in Amyotrophic Lateral Sclerosis.

PubMed

Szelechowski, M; Amoedo, N; Obre, E; Léger, C; Allard, L; Bonneu, M; Claverol, S; Lacombe, D; Oliet, S; Chevallier, S; Le Masson, G; Rossignol, R

2018-03-02

Mitochondrial dysfunction in the spinal cord is a hallmark of amyotrophic lateral sclerosis (ALS), but the neurometabolic alterations during early stages of the disease remain unknown. Here, we investigated the bioenergetic and proteomic changes in ALS mouse motor neurons and patients' skin fibroblasts. We first observed that SODG93A mice presymptomatic motor neurons display alterations in the coupling efficiency of oxidative phosphorylation, along with fragmentation of the mitochondrial network. The proteome of presymptomatic ALS mice motor neurons also revealed a peculiar metabolic signature with upregulation of most energy-transducing enzymes, including the fatty acid oxidation (FAO) and the ketogenic components HADHA and ACAT2, respectively. Accordingly, FAO inhibition altered cell viability specifically in ALS mice motor neurons, while uncoupling protein 2 (UCP2) inhibition recovered cellular ATP levels and mitochondrial network morphology. These findings suggest a novel hypothesis of ALS bioenergetics linking FAO and UCP2. Lastly, we provide a unique set of data comparing the molecular alterations found in human ALS patients' skin fibroblasts and SODG93A mouse motor neurons, revealing conserved changes in protein translation, folding and assembly, tRNA aminoacylation and cell adhesion processes.

Perspectives of drug-based neuroprotection targeting mitochondria.

PubMed

Procaccio, V; Bris, C; Chao de la Barca, J M; Oca, F; Chevrollier, A; Amati-Bonneau, P; Bonneau, D; Reynier, P

2014-05-01

Mitochondrial dysfunction has been reported in most neurodegenerative diseases. These anomalies include bioenergetic defect, respiratory chain-induced oxidative stress, defects of mitochondrial dynamics, increase sensitivity to apoptosis, and accumulation of damaged mitochondria with instable mitochondrial DNA. Significant progress has been made in our understanding of the pathophysiology of inherited mitochondrial disorders but most have no effective therapies. The development of new metabolic treatments will be useful not only for rare mitochondrial disorders but also for the wide spectrum of common age-related neurodegenerative diseases shown to be associated with mitochondrial dysfunction. A better understanding of the mitochondrial regulating pathways raised several promising perspectives of neuroprotection. This review focuses on the pharmacological approaches to modulate mitochondrial biogenesis, the removal of damaged mitochondria through mitophagy, scavenging free radicals and also dietary measures such as ketogenic diet. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Mitochondrial dysfunction in Gulf War illness revealed by 31Phosphorus Magnetic Resonance Spectroscopy: a case-control study.

PubMed

Koslik, Hayley J; Hamilton, Gavin; Golomb, Beatrice A

2014-01-01

Approximately 1/3 of 1990-1 Gulf War veterans developed chronic multisymptom health problems. Implicated exposures bear mechanisms that adversely affect mitochondria. Symptoms emphasize fatigue, cognition and muscle (brain and muscle are aerobically demanding); with protean additional domains affected, compatible with mitochondrial impairment. Recent evidence supports treatments targeting cell bioenergetics (coenzyme10) to benefit Gulf War illness symptoms. However, no evidence has directly documented mitochondrial or bioenergetic impairment in Gulf War illness. We sought to objectively assess for mitochondrial dysfunction, examining post-exercise phosphocreatine-recovery time constant (PCr-R) using (31)Phosphorus Magnetic Resonance Spectroscopy ((31)P-MRS), in Gulf War veterans with Gulf War illness compared to matched healthy controls. PCr-R has been described as a "robust and practical" index of mitochondrial status. Case-control study from 2012-2013. Fourteen community-dwelling Gulf War veterans and matched controls from the San Diego area comprised 7 men meeting CDC and Kansas criteria for Gulf War illness, and 7 non-deployed healthy controls matched 1:1 to cases on age, sex, and ethnicity. Calf muscle phosphocreatine was evaluated by (31)P-MRS at rest, through 5 minutes of foot pedal depression exercise, and in recovery, to assess PCr-R. Paired t-tests compared cases to matched controls. PCr-R was significantly prolonged in Gulf War illness cases vs their matched controls: control values, mean ± SD, 29.0 ± 8.7 seconds; case values 46.1 ± 18.0 seconds; difference 17.1 ± 14.9 seconds; p = 0.023. PCr-R was longer for cases relative to their matched controls for all but one pair; moreover while values clustered under 31 seconds for all but one control, they exceeded 35 seconds (with a spread up to 70 seconds) for all but one case. These data provide the first direct evidence supporting mitochondrial dysfunction in Gulf War illness. Findings merit replication in a larger study and/or corroboration with additional mitochondrial assessment tools.

Understanding the origin of non-immune cell-mediated weakness in the idiopathic inflammatory myopathies - potential role of ER stress pathways.

PubMed

Lightfoot, Adam P; Nagaraju, Kanneboyina; McArdle, Anne; Cooper, Robert G

2015-11-01

Discussion of endoplasmic reticulum (ER) stress pathway activation in idiopathic inflammatory myopathies (IIM), and downstream mechanisms causative of muscle weakness. In IIM, ER stress is an important pathogenic process, but how it causes muscle dysfunction is unknown. We discuss relevant pathways modified in response to ER stress in IIM: reactive oxygen species (ROS) generation and mitochondrial dysfunction, and muscle cytokine (myokine) generation. First, ER stress pathway activation can induce changes in mitochondrial bioenergetics and ROS production. ROS can oxidize cellular components, causing muscle contractile dysfunction and energy deficits. Novel compounds targeting ROS generation and/or mitochondrial dysfunction can improve muscle function in several myopathologies. Second, recent research has demonstrated that skeletal muscle produces multiple myokines. It is suggested that these play a role in causing muscle weakness. Myokines are capable of immune cell recruitment, thus contributing to perturbed muscle function. A characterization of myokines in IIM would clarify their pathogenic role, and so identify new therapeutic targets. ER stress pathway activation is clearly of etiological relevance in IIM. Research to better understand mechanisms of weakness downstream of ER stress is now required, and which may discover new therapeutic targets for nonimmune cell-mediated weakness.

Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease

PubMed Central

Lim, M. A.; Selak, M. A.; Xiang, Z.; Krainc, D.; Neve, R. L.; Kraemer, B. C.; Watts, J. L.

2012-01-01

A growing body of research indicates that amyotrophic lateral sclerosis (ALS) patients and mouse models of ALS exhibit metabolic dysfunction. A subpopulation of ALS patients possesses higher levels of resting energy expenditure and lower fat-free mass compared to healthy controls. Similarly, two mutant copper zinc superoxide dismutase 1 (mSOD1) mouse models of familial ALS possess a hypermetabolic phenotype. The pathophysiological relevance of the bioenergetic defects observed in ALS remains largely elusive. AMP-activated protein kinase (AMPK) is a key sensor of cellular energy status and thus might be activated in various models of ALS. Here, we report that AMPK activity is increased in spinal cord cultures expressing mSOD1, as well as in spinal cord lysates from mSOD1 mice. Reducing AMPK activity either pharmacologically or genetically prevents mSOD1-induced motor neuron death in vitro. To investigate the role of AMPK in vivo, we used Caenorhabditis elegans models of motor neuron disease. C. elegans engineered to express human mSOD1 (G85R) in neurons develops locomotor dysfunction and severe fecundity defects when compared to transgenic worms expressing human wild-type SOD1. Genetic reduction of aak-2, the ortholog of the AMPK α2 catalytic subunit in nematodes, improved locomotor behavior and fecundity in G85R animals. Similar observations were made with nematodes engineered to express mutant tat-activating regulatory (TAR) DNA-binding protein of 43 kDa molecular weight. Altogether, these data suggest that bioenergetic abnormalities are likely to be pathophysiologically relevant to motor neuron disease. PMID:22262909

Effects of exercise on obesity-induced mitochondrial dysfunction in skeletal muscle

PubMed Central

Heo, Jun-Won; No, Mi-Hyun; Park, Dong-Ho; Kang, Ju-Hee; Seo, Dae Yun; Han, Jin; Neufer, P. Darrell

2017-01-01

Obesity is known to induce inhibition of glucose uptake, reduction of lipid metabolism, and progressive loss of skeletal muscle function, which are all associated with mitochondrial dysfunction in skeletal muscle. Mitochondria are dynamic organelles that regulate cellular metabolism and bioenergetics, including ATP production via oxidative phosphorylation. Due to these critical roles of mitochondria, mitochondrial dysfunction results in various diseases such as obesity and type 2 diabetes. Obesity is associated with impairment of mitochondrial function (e.g., decrease in O2 respiration and increase in oxidative stress) in skeletal muscle. The balance between mitochondrial fusion and fission is critical to maintain mitochondrial homeostasis in skeletal muscle. Obesity impairs mitochondrial dynamics, leading to an unbalance between fusion and fission by favorably shifting fission or reducing fusion proteins. Mitophagy is the catabolic process of damaged or unnecessary mitochondria. Obesity reduces mitochondrial biogenesis in skeletal muscle and increases accumulation of dysfunctional cellular organelles, suggesting that mitophagy does not work properly in obesity. Mitochondrial dysfunction and oxidative stress are reported to trigger apoptosis, and mitochondrial apoptosis is induced by obesity in skeletal muscle. It is well known that exercise is the most effective intervention to protect against obesity. Although the cellular and molecular mechanisms by which exercise protects against obesity-induced mitochondrial dysfunction in skeletal muscle are not clearly elucidated, exercise training attenuates mitochondrial dysfunction, allows mitochondria to maintain the balance between mitochondrial dynamics and mitophagy, and reduces apoptotic signaling in obese skeletal muscle. PMID:29200899

Energy metabolism disorders in rare and common diseases. Toward bioenergetic modulation therapy and the training of a new generation of European scientists.

PubMed

Rossignol, Rodrigue

2015-06-01

Energy metabolism alterations are found in a large number of rare and common diseases of genetic or environmental origin. The number of patients that could benefit from bioenergetic modulation therapy (BIOMET) is therefore very important and includes individuals with pathologies as diverse as mitochondrial diseases, acute coronary syndrome, chronic kidney disease, asthma or even cancer. Although, the alteration of energy metabolism is disease specific and sometimes patient specific, the strategies for BIOMET could be common and target a series of bioenergetic regulatory mechanisms discussed in this article. An excellent training of scientists in the field of energy metabolism, related human diseases and drug discovery is also crucial to form a young generation of MDs, PHDs and Pharma or CRO-group leaders who will discover novel personalized bioenergetic medicines, through pharmacology, genetics, nutrition or adapted exercise training. The Mitochondrial European Educational Training (MEET) consortium was created to pursue this goal, and we dedicated here a special issue of Organelle in Focus (OiF) to highlight their objectives. A total of 10 OiFs articles constitute this Directed Issue on Mitochondrial Medicine. As part of this editorial article, we asked timely questions to the PR. Jan W. Smeitink, professor of Mitochondrial Medicine and CEO of Khondrion, a mitochondrial medicine company. He shared with us his objectives and strategies for the study of mitochondrial diseases and the identification of future treatments. This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies. Copyright © 2015 Elsevier Ltd. All rights reserved.

Brain levels of high-energy phosphate metabolites and executive function in geriatric depression.

PubMed

Harper, David G; Joe, Elizabeth B; Jensen, J Eric; Ravichandran, Caitlin; Forester, Brent P

2016-11-01

Depression in late life has been associated with difficulties in cognitive processing, particularly in the domains of executive function, processing speed and memory, and increases the risk of developing dementia suggesting a neurodegenerative phenotype. Mitochondrial dysfunction is frequently an early event in neurodegenerative illnesses and may be operative in patients with late life depression. Phosphorus magnetic resonance spectroscopy (31P MRS) allows for the quantification of bioenergetic molecules produced by mitochondria. Ten patients with late life depression and eight normal elderly controls were studied with Stroop color and interference tests, which are widely used measures of processing speed and executive function, respectively, followed by (31P) MRS 3-dimensional chemical-shift imaging measuring levels of adenosine triphosphate, phosphocreatine, inorganic phosphate, and pH over the whole brain. In all subjects, gray matter phosphocreatine was positively associated with Stroop interference. Levels of white matter adenosine triphosphate were associated with Stroop interference in subjects with late life depression but not normal elderly. There was also a complementary association between white matter inorganic phosphate and Stroop interference in late life depression patients. These findings suggest two independent sources of executive function dependence on bioenergetic state in the aging brain. The dependence of executive function performance in subjects with late life depression on ATP in white matter may be associated with mitochondrial impairment and is consistent with predictions of the vascular depression hypothesis. Further research with wider neuropsychological testing targeting bioenergetic markers could help clarify the scope of these effects. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Combinatorial therapy of exercise-preconditioning and nanocurcumin formulation supplementation improves cardiac adaptation under hypobaric hypoxia.

PubMed

Nehra, Sarita; Bhardwaj, Varun; Bansal, Anju; Saraswat, Deepika

2017-09-26

Chronic hypobaric hypoxia (cHH) mediated cardiac insufficiencies are associated with pathological damage. Sustained redox stress and work load are major causative agents of cardiac insufficiencies under cHH. Despite the advancements made in pharmacological (anti-oxidants, vasodilators) and non-pharmacological therapeutics (acclimatization strategies and schedules), only partial success has been achieved in improving cardiac acclimatization to cHH. This necessitates the need for potent combinatorial therapies to improve cardiac acclimatization at high altitudes. We hypothesize that a combinatorial therapy comprising preconditioning to mild aerobic treadmill exercise and supplementation with nanocurcumin formulation (NCF) consisting of nanocurcumin (NC) and pyrroloquinoline quinone (PQQ) might improve cardiac adaptation at high altitudes. Adult Sprague-Dawley rats pre-conditioned to treadmill exercise and supplemented with NCF were exposed to cHH (7620 m altitude corresponding to pO2~8% at 28±2°C, relative humidity 55%±1%) for 3 weeks. The rat hearts were analyzed for changes in markers of oxidative stress (free radical leakage, lipid peroxidation, manganese-superoxide dismutase [MnSOD] activity), cardiac injury (circulating cardiac troponin I [TnI] and T [cTnT], myocardial creatine kinase [CK-MB]), metabolic damage (lactate dehydrogenase [LDH] and acetyl-coenzyme A levels, lactate and pyruvate levels) and bio-energetic insufficiency (ATP, p-AMPKα). Significant modulations (p≤0.05) in cardiac redox status, metabolic damage, cardiac injury and bio-energetics were observed in rats receiving both NCF supplementation and treadmill exercise-preconditioning compared with rats receiving only one of the treatments. The combinatorial therapeutic strategy showed a tremendous improvement in cardiac acclimatization to cHH compared to either exercise-preconditioning or NCF supplementation alone which was evident from the effective modulation in redox, metabolic, contractile and bio-energetic homeostasis.

Mitochondrial lipids in neurodegeneration.

PubMed

Aufschnaiter, Andreas; Kohler, Verena; Diessl, Jutta; Peselj, Carlotta; Carmona-Gutierrez, Didac; Keller, Walter; Büttner, Sabrina

2017-01-01

Mitochondrial dysfunction is a common feature of many neurodegenerative diseases, including proteinopathies such as Alzheimer's or Parkinson's disease, which are characterized by the deposition of aggregated proteins in the form of insoluble fibrils or plaques. The distinct molecular processes that eventually result in mitochondrial dysfunction during neurodegeneration are well studied but still not fully understood. However, defects in mitochondrial fission and fusion, mitophagy, oxidative phosphorylation and mitochondrial bioenergetics have been linked to cellular demise. These processes are influenced by the lipid environment within mitochondrial membranes as, besides membrane structure and curvature, recruitment and activity of different proteins also largely depend on the respective lipid composition. Hence, the interaction of neurotoxic proteins with certain lipids and the modification of lipid composition in different cell compartments, in particular mitochondria, decisively impact cell death associated with neurodegeneration. Here, we discuss the relevance of mitochondrial lipids in the pathological alterations that result in neuronal demise, focussing on proteinopathies.

Coenzyme Q(10) , endothelial function, and cardiovascular disease.

PubMed

Littarru, Gian Paolo; Tiano, Luca; Belardinelli, Romualdo; Watts, Gerald F

2011-01-01

Since the time a precise role of coenzyme Q(10) (CoQ(10) ) in myocardial bioenergetics was established, the involvement of CoQ in the pathophysiology of heart failure was hypothesized. This provided the rationale for numerous clinical trials of CoQ(10) as adjunctive treatment for heart failure. A mild hypotensive effect of CoQ was reported in the early years of clinical use of this compound. We review early human and animal studies on the vascular effects of CoQ. We then focus on endothelial dysfunction in type 2 diabetes and the possible impact on this condition of antioxidants and nutritional supplements, and in particular the therapeutic effects of CoQ. The effect of CoQ(10) on endothelial dysfunction in ischemic heart disease is also reviewed together with recent data highlighting that treatment with CoQ(10) increases extracellular SOD activity. Copyright © 2011 International Union of Biochemistry and Molecular Biology, Inc.

The chicken or the egg: mitochondrial dysfunction as a cause or consequence of toxicity in Huntington’s disease

DOE PAGES

Polyzos, Aris A.; McMurray, Cynthia T.

2016-09-12

Mitochondrial dysfunction and ensuing oxidative damage is typically thought to be a primary cause of Huntington's disease, Alzheimer's disease, and Parkinson disease. There is little doubt that mitochondria (MT) become defective as neurons die, yet whether MT defects are the primary cause or a detrimental consequence of toxicity remains unanswered. Oxygen consumption rate (OCR) and glycolysis provide sensitive and informative measures of the functional status MT and the cells metabolic regulation, yet these measures differ depending on the sample source; species, tissue type, age at measurement, and whether MT are measured in purified form or in a cell. The effectsmore » of these various parameters are difficult to quantify and not fully understood, but clearly have an impact on interpreting the bioenergetics of MT or their failure in disease states. A major goal of the review is to discuss issues and coalesce detailed information into a reference table to help in assessing mitochondrial dysfunction as a cause or consequence of Huntington's disease.« less

Melatonin and human mitochondrial diseases

PubMed Central

Sharafati-Chaleshtori, Reza; Shirzad, Hedayatollah; Rafieian-Kopaei, Mahmoud; Soltani, Amin

2017-01-01

Mitochondrial dysfunction is one of the main causative factors in a wide variety of complications such as neurodegenerative disorders, ischemia/reperfusion, aging process, and septic shock. Decrease in respiratory complex activity, increase in free radical production, increase in mitochondrial synthase activity, increase in nitric oxide production, and impair in electron transport system and/or mitochondrial permeability are considered as the main factors responsible for mitochondrial dysfunction. Melatonin, the pineal gland hormone, is selectively taken up by mitochondria and acts as a powerful antioxidant, regulating the mitochondrial bioenergetic function. Melatonin increases the permeability of membranes and is the stimulator of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. It also acts as an inhibitor of lipoxygenase. Melatonin can cause resistance to oxidation damage by fixing the microsomal membranes. Melatonin has been shown to retard aging and inhibit neurodegenerative disorders, ischemia/reperfusion, septic shock, diabetes, cancer, and other complications related to oxidative stress. The purpose of the current study, other than introducing melatonin, was to present the recent findings on clinical effects in diseases related to mitochondrial dysfunction including diabetes, cancer, gastrointestinal diseases, and diseases related to brain function. PMID:28400824

The chicken or the egg: mitochondrial dysfunction as a cause or consequence of toxicity in Huntington’s disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Polyzos, Aris A.; McMurray, Cynthia T.

Mitochondrial dysfunction and ensuing oxidative damage is typically thought to be a primary cause of Huntington's disease, Alzheimer's disease, and Parkinson disease. There is little doubt that mitochondria (MT) become defective as neurons die, yet whether MT defects are the primary cause or a detrimental consequence of toxicity remains unanswered. Oxygen consumption rate (OCR) and glycolysis provide sensitive and informative measures of the functional status MT and the cells metabolic regulation, yet these measures differ depending on the sample source; species, tissue type, age at measurement, and whether MT are measured in purified form or in a cell. The effectsmore » of these various parameters are difficult to quantify and not fully understood, but clearly have an impact on interpreting the bioenergetics of MT or their failure in disease states. A major goal of the review is to discuss issues and coalesce detailed information into a reference table to help in assessing mitochondrial dysfunction as a cause or consequence of Huntington's disease.« less

Metabolic Plasticity in Cancer Cells: Reconnecting Mitochondrial Function to Cancer Control

PubMed Central

Ramanujan, V. Krishnan

2015-01-01

Anomalous increase in glycolytic activity defines one of the key metabolic alterations in cancer cells. A realization of this feature has led to critical advancements in cancer detection techniques such as positron emission tomography (PET) as well as a number of therapeutic avenues targeting the key glycolytic steps within a cancer cell. A normal healthy cell’s survival relies on a sensitive balance between the primordial glycolysis and a more regulated mitochondrial bioenergetics. The salient difference between these two bioenergetics pathways is that oxygen availability is an obligatory requirement for mitochondrial pathway while glycolysis can function without oxygen. Early observations that some cancer cells up-regulate glycolytic activity even in the presence of oxygen (aerobic glycolysis) led to a hypothesis that such an altered cancer cell metabolism stems from inherent mitochondrial dysfunction. While a general validity of this hypothesis is still being debated, a number of recent research efforts have yielded clarity on the physiological origins of this aerobic glycolysis phenotype in cancer cells. Building on these recent studies, we present a generalized scheme of cancer cell metabolism and propose a novel hypothesis that might rationalize new avenues of cancer intervention. PMID:26457230

Brain cortex mitochondrial bioenergetics in synaptosomes and non-synaptic mitochondria during aging.

PubMed

Lores-Arnaiz, Silvia; Lombardi, Paulina; Karadayian, Analía G; Orgambide, Federico; Cicerchia, Daniela; Bustamante, Juanita

2016-02-01

Alterations in mitochondrial bioenergetics have been associated with brain aging. In order to evaluate the susceptibility of brain cortex synaptosomes and non-synaptic mitochondria to aging-dependent dysfunction, male Swiss mice of 3 or 17 months old were used. Mitochondrial function was evaluated by oxygen consumption, mitochondrial membrane potential and respiratory complexes activity, together with UCP-2 protein expression. Basal respiration and respiration driving proton leak were decreased by 26 and 33 % in synaptosomes from 17-months old mice, but spare respiratory capacity was not modified by aging. Succinate supported state 3 respiratory rate was decreased by 45 % in brain cortex non-synaptic mitochondria from 17-month-old mice, as compared with young animals, but respiratory control was not affected. Synaptosomal mitochondria would be susceptible to undergo calcium-induced depolarization in 17 months-old mice, while non-synaptic mitochondria would not be affected by calcium overload. UCP-2 was significantly up-regulated in both synaptosomal and submitochondrial membranes from 17-months old mice, compared to young animals. UCP-2 upregulation seems to be a possible mechanism by which mitochondria would be resistant to suffer oxidative damage during aging.

Simulated weightlessness - Effects on bioenergetic balance

NASA Technical Reports Server (NTRS)

Jordan, J. P.; Sykes, H. A.; Crownover, J. C.; Schatte, C. L.; Simmons, J. B., II; Jordan, D. P.

1980-01-01

As a prelude to a flight experiment, an attempt was made to separate energy requirements associated with gravity from all other metabolic needs. The biological effects of weightlessness were simulated by suspending animals in a harness so that antigravity muscles were not supporting the body. Twelve pairs of rats were allowed to adapt to wearing a harness for 5 d. Experimental animals were then suspended in harness for 7 d followed by recovery for 7 d. Control animals were harnessed but never suspended. Oxygen consumption, carbon dioxide production and rate of (C-14)O2 expiration from radio-labeled glucose were monitored on selected days. Food intake and body mass were recorded daily. Metabolic rate decreased in experimental animals during 7 d of suspension and returned to normal during recovery. Although some of the metabolic changes may have related to variation in food intake, simulated weightlessness appears to directly affect bioenergetic balance.

Remote bioenergetics measurements in wild fish: Opportunities and challenges.

PubMed

Cooke, Steven J; Brownscombe, Jacob W; Raby, Graham D; Broell, Franziska; Hinch, Scott G; Clark, Timothy D; Semmens, Jayson M

2016-12-01

The generalized energy budget for fish (i.e., Energy Consumed=Metabolism+Waste+Growth) is as relevant today as when it was first proposed decades ago and serves as a foundational concept in fish biology. Yet, generating accurate measurements of components of the bioenergetics equation in wild fish is a major challenge. How often does a fish eat and what does it consume? How much energy is expended on locomotion? How do human-induced stressors influence energy acquisition and expenditure? Generating answers to these questions is important to fisheries management and to our understanding of adaptation and evolutionary processes. The advent of electronic tags (transmitters and data loggers) has provided biologists with improved opportunities to understand bioenergetics in wild fish. Here, we review the growing diversity of electronic tags with a focus on sensor-equipped devices that are commercially available (e.g., heart rate/electrocardiogram, electromyogram, acceleration, image capture). Next, we discuss each component of the bioenergetics model, recognizing that most research to date has focused on quantifying the activity component of metabolism, and identify ways in which the other, less studied components (e.g., consumption, specific dynamic action component of metabolism, somatic growth, reproductive investment, waste) could be estimated remotely. We conclude with a critical but forward-looking appraisal of the opportunities and challenges in using existing and emerging electronic sensor-tags for the study of fish energetics in the wild. Electronic tagging has become a central and widespread tool in fish ecology and fisheries management; the growing and increasingly affordable toolbox of sensor tags will ensure this trend continues, which will lead to major advances in our understanding of fish biology over the coming decades. Copyright © 2016 Elsevier Inc. All rights reserved.

Adaptive mitochondrial reprogramming and resistance to PI3K therapy.

PubMed

Ghosh, Jagadish C; Siegelin, Markus D; Vaira, Valentina; Faversani, Alice; Tavecchio, Michele; Chae, Young Chan; Lisanti, Sofia; Rampini, Paolo; Giroda, Massimo; Caino, M Cecilia; Seo, Jae Ho; Kossenkov, Andrew V; Michalek, Ryan D; Schultz, David C; Bosari, Silvano; Languino, Lucia R; Altieri, Dario C

2015-03-01

Small molecule inhibitors of phosphatidylinositol-3 kinase (PI3K) have been developed as molecular therapy for cancer, but their efficacy in the clinic is modest, hampered by resistance mechanisms. We studied the effect of PI3K therapy in patient-derived tumor organotypic cultures (from five patient samples), three glioblastoma (GBM) tumor cell lines, and an intracranial model of glioblastoma in immunocompromised mice (n = 4-5 mice per group). Mechanisms of therapy-induced tumor reprogramming were investigated in a global metabolomics screening, analysis of mitochondrial bioenergetics and cell death, and modulation of protein phosphorylation. A high-throughput drug screening was used to identify novel preclinical combination therapies with PI3K inhibitors, and combination synergy experiments were performed. All statistical methods were two-sided. PI3K therapy induces global metabolic reprogramming in tumors and promotes the recruitment of an active pool of the Ser/Thr kinase, Akt2 to mitochondria. In turn, mitochondrial Akt2 phosphorylates Ser31 in cyclophilin D (CypD), a regulator of organelle functions. Akt2-phosphorylated CypD supports mitochondrial bioenergetics and opposes tumor cell death, conferring resistance to PI3K therapy. The combination of a small-molecule antagonist of CypD protein folding currently in preclinical development, Gamitrinib, plus PI3K inhibitors (PI3Ki) reverses this adaptive response, produces synergistic anticancer activity by inducing mitochondrial apoptosis, and extends animal survival in a GBM model (vehicle: median survival = 28.5 days; Gamitrinib+PI3Ki: median survival = 40 days, P = .003), compared with single-agent treatment (PI3Ki: median survival = 32 days, P = .02; Gamitrinib: median survival = 35 days, P = .008 by two-sided unpaired t test). Small-molecule PI3K antagonists promote drug resistance by repurposing mitochondrial functions in bioenergetics and cell survival. Novel combination therapies that target mitochondrial adaptation can dramatically improve on the efficacy of PI3K therapy in the clinic. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Shilajit attenuates behavioral symptoms of chronic fatigue syndrome by modulating the hypothalamic-pituitary-adrenal axis and mitochondrial bioenergetics in rats.

PubMed

Surapaneni, Dinesh Kumar; Adapa, Sree Rama Shiva Shanker; Preeti, Kumari; Teja, Gangineni Ravi; Veeraragavan, Muruganandam; Krishnamurthy, Sairam

2012-08-30

Shilajit has been used as a rejuvenator for ages in Indian ancient traditional medicine and has been validated for a number of pharmacological activities. The effect of processed shilajit which was standardized to dibenzo-α-pyrones (DBPs;0.43% w/w), DBP-chromoproteins (DCPs; 20.45% w/w) and fulvic acids (56.75% w/w) was evaluated in a rat model of chronic fatigue syndrome (CFS). The mitochondrial bioenergetics and the activity of hypothalamus-pituitary-adrenal (HPA) axis were evaluated for the plausible mechanism of action of shilajit. CFS was induced by forcing the rats to swim for 15mins for 21 consecutive days. The rats were treated with shilajit (25, 50 and 100mg/kg) for 21 days before exposure to stress procedure. The behavioral consequence of CFS was measured in terms of immobility and the climbing period. The post-CFS anxiety level was assessed by elevated plus maze (EPM) test. Plasma corticosterone and adrenal gland weight were estimated as indices of HPA axis activity. Analysis of mitochondrial complex chain enzymes (Complex I, II, IV and V) and mitochondrial membrane potential (MMP) in prefrontal cortex (PFC) were performed to evaluate the mitochondrial bioenergetics and integrity respectively. Shilajit reversed the CFS-induced increase in immobility period and decrease in climbing behavior as well as attenuated anxiety in the EPM test. Shilajit reversed CFS-induced decrease in plasma corticosterone level and loss of adrenal gland weight indicating modulation of HPA axis. Shilajit prevented CFS-induced mitochondrial dysfunction by stabilizing the complex enzyme activities and the loss of MMP. Shilajit reversed CFS-induced mitochondrial oxidative stress in terms of NO concentration and, LPO, SOD and catalase activities. The results indicate that shilajit mitigates the effects of CFS in this model possibly through the modulation of HPA axis and preservation of mitochondrial function and integrity. The reversal of CFS-induced behavioral symptoms and mitochondrial bioenergetics by shilajit indicates mitochondria as a potential target for treatment of CFS. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Bioenergetics in the pathogenesis, progression and treatment of cardiovascular disorders.

PubMed

Tanner, H A

1995-05-01

The aim of this manuscript is to review perturbations in bioenergetics that are redundant denominators in the diversity of factors mediating the pathogenesis and progression of coronary heart disease (CHD), congestive heart failure (CHF), hypertension and arrhythmias. This paper likewise assesses the pharmacodynamics of widely prescribed drugs that enhance cellular respiration, maintain positive inotropic, chronotropic, dromotropic cardiac effects, sustain myocardial biosynthesis, reverse the morbidity of heart disease, and assure low levels of toxicity commensurate with the agent's biocompatability. Conversely, it is essential to delineate the modality of xenobiotic drugs that inhibit energy transformations, enhance the pathogenesis of CHD, worsen survival in CHF, provoke arrhythmogenic effects, and induce serious side-effects. Documented evidence, derived from biochemical, physiological and pharmacological data sources, consistently links inhibited mitochondrial decarboxylation to aberrations in cholesterol metabolism, biosynthesis, and calcium balance. Underutilized citrates evolved from inhibited decarboxylation are degraded to acetyl CoA. The acetate is the source of steroid synthesis; its carbon atoms form the molecular basis for all endogenous cholesterol. Myocardial anoxia, a consequence of the atheromatous plaque, inhibits ATP production, impairs biosynthesis, induces negative cardiac inotropic and chronotropic effects, and enhances the pathogenesis of CHF. Inhibited decarboxylation is likewise a factor in the mobilization of in situ cardiac Ca2+, resulting in arrhythmias provoked by the cation's deficiency. The restoration of calcium homeostasis decreases peripheral vasotension, reducing hypertension. Parameters drawn from endocrinopathies and the new physiological dimension of microgravity are developed to illustrate the detrimental effect of inhibited bioenergetics on cardiac pathomorphism and cardiovascular dysfunction. In conclusion, anabolic agents, adjunctive to a productive life-style, can provide the rational basis for the prevention and treatment of cardiac diseases. Failure to understand mechanisms generating cardiovascular morbidity eventuates in ineffective and empirical treatment.

Hemorrhagic shock-induced cerebral bioenergetic imbalance is corrected by pharmacologic treatment with EF24 in a rat model.

PubMed

Rao, Geeta; Xie, Jun; Hedrick, Andria; Awasthi, Vibhudutta

2015-12-01

Maintenance of cerebral viability and function is an important goal of critical care in victims of injury due to ischemia and hypovolemia. As part of the multiple organ dysfunction syndrome, the brain function after trauma is influenced by the systemic inflammatory response. We investigated the effect of EF24, an anti-inflammatory bis-chalcone, on cerebral bioenergetics in a rat model of 45% hemorrhagic shock. The rats were treated with EF24 (0.4 mg/kg) or EF24 with an artificial oxygen carrier liposome-encapsulated hemoglobin (LEH). The volume of LEH administered was equal to the shed blood. The brain was collected after 6 h of shock for biochemical assays. EF24 treatment showed significant recovery of ATP, phosphocreatine, and NAD/NADH ratio. It also increased citrate synthase activity and cytochrome c oxidase subunit IV expression which were reduced in shock brain. Furthermore, it reduced the shock-induced accumulation of pyruvate and pyruvate dehydrogenase kinase-1 expression, suggesting that EF24 treatment improves cerebral energetics by restoring perturbed pyruvate metabolism in the mitochondria. These effects of EF24 were associated with reduced poly(ADP-ribose) polymerase cleavage and a significant improvement in the levels of nerve growth factor and brain-derived neurotrophic factor in shock brain. Co-administration of LEH with EF24 was only marginally more effective as compared to the treatment with EF24 alone. These results show that EF24 treatment sets up a pro-survival phenotype in shock by resurrecting cerebral bioenergetics. Since EF24 was effective in the absence of accompanying fluid resuscitation, it has potential utility as a pre-hospital pharmacotherapy in shock due to accidental blood loss. Copyright © 2015 Elsevier Ltd. All rights reserved.

Hyperglycemia induced damage to mitochondrial respiration in renal mesangial and tubular cells: Implications for diabetic nephropathy.

PubMed

Czajka, Anna; Malik, Afshan N

2016-12-01

Damage to renal tubular and mesangial cells is central to the development of diabetic nephropathy (DN), a complication of diabetes which can lead to renal failure. Mitochondria are the site of cellular respiration and produce energy in the form of ATP via oxidative phosphorylation, and mitochondrial dysfunction has been implicated in DN. Since the kidney is an organ with high bioenergetic needs, we postulated that hyperglycemia causes damage to renal mitochondria resulting in bioenergetic deficit. The bioenergetic profiles and the effect of hyperglycemia on cellular respiration of human primary mesangial (HMCs) and proximal tubular cells (HK-2) were compared in normoglycemic and hyperglycemic conditions using the seahorse bio-analyzer. In normoglycemia, HK-2 had significantly lower basal, ATP-linked and maximal respiration rates, and lower reserve capacity compared to HMCs. Hyperglycemia caused a down-regulation of all respiratory parameters within 4 days in HK-2 but not in HMCs. After 8 days of hyperglycemia, down-regulation of respiratory parameters persisted in tubular cells with compensatory up-regulated glycolysis. HMCs had reduced maximal respiration and reserve capacity at 8 days, and by 12 days had compromised mitochondrial respiration despite which they did not enhance glycolysis. These data suggest that diabetes is likely to lead to a cellular deficit in ATP production in both cell types, although with different sensitivities, and this mechanism could significantly contribute to the cellular damage seen in the diabetic kidney. Prevention of diabetes induced damage to renal mitochondrial respiration may be a novel therapeutic approach for the prevention/treatment of DN. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Mechanical ventilation causes pulmonary mitochondrial dysfunction and delayed alveolarization in neonatal mice.

PubMed

Ratner, Veniamin; Sosunov, Sergey A; Niatsetskaya, Zoya V; Utkina-Sosunova, Irina V; Ten, Vadim S

2013-12-01

Hyperoxia inhibits pulmonary bioenergetics, causing delayed alveolarization in mice. We hypothesized that mechanical ventilation (MV) also causes a failure of bioenergetics to support alveolarization. To test this hypothesis, neonatal mice were ventilated with room air for 8 hours (prolonged) or for 2 hours (brief) with 15 μl/g (aggressive) tidal volume (Tv), or for 8 hours with 8 μl/g (gentle) Tv. After 24 hours or 10 days of recovery, lung mitochondria were examined for adenosine diphosphate (ADP)-phosphorylating respiration, using complex I (C-I)-dependent, complex II (C-II)-dependent, or cytochrome C oxidase (C-IV)-dependent substrates, ATP production rate, and the activity of C-I and C-II. A separate cohort of mice was exposed to 2,4-dinitrophenol (DNP), a known uncoupler of oxidative phosphorylation. At 10 days of recovery, pulmonary alveolarization and the expression of vascular endothelial growth factor (VEGF) were assessed. Sham-operated littermates were used as control mice. At 24 hours after aggressive MV, mitochondrial ATP production rates and the activity of C-I and C-II were significantly decreased compared with control mice. However, at 10 days of recovery, only mice exposed to prolonged-aggressive MV continued to exhibit significantly depressed mitochondrial respiration. This was associated with significantly poorer alveolarization and VEGF expression. In contrast, mice exposed to brief-aggressive or prolonged-gentle MV exhibited restored mitochondrial ADP-phosphorylation, normal alveolarization and pulmonary VEGF content. Exposure to DNP fully replicated the phenotype consistent with alveolar developmental arrest. Our data suggest that the failure of bioenergetics to support normal lung development caused by aggressive and prolonged ventilation should be considered a fundamental mechanism for the development of bronchopulmonary dysplasia in premature neonates.

Hemorrhagic shock-induced cerebral bioenergetic imbalance is corrected by pharmacologic treatment with EF24 in a rat model

PubMed Central

Rao, Geeta; Xie, Jun; Hedrick, Andria; Awasthi, Vibhudutta

2015-01-01

Maintenance of cerebral viability and function is an important goal of critical care in victims of injury due to ischemia and hypovolemia. As part of the multiple organ dysfunction syndrome, the brain function after trauma is influenced by systemic inflammatory response. We investigated the effect of EF24, an anti-inflammatory bis-chalcone, on cerebral bioenergetics in a rat model of 45% hemorrhagic shock. The rats were treated with EF24 (0.4 mg/kg) or EF24 with an artificial oxygen carrier liposome-encapsulated hemoglobin (LEH). The volume of LEH administered was equal to the shed blood. The brain was collected after 6 h of shock for biochemical assays. EF24 treatment showed significant recovery of ATP, phosphocreatine, and NAD/NADH ratio. It also increased citrate synthase activity and cytochrome c oxidase subunit IV expression which were reduced in shock brain. Furthermore, it reduced the shock-induced accumulation of pyruvate and pyruvate dehydrogenase kinase-1 expression, suggesting that EF24 treatment improves cerebral energetics by restoring perturbed pyruvate metabolism in the mitochondria. These effects of EF24 were associated with reduced poly(ADP-ribose) polymerase cleavage and a significant improvement in the levels of nerve growth factor and brain-derived neurotrophic factor in shock brain. Co-administration of LEH with EF24 was only marginally more effective as compared to the treatment with EF24 alone. These results show that EF24 treatment sets up a pro-survival phenotype in shock by resurrecting cerebral bioenergetics. Since EF24 was effective in the absence of accompanying fluid resuscitation, it has potential utility as a pre-hospital pharmacotherapy in shock due to accidental blood loss. PMID:26232641

The c-ring stoichiometry of ATP synthase is adapted to cell physiological requirements of alkaliphilic Bacillus pseudofirmus OF4

PubMed Central

Preiss, Laura; Klyszejko, Adriana L.; Hicks, David B.; Liu, Jun; Fackelmayer, Oliver J.; Yildiz, Özkan; Krulwich, Terry A.; Meier, Thomas

2013-01-01

The c-rings of ATP synthases consist of individual c-subunits, all of which harbor a conserved motif of repetitive glycine residues (GxGxGxG) important for tight transmembrane α-helix packing. The c-ring stoichiometry determines the number of ions transferred during enzyme operation and has a direct impact on the ion-to-ATP ratio, a cornerstone parameter of cell bioenergetics. In the extreme alkaliphile Bacillus pseudofirmus OF4, the glycine motif is replaced by AxAxAxA. We performed a structural study on two mutants with alanine-to-glycine changes using atomic force microscopy and X-ray crystallography, and found that mutants form smaller c12 rings compared with the WT c13. The molar growth yields of B. pseudofirmus OF4 cells on malate further revealed that the c12 mutants have a considerably reduced capacity to grow on limiting malate at high pH. Our results demonstrate that the mutant ATP synthases with either c12 or c13 can support ATP synthesis, and also underscore the critical importance of an alanine motif with c13 ring stoichiometry for optimal growth at pH >10. The data indicate a direct connection between the precisely adapted ATP synthase c-ring stoichiometry and its ion-to-ATP ratio on cell physiology, and also demonstrate the bioenergetic challenges and evolutionary adaptation strategies of extremophiles. PMID:23613590

Transgenerational Adaptation to Pollution Changes Energy Allocation in Populations of Nematodes.

PubMed

Goussen, Benoit; Péry, Alexandre R R; Bonzom, Jean-Marc; Beaudouin, Rémy

2015-10-20

Assessing the evolutionary responses of long-term exposed populations requires multigeneration ecotoxicity tests. However, the analysis of the data from these tests is not straightforward. Mechanistic models allow the in-depth analysis of the variation of physiological traits over many generations, by quantifying the trend of the physiological and toxicological parameters of the model. In the present study, a bioenergetic mechanistic model has been used to assess the evolution of two populations of the nematode Caenorhabditis elegans in control conditions or exposed to uranium. This evolutionary pressure resulted in a brood size reduction of 60%. We showed an adaptation of individuals of both populations to experimental conditions (increase of maximal length, decrease of growth rate, decrease of brood size, and decrease of the elimination rate). In addition, differential evolution was also highlighted between the two populations once the maternal effects had been diminished after several generations. Thus, individuals that were greater in maximal length, but with apparently a greater sensitivity to uranium were selected in the uranium population. In this study, we showed that this bioenergetics mechanistic modeling approach provided a precise, certain, and powerful analysis of the life strategy of C. elegans populations exposed to heavy metals resulting in an evolutionary pressure across successive generations.

Endoplasmic reticulum: ER stress regulates mitochondrial bioenergetics

PubMed Central

Bravo, Roberto; Gutierrez, Tomás; Paredes, Felipe; Gatica, Damián; Rodriguez, Andrea E.; Pedrozo, Zully; Chiong, Mario; Parra, Valentina; Quest, Andrew F.G.; Rothermel, Beverly A.; Lavandero, Sergio

2014-01-01

Endoplasmic reticulum (ER) stress activates an adaptive unfolded protein response (UPR) that facilitates cellular repair, however, under prolonged ER stress, the UPR can ultimately trigger apoptosis thereby terminating damaged cells. The molecular mechanisms responsible for execution of the cell death program are relatively well characterized, but the metabolic events taking place during the adaptive phase of ER stress remain largely undefined. Here we discuss emerging evidence regarding the metabolic changes that occur during the onset of ER stress and how ER influences mitochondrial function through mechanisms involving calcium transfer, thereby facilitating cellular adaptation. Finally, we highlight how dysregulation of ER–mitochondrial calcium homeostasis during prolonged ER stress is emerging as a novel mechanism implicated in the onset of metabolic disorders. PMID:22064245

Mitochondrial Function in Allergic Disease.

PubMed

Iyer, Divyaanka; Mishra, Navya; Agrawal, Anurag

2017-05-01

The connections between allergy, asthma and metabolic syndrome are becoming increasingly clear. Recent research suggests a unifying mitochondrial link between the diverse phenotypes of these interlinked morbidities. The scope of this review is to highlight cellular mechanisms, epidemiology and environmental allergens influencing mitochondrial function and its importance in allergy and asthma. We briefly also consider the potential of mitochondria-targeted therapies in prevention and cure. Recent research has shown allergy, asthma and metabolic syndrome to be linked to mitochondrial dysfunction. Environmental pollutants and allergens are observed to cause mitochondrial dysfunction, primarily by inducing oxidative stress and ROS production. Malfunctioning mitochondria change the bioenergetics of the cell and its metabolic profile to favour systemic inflammation, which drives all three types of morbidities. Given the existing experimental evidence, approaches targeting mitochondria (e.g. antioxidant therapy and mitochondrial replacement) are being conducted in relevant disease models-with some progressing towards clinical trials, making mitochondrial function the focus of translational therapy research in asthma, allergy and linked metabolic syndrome.

Alkaliphilic Bacteria with Impact on Industrial Applications, Concepts of Early Life Forms, and Bioenergetics of ATP Synthesis

PubMed Central

Preiss, Laura; Hicks, David B.; Suzuki, Shino; Meier, Thomas; Krulwich, Terry Ann

2015-01-01

Alkaliphilic bacteria typically grow well at pH 9, with the most extremophilic strains growing up to pH values as high as pH 12–13. Interest in extreme alkaliphiles arises because they are sources of useful, stable enzymes, and the cells themselves can be used for biotechnological and other applications at high pH. In addition, alkaline hydrothermal vents represent an early evolutionary niche for alkaliphiles and novel extreme alkaliphiles have also recently been found in alkaline serpentinizing sites. A third focus of interest in alkaliphiles is the challenge raised by the use of proton-coupled ATP synthases for oxidative phosphorylation by non-fermentative alkaliphiles. This creates a problem with respect to tenets of the chemiosmotic model that remains the core model for the bioenergetics of oxidative phosphorylation. Each of these facets of alkaliphilic bacteria will be discussed with a focus on extremely alkaliphilic Bacillus strains. These alkaliphilic bacteria have provided a cogent experimental system to probe adaptations that enable their growth and oxidative phosphorylation at high pH. Adaptations are clearly needed to enable secreted or partially exposed enzymes or protein complexes to function at the high external pH. Also, alkaliphiles must maintain a cytoplasmic pH that is significantly lower than the pH of the outside medium. This protects cytoplasmic components from an external pH that is alkaline enough to impair their stability or function. However, the pH gradient across the cytoplasmic membrane, with its orientation of more acidic inside than outside, is in the reverse of the productive orientation for bioenergetic work. The reversed gradient reduces the trans-membrane proton-motive force available to energize ATP synthesis. Multiple strategies are hypothesized to be involved in enabling alkaliphiles to circumvent the challenge of a low bulk proton-motive force energizing proton-coupled ATP synthesis at high pH. PMID:26090360

Alkaliphilic Bacteria with Impact on Industrial Applications, Concepts of Early Life Forms, and Bioenergetics of ATP Synthesis.

PubMed

Preiss, Laura; Hicks, David B; Suzuki, Shino; Meier, Thomas; Krulwich, Terry Ann

2015-01-01

Alkaliphilic bacteria typically grow well at pH 9, with the most extremophilic strains growing up to pH values as high as pH 12-13. Interest in extreme alkaliphiles arises because they are sources of useful, stable enzymes, and the cells themselves can be used for biotechnological and other applications at high pH. In addition, alkaline hydrothermal vents represent an early evolutionary niche for alkaliphiles and novel extreme alkaliphiles have also recently been found in alkaline serpentinizing sites. A third focus of interest in alkaliphiles is the challenge raised by the use of proton-coupled ATP synthases for oxidative phosphorylation by non-fermentative alkaliphiles. This creates a problem with respect to tenets of the chemiosmotic model that remains the core model for the bioenergetics of oxidative phosphorylation. Each of these facets of alkaliphilic bacteria will be discussed with a focus on extremely alkaliphilic Bacillus strains. These alkaliphilic bacteria have provided a cogent experimental system to probe adaptations that enable their growth and oxidative phosphorylation at high pH. Adaptations are clearly needed to enable secreted or partially exposed enzymes or protein complexes to function at the high external pH. Also, alkaliphiles must maintain a cytoplasmic pH that is significantly lower than the pH of the outside medium. This protects cytoplasmic components from an external pH that is alkaline enough to impair their stability or function. However, the pH gradient across the cytoplasmic membrane, with its orientation of more acidic inside than outside, is in the reverse of the productive orientation for bioenergetic work. The reversed gradient reduces the trans-membrane proton-motive force available to energize ATP synthesis. Multiple strategies are hypothesized to be involved in enabling alkaliphiles to circumvent the challenge of a low bulk proton-motive force energizing proton-coupled ATP synthesis at high pH.

Reevaluation of a walleye (Sander vitreus) bioenergetics model

USGS Publications Warehouse

Madenjian, Charles P.; Wang, Chunfang

2013-01-01

Walleye (Sander vitreus) is an important sport fish throughout much of North America, and walleye populations support valuable commercial fisheries in certain lakes as well. Using a corrected algorithm for balancing the energy budget, we reevaluated the performance of the Wisconsin bioenergetics model for walleye in the laboratory. Walleyes were fed rainbow smelt (Osmerus mordax) in four laboratory tanks each day during a 126-day experiment. Feeding rates ranged from 1.4 to 1.7 % of walleye body weight per day. Based on a statistical comparison of bioenergetics model predictions of monthly consumption with observed monthly consumption, we concluded that the bioenergetics model estimated food consumption by walleye without any significant bias. Similarly, based on a statistical comparison of bioenergetics model predictions of weight at the end of the monthly test period with observed weight, we concluded that the bioenergetics model predicted walleye growth without any detectable bias. In addition, the bioenergetics model predictions of cumulative consumption over the 126-day experiment differed fromobserved cumulative consumption by less than 10 %. Although additional laboratory and field testing will be needed to fully evaluate model performance, based on our laboratory results, the Wisconsin bioenergetics model for walleye appears to be providing unbiased predictions of food consumption.

Mitochondria and ageing: role in heart, skeletal muscle and adipose tissue

PubMed Central

Boengler, Kerstin; Kosiol, Maik; Mayr, Manuel; Schulz, Rainer

2017-01-01

Abstract Age is the most important risk factor for most diseases. Mitochondria play a central role in bioenergetics and metabolism. In addition, several lines of evidence indicate the impact of mitochondria in lifespan determination and ageing. The best‐known hypothesis to explain ageing is the free radical theory, which proposes that cells, organs, and organisms age because they accumulate reactive oxygen species (ROS) damage over time. Mitochondria play a central role as the principle source of intracellular ROS, which are mainly formed at the level of complex I and III of the respiratory chain. Dysfunctional mitochondria generating less ATP have been observed in various aged organs. Mitochondrial dysfunction comprises different features including reduced mitochondrial content, altered mitochondrial morphology, reduced activity of the complexes of the electron transport chain, opening of the mitochondrial permeability transition pore, and increased ROS formation. Furthermore, abnormalities in mitochondrial quality control or defects in mitochondrial dynamics have also been linked to senescence. Among the tissues affected by mitochondrial dysfunction are those with a high‐energy demand and thus high mitochondrial content. Therefore, the present review focuses on the impact of mitochondria in the ageing process of heart and skeletal muscle. In this article, we review different aspects of mitochondrial dysfunction and discuss potential therapeutic strategies to improve mitochondrial function. Finally, novel aspects of adipose tissue biology and their involvement in the ageing process are discussed. PMID:28432755

Calculation of Oyster Benefits with a Bioenergetics Model of the Virginia Oyster

DTIC Science & Technology

2014-11-01

White, M., Powell. E., and Ray, S. (1988). “Effects of parasitism by the pyramidellid gastropod Boonea impressa on the net productivity of oysters...Effects of parasitism by the pyramidellid gastropod Boonea impressa on the net productivity of oysters (Crassostrea viginica),” Estuarine Coastal...Wisconsin Fish Model (Hanson et al. 1997) and was adapted for a model of Atlantic menhaden in Chesapeake Bay (Dalyander and Cerco 2010). Subsequent

cAMP and Mitochondria

PubMed Central

Valsecchi, Federica; Ramos-Espiritu, Lavoisier S.; Buck, Jochen; Levin, Lonny R.

2013-01-01

Phosphorylation of mitochondrial proteins has emerged as a major regulatory mechanism for metabolic adaptation. cAMP signaling and PKA phosphorylation of mitochondrial proteins have just started to be investigated, and the presence of cAMP-generating enzymes and PKA inside mitochondria is still controversial. Here, we discuss the role of cAMP in regulating mitochondrial bioenergetics through protein phosphorylation and the evidence for soluble adenylyl cyclase as the source of cAMP inside mitochondria. PMID:23636265

Measuring bioenergetics in T cells using a Seahorse Extracellular Flux Analyzer

PubMed Central

van der Windt, Gerritje J.W.; Chang, Chih-Hao; Pearce, Erika L.

2016-01-01

This unit contains several protocols to determine the energy utilization of T cells in real-time using a Seahorse Extracellular Flux Analyzer (www.seahorsebio.com). The advantages to using this machine over traditional metabolic assays include the simultaneous measurement of glycolysis and mitochondrial respiration, in real-time, on relatively small numbers of cells, without any radioactivity. The Basic Protocol describes a standard mitochondrial stress test on the XFe96, which yields information about oxidative phosphorylation and glycolysis, two energy-generating pathways. The alternate protocols provide examples of adaptations to the Basic Protocol, including adjustments for the use of the XFe24. A protocol for real-time bioenergetic responses to T cell activation allows for the analysis of immediate metabolic changes after T cell receptor stimulation. Specific substrate utilization can be determined by the use of differential assay media, or the injection of drugs that specifically affect certain metabolic processes. Accurate cell numbers, purity, and viability are critical to obtain reliable results. PMID:27038461

Measuring Bioenergetics in T Cells Using a Seahorse Extracellular Flux Analyzer.

PubMed

van der Windt, Gerritje J W; Chang, Chih-Hao; Pearce, Erika L

2016-04-01

This unit contains several protocols to determine the energy utilization of T cells in real-time using a Seahorse Extracellular Flux Analyzer (http://www.seahorsebio.com). The advantages to using this machine over traditional metabolic assays include the simultaneous measurement of glycolysis and mitochondrial respiration, in real-time, on relatively small numbers of cells, without any radioactivity. The Basic Protocol describes a standard mitochondrial stress test on the XF(e) 96, which yields information about oxidative phosphorylation and glycolysis, two energy-generating pathways. The alternate protocols provide examples of adaptations to the Basic Protocol, including adjustments for the use of the XF(e) 24. A protocol for real-time bioenergetic responses to T cell activation allows for the analysis of immediate metabolic changes after T cell receptor stimulation. Specific substrate utilization can be determined by the use of differential assay media, or the injection of drugs that specifically affect certain metabolic processes. Accurate cell numbers, purity, and viability are critical to obtain reliable results. Copyright © 2016 John Wiley & Sons, Inc.

Applications of bioenergetics models to fish ecology and management: where do we go from here?

USGS Publications Warehouse

Hansen, Michael J.; Boisclair, Daniel; Brandt, Stephen B.; Hewett, Steven W.; Kitchell, James F.; Lucas, Martyn C.; Ney, John J.

1993-01-01

Papers and panel discussions given during a 1992 symposium on bioenergetics models are summarized. Bioenergetics models have been applied to a variety of research and management questions related to fish stocks, populations, food webs, and ecosystems. Applications include estimates of the intensity and dynamics of predator-prey interactions, nutrient cycling within aquatic food webs of varying trophic structure, and food requirements of single animals, whole populations, and communities of fishes. As tools in food web and ecosystem applications, bioenergetics models have been used to compare forage consumption by salmonid predators across the Laurentian Great Lakes for single populations and whole communities, and to estimate the growth potential of pelagic predators in Chesapeake Bay and Lake Ontario. Some critics say that bioenergetics models lack sufficient detail to produce reliable results in such field applications, whereas others say that the models are too complex to be useful tools for fishery managers. Nevertheless, bioenergetics models have achieved notable predictive successes. Improved estimates are needed for model parameters such as metabolic costs of activity, and more complete studies are needed of the bioenergetics of larval and juvenile fishes. Future research on bioenergetics should include laboratory and field measurements of key model parameters such as weight-dependent maximum consumption, respiration and activity, and thermal habitats actually occupied by fish. Future applications of bioenergetics models to fish populations also depend on accurate estimates of population sizes and survival rates.

Déjà vu with a twist: transglutaminases in bioenergetics and transcriptional dysfunction in Huntington's disease

PubMed Central

Kazemi-Esfarjani, Parsa; La Spada, Albert R

2010-01-01

The article by McConoughey et al in the current issue of EMBO Molecular Medicine examines the contribution of transglutaminase 2 (TG2) to Huntington's disease (HD) pathogenesis. The authors find that TG2 inhibition can ameliorate HD neurodegeneration, and thereby elevate the status of transglutaminases (TGs) to a major therapeutic target—not because of their well-known activity in mutant protein aggregation, but instead based upon their ability to epigenetically modulate transcription and energy production. While the reintroduction of TG inhibition as a therapy for HD may evoke feelings of déjà vu, the outcome this time around could go in a dramatically different direction. PMID:20730854

Amino acid fermentation at the origin of the genetic code.

PubMed

de Vladar, Harold P

2012-02-10

There is evidence that the genetic code was established prior to the existence of proteins, when metabolism was powered by ribozymes. Also, early proto-organisms had to rely on simple anaerobic bioenergetic processes. In this work I propose that amino acid fermentation powered metabolism in the RNA world, and that this was facilitated by proto-adapters, the precursors of the tRNAs. Amino acids were used as carbon sources rather than as catalytic or structural elements. In modern bacteria, amino acid fermentation is known as the Stickland reaction. This pathway involves two amino acids: the first undergoes oxidative deamination, and the second acts as an electron acceptor through reductive deamination. This redox reaction results in two keto acids that are employed to synthesise ATP via substrate-level phosphorylation. The Stickland reaction is the basic bioenergetic pathway of some bacteria of the genus Clostridium. Two other facts support Stickland fermentation in the RNA world. First, several Stickland amino acid pairs are synthesised in abiotic amino acid synthesis. This suggests that amino acids that could be used as an energy substrate were freely available. Second, anticodons that have complementary sequences often correspond to amino acids that form Stickland pairs. The main hypothesis of this paper is that pairs of complementary proto-adapters were assigned to Stickland amino acids pairs. There are signatures of this hypothesis in the genetic code. Furthermore, it is argued that the proto-adapters formed double strands that brought amino acid pairs into proximity to facilitate their mutual redox reaction, structurally constraining the anticodon pairs that are assigned to these amino acid pairs. Significance tests which randomise the code are performed to study the extent of the variability of the energetic (ATP) yield. Random assignments can lead to a substantial yield of ATP and maintain enough variability, thus selection can act and refine the assignments into a proto-code that optimises the energetic yield. Monte Carlo simulations are performed to evaluate the establishment of these simple proto-codes, based on amino acid substitutions and codon swapping. In all cases, donor amino acids are assigned to anticodons composed of U+G, and have low redundancy (1-2 codons), whereas acceptor amino acids are assigned to the the remaining codons. These bioenergetic and structural constraints allow for a metabolic role for amino acids before their co-option as catalyst cofactors.

Development of a bioenergetics model for age-0 American Shad

USGS Publications Warehouse

Sauter, Sally T.

2011-01-01

Bioenergetics modeling can be used as a tool to investigate the impact of non-native age-0 American shad (Alosa sapidissima) on reservoir and estuary food webs. The model can increase our understanding of how these fish influence lower trophic levels as well as predatory fish populations that feed on juvenile salmonids. Bioenergetics modeling can be used to investigate ecological processes, evaluate alternative research hypotheses, provide decision support, and quantitative prediction. Bioenergetics modeling has proven to be extremely useful in fisheries research (Ney et al. 1993,Chips and Wahl 2008, Petersen et al. 2008). If growth and diet parameters are known, the bioenergetics model can be used to quantify the relative amount of zooplankton or insects consumed by age-0 American shad. When linked with spatial and temporal information on fish abundance, model output can guide inferential hypothesis development to demonstrate where the greatest impacts of age-0 American shad might occur.

Bioenergetics modeling is particularly useful when research questions involve multiple species and trophic levels (e.g. plankton communities). Bioenergetics models are mass-balance equations where the energy acquired from food is partitioned between maintenance costs, waste products, and growth (Winberg 1956). Specifically, the Wisconsin bioenergetics model (Hanson et al. 1997) is widely used in fisheries science. Researchers have extensively tested, reviewed, and improved on this modeling approach for over 30 years (Petersen et al. 2008). Development of a bioenergetics model for any species requires three key components: 1) determine physiological parameters for the model through laboratory experiments or incorporate data from a closely related species, 2) corroboration of the model with growth and consumption estimates from independent research, and 3) error analysis of model parameters.

Wisconsin bioenergetics models have been parameterized for many of the salmonids and predatory fishes encountered in the lower Columbia River (Petersen and Ward 1999). The Wisconsin bioenergetics model has not been developed for American shad, however Limburg (1996) parameterized a simplified bioenergetics growth model for this species. A common application for the Wisconsin bioenergetics model is to estimate the consumption or growth of a fish population under different temperature and feeding scenarios (Ney 1993). One advantage of the bioenergetics approach is that consumption can be estimated without direct field measurements of predation rate (prey·predator^-1· day^-1; Petersen and Ward 1999). Field estimates of fish consumption are time consuming and costly to determine, and estimates may show wide variance due to environmental and sampling variability. However, the consumption parameters used in a newly developed bioenergetics model must be verified with field and laboratory estimates of consumption (Ney 1993).

The objective of this research was to parameterize a Wisconsin bioenergetics model for age-0 American shad using published physiological data on American shad and closely related alosine species. The American shad bioenergetics model will be used as a tool to explore various hypotheses about how age-0 American shad directly and indirectly affect Columbia River salmon through ecological interactions in lower Columbia River food webs. One over-arching focus of the larger research project was to identify potential interactions between age-0 American shad and juvenile salmonids, addressing potential outcomes through bioenergetics modeling scenarios. This report contains two bioenergetics modeling applications to demonstrate how these models can be used to address management questions and direct research effort. The first modeling application uses the American shad bioenergetics model described in this report to explore prey consumption by age-0 American shad (Chapter 1, this report). Dietary data on age-0 American shad and previously published reports on the diet of juvenile fall Chinook salmon (Rondorf et al. 1990, USGS unpublished data) suggested there might be considerable dietary overlap between these species in the lower Columbia River. The U.S. Geological Survey (USGS) was interested in using the American shad bioenergetics model to explore hypotheses concerning dietary overlap between age-0 American shad and emigrating fall Chinook salmon. The second modeling application uses the fall Chinook salmon bioenergetics model (Koehler et al. 2006) to explore the growth potential of juvenile fall Chinook salmon predating on age-0 American shad in the lower Columbia River. This modeling was based dietary information on a small number of age-0 fall Chinook salmon (n = 13) collected in John Day Reservoir in 1994 - 1996 (unpublished USGS data). Analysis of this dietary data found that these salmonids were feeding primarily on age-0 American shad (> 75% by weight).

Effects of OXPHOS complex deficiencies and ESA dysfunction in working intact skeletal muscle: implications for mitochondrial myopathies.

PubMed

Korzeniewski, Bernard

2015-10-01

The effects of inborn oxidative phosphorylation (OXPHOS) complex deficiencies or possible each-step activation (ESA) dysfunction on the bioenergetic system in working intact skeletal muscle are studied using a computer model of OXPHOS published previously. The curves representing the dependencies of V˙O2 and metabolite concentrations on single complex activity, entire OXPHOS activity or ESA intensity exhibit a characteristic threshold at some OXPHOS complex activity/ESA intensity. This threshold for V˙O2 of single complex activities is significantly lower in intact muscle during moderate and heavy work, than in isolated mitochondria in state 3. Metabolite concentrations and pH in working muscle start to change significantly at much higher OXPHOS complex activities/ESA intensities than V˙O2. The effect of entire OXPHOS deficiency or ESA dysfunction is potentially much stronger than the effect of a single complex deficiency. Implications of these findings for the genesis of mitochondrial myopathies are discussed. It is concluded that V˙O2 in state 3 and its dependence on complex activity in isolated mitochondria is not a universal quantitative determinant of the effect of mitochondrial dysfunctions in vivo. Moderate and severe mitochondria dysfunctions are defined: the former affect significantly only metabolite concentrations and pH, while the latter also decrease significantly V˙O2 in intact skeletal muscle during work. The dysfunction-caused decrease in V˙O2/oxidative ATP synthesis flux, disturbance of metabolite homeostasis, elevated ROS production and anaerobic glycolysis recruitment can account for such mitochondrial myopathy symptoms as muscle weakness, exercise intolerance (exertional fatigue) and lactic acidosis. Copyright © 2015 Elsevier B.V. All rights reserved.

Bioenergetics modeling of percid fishes: Chapter 14

USGS Publications Warehouse

Madenjian, Charles P.; Kestemont, Patrick; Dabrowski, Konrad; Summerfelt, Robert C.

2015-01-01

A bioenergetics model for a percid fish represents a quantitative description of the fish’s energy budget. Bioenergetics modeling can be used to identify the important factors determining growth of percids in lakes, rivers, or seas. For example, bioenergetics modeling applied to yellow perch (Perca flavescens) in the western and central basins of Lake Erie revealed that the slower growth in the western basin was attributable to limitations in suitably sized prey in western Lake Erie, rather than differences in water temperature between the two basins. Bioenergetics modeling can also be applied to a percid population to estimate the amount of food being annually consumed by the percid population. For example, bioenergetics modeling applied to the walleye (Sander vitreus) population in Lake Erie has provided fishery managers valuable insights into changes in the population’s predatory demand over time. In addition, bioenergetics modeling has been used to quantify the effect of the difference in growth between the sexes on contaminant accumulation in walleye. Field and laboratory evaluations of percid bioenergetics model performance have documented a systematic bias, such that the models overestimate consumption at low feeding rates but underestimate consumption at high feeding rates. However, more recent studies have shown that this systematic bias was due, at least in part, to an error in the energy budget balancing algorithm used in the computer software. Future research work is needed to more thoroughly assess the field and laboratory performance of percid bioenergetics models and to quantify differences in activity and standard metabolic rate between the sexes of mature percids.

Platelet biomechanics, platelet bioenergetics, and applications to clinical practice and translational research.

PubMed

George, Mitchell J; Bynum, James; Nair, Prajeeda; Cap, Andrew P; Wade, Charles E; Cox, Charles S; Gill, Brijesh S

2018-07-01

The purpose of this review is to explore the relationship between platelet bioenergetics and biomechanics and how this relationship affects the clinical interpretation of platelet function devices. Recent experimental and technological advances highlight platelet bioenergetics and biomechanics as alternative avenues for collecting clinically relevant data. Platelet bioenergetics drive energy production for key biomechanical processes like adhesion, spreading, aggregation, and contraction. Platelet function devices like thromboelastography, thromboelastometry, and aggregometry measure these biomechanical processes. Platelet storage, stroke, sepsis, trauma, or the activity of antiplatelet drugs alters measures of platelet function. However, the specific mechanisms governing these alterations in platelet function and how they relate to platelet bioenergetics are still under investigation.

Inhibition of autophagy and glycolysis by nitric oxide during hypoxia-reoxygenation impairs cellular bioenergetics and promotes cell death in primary neurons.

PubMed

Benavides, Gloria A; Liang, Qiuli; Dodson, Matthew; Darley-Usmar, Victor; Zhang, Jianhua

2013-12-01

Excessive nitric oxide (NO) production is known to damage mitochondrial proteins and the autophagy repair pathway and so can potentially contribute to neurotoxicity. Accordingly, we hypothesized that protection against protein damage from reactive oxygen and nitrogen species under conditions of low oxygen by the autophagy pathway in neurons would be impaired by NO and enhance bioenergetic dysfunction. Rat primary cortical neurons had the same basal cellular respiration in hypoxia as in normoxia, whereas NO-exposed cells exhibited a gradual decrease in mitochondrial respiration in hypoxia. Upon reoxygenation, the respiration in NO-treated cells did not recover to prehypoxic levels. Hypoxia-reoxygenation in the presence of NO was associated with inhibition of autophagy, and the inability to recover during reoxygenation was exacerbated by an inhibitor of autophagy, 3-methyladenine. The effects of hypoxia could be recapitulated by inhibiting glycolytic flux under normoxic conditions. Under both normoxic and hypoxic conditions NO exposure induced immediate stimulation of glycolysis, but prolonged NO exposure, associated with irreversible inhibition of mitochondrial respiration in hypoxia, inhibited glycolysis. Importantly, we found that NO inhibited basal respiration under normoxic conditions only when glucose was absent from the medium or glycolysis was inhibited by 2-deoxy-d-glucose, revealing a novel NO-dependent mechanism for the inhibition of mitochondrial respiration that is modulated by glycolysis. Taken together these data suggest an oxygen-dependent interaction between mitochondrial respiration, glycolysis, and autophagy in protecting neuronal cells exposed to NO. Importantly, they indicate that mitochondrial dysfunction is intimately linked to a failure of glycolytic flux induced by exposure to NO. In addition, these studies provide new insights into the understanding of how autophagy and NO may play interactive roles in neuroinflammation-induced cellular damage, which is pertinent to our understanding of the pathology of neurodegenerative diseases in which excessive NO is generated. © 2013 Elsevier Inc. All rights reserved.

Mitochondrial transfer from Wharton's jelly-derived mesenchymal stem cells to mitochondria-defective cells recaptures impaired mitochondrial function.

PubMed

Lin, Hung-Yu; Liou, Chia-Wei; Chen, Shang-Der; Hsu, Te-Yao; Chuang, Jiin-Haur; Wang, Pei-Wen; Huang, Sheng-Teng; Tiao, Mao-Meng; Chen, Jin-Bor; Lin, Tsu-Kung; Chuang, Yao-Chung

2015-05-01

Adult mesenchymal stem cell (MSC)-conducted mitochondrial transfer has been recently shown to rescue cellular bioenergetics and prevent cell death caused by mitochondrial dysfunction. Wharton's jelly-derived MSCs (WJMSCs) harvested from postpartum umbilical cords are an accessible and abundant source of stem cells. This study aimed to determine the capability of WJMSCs to transfer their own mitochondria and rescue impaired oxidative phosphorylation (OXPHOS) and bioenergetics caused by mitochondrial DNA defects. To do this, WJMSCs were co-cultured with mitochondrial DNA (mtDNA)-depleted ρ(0) cells and the recapture of mitochondrial function was evaluated. WJMSCs were shown to be capable of transferring their own mitochondria into ρ(0) cells and underwent interorganellar mixture within these cells. Permissive culture media (BrdU-containing and pyruvate- and uridine-free) sieved out a survival cell population from the co-cultured WJMSCs (BrdU-sensitive) and ρ(0) cells (pyruvate/uridine-free). The survival cells had mtDNA identical to that of WJMSCs, whereas they expressed cellular markers identical to that of ρ(0) cells. Importantly, these ρ(0)-plus -WJMSC-mtDNA (ρ(+W)) cells recovered the expression of mtDNA-encoded proteins and exhibited functional oxygen consumption and respiratory control, as well as the activity of electron transport chain (ETC) complexes I, II, III and IV. In addition, ETC complex V-inhibitor-sensitive ATP production and metabolic shifting were also recovered. Furthermore, cellular behaviors including attachment-free proliferation, aerobic viability and OXPHOS-reliant cellular motility were also regained after mitochondrial transfer by WJMSCs. The therapeutic effect of WJMSCs-derived mitochondrial transfer was able to stably sustain for at least 45 passages. In conclusion, this study suggests that WJMSCs may serve as a potential therapeutic strategy for diseases linked to mitochondrial dysfunction through the donation of healthy mitochondria to cells with genetic mitochondrial defects. Copyright © 2015 Elsevier B.V. All rights reserved.

Integrated computational model of the bioenergetics of isolated lung mitochondria

PubMed Central

Zhang, Xiao; Jacobs, Elizabeth R.; Camara, Amadou K. S.; Clough, Anne V.

2018-01-01

Integrated computational modeling provides a mechanistic and quantitative framework for describing lung mitochondrial bioenergetics. Thus, the objective of this study was to develop and validate a thermodynamically-constrained integrated computational model of the bioenergetics of isolated lung mitochondria. The model incorporates the major biochemical reactions and transport processes in lung mitochondria. A general framework was developed to model those biochemical reactions and transport processes. Intrinsic model parameters such as binding constants were estimated using previously published isolated enzymes and transporters kinetic data. Extrinsic model parameters such as maximal reaction and transport velocities were estimated by fitting the integrated bioenergetics model to published and new tricarboxylic acid cycle and respirometry data measured in isolated rat lung mitochondria. The integrated model was then validated by assessing its ability to predict experimental data not used for the estimation of the extrinsic model parameters. For example, the model was able to predict reasonably well the substrate and temperature dependency of mitochondrial oxygen consumption, kinetics of NADH redox status, and the kinetics of mitochondrial accumulation of the cationic dye rhodamine 123, driven by mitochondrial membrane potential, under different respiratory states. The latter required the coupling of the integrated bioenergetics model to a pharmacokinetic model for the mitochondrial uptake of rhodamine 123 from buffer. The integrated bioenergetics model provides a mechanistic and quantitative framework for 1) integrating experimental data from isolated lung mitochondria under diverse experimental conditions, and 2) assessing the impact of a change in one or more mitochondrial processes on overall lung mitochondrial bioenergetics. In addition, the model provides important insights into the bioenergetics and respiration of lung mitochondria and how they differ from those of mitochondria from other organs. To the best of our knowledge, this model is the first for the bioenergetics of isolated lung mitochondria. PMID:29889855

Integrated computational model of the bioenergetics of isolated lung mitochondria.

PubMed

Zhang, Xiao; Dash, Ranjan K; Jacobs, Elizabeth R; Camara, Amadou K S; Clough, Anne V; Audi, Said H

2018-01-01

Integrated computational modeling provides a mechanistic and quantitative framework for describing lung mitochondrial bioenergetics. Thus, the objective of this study was to develop and validate a thermodynamically-constrained integrated computational model of the bioenergetics of isolated lung mitochondria. The model incorporates the major biochemical reactions and transport processes in lung mitochondria. A general framework was developed to model those biochemical reactions and transport processes. Intrinsic model parameters such as binding constants were estimated using previously published isolated enzymes and transporters kinetic data. Extrinsic model parameters such as maximal reaction and transport velocities were estimated by fitting the integrated bioenergetics model to published and new tricarboxylic acid cycle and respirometry data measured in isolated rat lung mitochondria. The integrated model was then validated by assessing its ability to predict experimental data not used for the estimation of the extrinsic model parameters. For example, the model was able to predict reasonably well the substrate and temperature dependency of mitochondrial oxygen consumption, kinetics of NADH redox status, and the kinetics of mitochondrial accumulation of the cationic dye rhodamine 123, driven by mitochondrial membrane potential, under different respiratory states. The latter required the coupling of the integrated bioenergetics model to a pharmacokinetic model for the mitochondrial uptake of rhodamine 123 from buffer. The integrated bioenergetics model provides a mechanistic and quantitative framework for 1) integrating experimental data from isolated lung mitochondria under diverse experimental conditions, and 2) assessing the impact of a change in one or more mitochondrial processes on overall lung mitochondrial bioenergetics. In addition, the model provides important insights into the bioenergetics and respiration of lung mitochondria and how they differ from those of mitochondria from other organs. To the best of our knowledge, this model is the first for the bioenergetics of isolated lung mitochondria.

[The mechanism of phenoptosis: 2. Hayflick limit is caused by the programmed attenuation of bioenergetics].

PubMed

Trubitsin, A G

2010-01-01

This article continues earlier started theme on a substantiation of the programmed aging mechanism (phenoptosis). The concept underlying this mechanism is that the life represents a lot of the interconnected physical and chemical processes moving by the bioenergetics. The gradual programmed decrease of the level of bioenergetics causes the slow and coordinated attenuation of all physiological functions, i.e. aging. For a convincing substantiation of such mechanism it is necessary to show, how attenuation of bioenergetics causes the basic nocuous processes accompanying aging. It is shown earlier that the age dependent decrease in level of bioenergetics causes increase in production of reactive oxygen species by mitochondria and decrease in overall level of protein synthesis. The proof that Hayflick limit is also caused by the decrease in level of bioenergetics is presented in this article. Decrease in level of bioenergetics below certain critical level deprives a cell the ability to pass the restriction point of G1-phase of proliferative cycle. The inhibitor of cyclin-dependent kinase, p27, prevents the passage through this critical point in all normal cells. During division of normal somatic cells p27 is removed by cyclin E-Cdk2 complex. Interaction p27 with cyclin E-Cdk2 complex can have two consequences. At the normal physiological level of bioenergetics the cyclin E-Cdk2 phosphorylates p27, then the latter is destroyed by proteolytic enzymes--the cell enters in S-phase. When the programme decreases the bioenergetics level below certain value the cyclin E-Cdk2 becomes the target for p27. As a result the inhibitor evacuation stops and restriction point becomes closed--a cell enters irreversible proliferative rest.

Experimental evidence that bioenergetics disruption is not mainly involved in the brain injury of glutaryl-CoA dehydrogenase deficient mice submitted to lysine overload.

PubMed

Amaral, Alexandre Umpierrez; Cecatto, Cristiane; Seminotti, Bianca; Ribeiro, César Augusto; Lagranha, Valeska Lizzi; Pereira, Carolina Coffi; de Oliveira, Francine Hehn; de Souza, Diogo Gomes; Goodman, Stephen; Woontner, Michael; Wajner, Moacir

2015-09-16

Bioenergetics dysfunction has been postulated as an important pathomechanism of brain damage in glutaric aciduria type I, but this is still under debate. We investigated activities of citric acid cycle (CAC) enzymes, lactate release, respiration and membrane potential (ΔΨm) in mitochondrial preparations from cerebral cortex and striatum of 30-day-old glutaryl-CoA dehydrogenase deficient (Gcdh-/-) and wild type mice fed a baseline or a high lysine (Lys, 4.7%) chow for 60 or 96h. Brain histological analyses were performed in these animals, as well as in 90-day-old animals fed a baseline or a high Lys chow during 30 days starting at 60-day-old. A moderate reduction of citrate synthase and isocitrate dehydrogenase activities was observed only in the striatum from 30-day-old Gcdh-/- animals submitted to a high Lys chow. In contrast, the other CAC enzyme activities, lactate release, the respiratory parameters state 3, state 4, the respiratory control ratio and CCCP-stimulated (uncoupled) state, as well as ΔΨm were not altered in the striatum. Similarly, none of the evaluated parameters were changed in the cerebral cortex from these animals under baseline or Lys overload. On the other hand, histological analyses revealed the presence of intense vacuolation in the cerebral cortex of 60 and 90-day-old Gcdh-/- mice fed a baseline chow and in the striatum of 90-day-old Gcdh-/- mice submitted to Lys overload for 30 days. Taken together, the present data demonstrate mild impairment of bioenergetics homeostasis and marked histological alterations in striatum from Gcdh-/- mice under a high Lys chow, suggesting that disruption of energy metabolism is not mainly involved in the brain injury of these animals. Copyright © 2015 Elsevier B.V. All rights reserved.

The methyl donor S-adenosylmethionine prevents liver hypoxia and dysregulation of mitochondrial bioenergetic function in a rat model of alcohol-induced fatty liver disease.

PubMed

King, Adrienne L; Mantena, Sudheer K; Andringa, Kelly K; Millender-Swain, Telisha; Dunham-Snary, Kimberly J; Oliva, Claudia R; Griguer, Corinne E; Bailey, Shannon M

2016-10-01

Mitochondrial dysfunction and bioenergetic stress play an important role in the etiology of alcoholic liver disease. Previous studies from our laboratory show that the primary methyl donor S-Adenosylmethionine (SAM) minimizes alcohol-induced disruptions in several mitochondrial functions in the liver. Herein, we expand on these earlier observations to determine whether the beneficial actions of SAM against alcohol toxicity extend to changes in the responsiveness of mitochondrial respiration to inhibition by nitric oxide (NO), induction of the mitochondrial permeability transition (MPT) pore, and the hypoxic state of the liver. For this, male Sprague-Dawley rats were pair-fed control and alcohol-containing liquid diets with and without SAM for 5 weeks and liver hypoxia, mitochondrial respiration, MPT pore induction, and NO-dependent control of respiration were examined. Chronic alcohol feeding significantly enhanced liver hypoxia, whereas SAM supplementation attenuated hypoxia in livers of alcohol-fed rats. SAM supplementation prevented alcohol-mediated decreases in mitochondrial state 3 respiration and cytochrome c oxidase activity. Mitochondria isolated from livers of alcohol-fed rats were more sensitive to calcium-mediated MPT pore induction (i.e., mitochondrial swelling) than mitochondria from pair-fed controls, whereas SAM treatment normalized sensitivity for calcium-induced swelling in mitochondria from alcohol-fed rats. Liver mitochondria from alcohol-fed rats showed increased sensitivity to NO-dependent inhibition of respiration compared with pair-fed controls. In contrast, mitochondria isolated from the livers of SAM treated alcohol-fed rats showed no change in the sensitivity to NO-mediated inhibition of respiration. Collectively, these findings indicate that the hepato-protective effects of SAM against alcohol toxicity are mediated, in part, through a mitochondrial mechanism involving preservation of key mitochondrial bioenergetic parameters and the attenuation of hypoxic stress. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Mitochondrial Dysfunction in Parkinson's Disease.

PubMed

Moon, Hyo Eun; Paek, Sun Ha

2015-06-01

Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta (SNc) with motor and nonmotor symptoms. Defective mitochondrial function and increased oxidative stress (OS) have been demonstrated as having an important role in PD pathogenesis, although the underlying mechanism is not clear. The etiopathogenesis of sporadic PD is complex with variable contributions of environmental factors and genetic susceptibility. Both these factors influence various mitochondrial aspects, including their life cycle, bioenergetic capacity, quality control, dynamic changes of morphology and connectivity (fusion, fission), subcellular distribution (transport), and the regulation of cell death pathways. Mitochondrial dysfunction has mainly been reported in various non-dopaminergic cells and tissue samples from human patients as well as transgenic mouse and fruit fly models of PD. Thus, the mitochondria represent a highly promising target for the development of PD biomarkers. However, the limited amount of dopaminergic neurons prevented investigation of their detailed study. For the first time, we established human telomerase reverse transcriptase (hTERT)-immortalized wild type, idiopathic and Parkin deficient mesenchymal stromal cells (MSCs) isolated from the adipose tissues of PD patients, which could be used as a good cellular model to evaluate mitochondrial dysfunction for the better understanding of PD pathology and for the development of early diagnostic markers and effective therapy targets of PD. In this review, we examine evidence for the roles of mitochondrial dysfunction and increased OS in the neuronal loss that leads to PD and discuss how this knowledge further improve the treatment for patients with PD.

Dysfunction of Rapid Neural Adaptation in Dyslexia.

PubMed

Perrachione, Tyler K; Del Tufo, Stephanie N; Winter, Rebecca; Murtagh, Jack; Cyr, Abigail; Chang, Patricia; Halverson, Kelly; Ghosh, Satrajit S; Christodoulou, Joanna A; Gabrieli, John D E

2016-12-21

Identification of specific neurophysiological dysfunctions resulting in selective reading difficulty (dyslexia) has remained elusive. In addition to impaired reading development, individuals with dyslexia frequently exhibit behavioral deficits in perceptual adaptation. Here, we assessed neurophysiological adaptation to stimulus repetition in adults and children with dyslexia for a wide variety of stimuli, spoken words, written words, visual objects, and faces. For every stimulus type, individuals with dyslexia exhibited significantly diminished neural adaptation compared to controls in stimulus-specific cortical areas. Better reading skills in adults and children with dyslexia were associated with greater repetition-induced neural adaptation. These results highlight a dysfunction of rapid neural adaptation as a core neurophysiological difference in dyslexia that may underlie impaired reading development. Reduced neurophysiological adaptation may relate to prior reports of reduced behavioral adaptation in dyslexia and may reveal a difference in brain functions that ultimately results in a specific reading impairment. Copyright © 2016 Elsevier Inc. All rights reserved.

Neurohormetic Phytochemicals: An Evolutionary - Bioenergetic Perspective

PubMed Central

Murugaiyah, Vikneswaran; Mattson, Mark P.

2015-01-01

The impact of dietary factors on brain health and vulnerability to disease is increasingly appreciated. The results of epidemiological studies, and intervention trials in animal models suggest that diets rich in phytochemicals can enhance neuroplasticity and resistance to neurodegeneration. Here we describe how interactions of plants and animals during their co-evolution, and resulting reciprocal adaptations, have shaped the remarkable characteristics of phytochemicals and their effects on the physiology of animal cells in general, and neurons in particular. Survival advantages were conferred upon plants capable of producing noxious bitter-tasting chemicals, and on animals able to tolerate the phytochemicals and consume the plants as an energy source. The remarkably diverse array of phytochemicals present in modern fruits, vegetables spices, tea and coffee may have arisen, in part, from the acquisition of adaptive cellular stress responses and detoxification enzymes in animals that enabled them to consume plants containing potentially toxic chemicals. Interestingly, some of the same adaptive stress response mechanisms that protect neurons against noxious phytochemicals are also activated by dietary energy restriction and vigorous physical exertion, two environmental challenges that shaped brain evolution. In this perspective article, we describe some of the signaling pathways relevant to cellular energy metabolism that are modulated by ‘neurohormetic phytochemicals’ (potentially toxic chemicals produced by plants that have beneficial effects on animals when consumed in moderate amounts). We highlight the cellular bioenergetics-related sirtuin, adenosine monophosphate activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and insulin-like growth factor 1 (IGF-1) pathways. The inclusion of dietary neurohormetic phytochemicals in an overall program for brain health that also includes exercise and energy restriction may find applications in the prevention and treatment of a range of neurological disorders. PMID:25861940

Neurohormetic phytochemicals: An evolutionary-bioenergetic perspective.

PubMed

Murugaiyah, Vikneswaran; Mattson, Mark P

2015-10-01

The impact of dietary factors on brain health and vulnerability to disease is increasingly appreciated. The results of epidemiological studies, and intervention trials in animal models suggest that diets rich in phytochemicals can enhance neuroplasticity and resistance to neurodegeneration. Here we describe how interactions of plants and animals during their co-evolution, and resulting reciprocal adaptations, have shaped the remarkable characteristics of phytochemicals and their effects on the physiology of animal cells in general, and neurons in particular. Survival advantages were conferred upon plants capable of producing noxious bitter-tasting chemicals, and on animals able to tolerate the phytochemicals and consume the plants as an energy source. The remarkably diverse array of phytochemicals present in modern fruits, vegetables spices, tea and coffee may have arisen, in part, from the acquisition of adaptive cellular stress responses and detoxification enzymes in animals that enabled them to consume plants containing potentially toxic chemicals. Interestingly, some of the same adaptive stress response mechanisms that protect neurons against noxious phytochemicals are also activated by dietary energy restriction and vigorous physical exertion, two environmental challenges that shaped brain evolution. In this perspective article, we describe some of the signaling pathways relevant to cellular energy metabolism that are modulated by 'neurohormetic phytochemicals' (potentially toxic chemicals produced by plants that have beneficial effects on animals when consumed in moderate amounts). We highlight the cellular bioenergetics-related sirtuin, adenosine monophosphate activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and insulin-like growth factor 1 (IGF-1) pathways. The inclusion of dietary neurohormetic phytochemicals in an overall program for brain health that also includes exercise and energy restriction may find applications in the prevention and treatment of a range of neurological disorders. Published by Elsevier Ltd.

Muscle Bioenergetic Considerations for Intrinsic Laryngeal Skeletal Muscle Physiology

ERIC Educational Resources Information Center

Sandage, Mary J.; Smith, Audrey G.

2017-01-01

Purpose: Intrinsic laryngeal skeletal muscle bioenergetics, the means by which muscles produce fuel for muscle metabolism, is an understudied aspect of laryngeal physiology with direct implications for voice habilitation and rehabilitation. The purpose of this review is to describe bioenergetic pathways identified in limb skeletal muscle and…

Downregulation of the expression of mitochondrial electron transport complex genes in autism brains.

PubMed

Anitha, Ayyappan; Nakamura, Kazuhiko; Thanseem, Ismail; Matsuzaki, Hideo; Miyachi, Taishi; Tsujii, Masatsugu; Iwata, Yasuhide; Suzuki, Katsuaki; Sugiyama, Toshiro; Mori, Norio

2013-05-01

Mitochondrial dysfunction (MtD) and abnormal brain bioenergetics have been implicated in autism, suggesting possible candidate genes in the electron transport chain (ETC). We compared the expression of 84 ETC genes in the post-mortem brains of autism patients and controls. Brain tissues from the anterior cingulate gyrus, motor cortex, and thalamus of autism patients (n = 8) and controls (n = 10) were obtained from Autism Tissue Program, USA. Quantitative real-time PCR arrays were used to quantify gene expression. We observed reduced expression of several ETC genes in autism brains compared to controls. Eleven genes of Complex I, five genes each of Complex III and Complex IV, and seven genes of Complex V showed brain region-specific reduced expression in autism. ATP5A1 (Complex V), ATP5G3 (Complex V) and NDUFA5 (Complex I) showed consistently reduced expression in all the brain regions of autism patients. Upon silencing ATP5A1, the expression of mitogen-activated protein kinase 13 (MAPK13), a p38 MAPK responsive to stress stimuli, was upregulated in HEK 293 cells. This could have been induced by oxidative stress due to impaired ATP synthesis. We report new candidate genes involved in abnormal brain bioenergetics in autism, supporting the hypothesis that mitochondria, critical for neurodevelopment, may play a role in autism. © 2012 The Authors; Brain Pathology © 2012 International Society of Neuropathology.

Physical and sporting activities improve vestibular afferent usage and balance in elderly human subjects.

PubMed

Gauchard, G C; Jeandel, C; Perrin, P P

2001-01-01

Ageing is associated with a reduction in balance, in particular through dysfunction of each level of postural control, which results in an increased risk of falling. Conversely, the practice of physical activities has been shown to modulate postural control in elderly people. This study examined the potential positive effects of two types of regular physical and sporting activities on vestibular information and their relation to posture. Gaze and postural stabilisation was evaluated by caloric and rotational vestibular tests on 18 healthy subjects over the age of 60 who regularly practised low-energy or bioenergetic physical activities and on 18 controls of a similar age who only walked on a regular basis. These subjects were also submitted to static and dynamic posturographic tests. The control group displayed less balance control, with a lower vestibular sensitivity and a relatively high dependency on vision compared to the group practising low-energy physical activities, which had better postural control with good vestibular sensitivity and less dependency on vision. The postural control and vestibular sensitivity of subjects practising bioenergetic activities was average, and required higher visual afferent contribution. Low-energy exercises, already shown to have the most positive impact on balance control by relying more on proprioception, also appear to develop or maintain a high level of vestibular sensitivity allowing elderly people practising such exercises to reduce the weight of vision. Copyright 2001 S. Karger AG, Basel

Rewiring of embryonic glucose metabolism via suppression of PFK-1 and aldolase during mouse chorioallantoic branching

PubMed Central

Sugiura, Yuki; Honda, Kurara; Kondo, Koki; Miura, Masayuki

2017-01-01

Adapting the energy metabolism state to changing bioenergetic demands is essential for mammalian development accompanying massive cell proliferation and cell differentiation. However, it remains unclear how developing embryos meet the changing bioenergetic demands during the chorioallantoic branching (CB) stage, when the maternal-fetal exchange of gases and nutrients is promoted. In this study, using metabolome analysis with mass-labeled glucose, we found that developing embryos redirected glucose carbon flow into the pentose phosphate pathway via suppression of the key glycolytic enzymes PFK-1 and aldolase during CB. Concomitantly, embryos exhibited an increase in lactate pool size and in the fractional contribution of glycolysis to lactate biosynthesis. Imaging mass spectrometry visualized lactate-rich tissues, such as the dorsal or posterior neural tube, somites and head mesenchyme. Furthermore, we found that the heterochronic gene Lin28a could act as a regulator of the metabolic changes observed during CB. Perturbation of glucose metabolism rewiring by suppressing Lin28a downregulation resulted in perinatal lethality. Thus, our work demonstrates that developing embryos rewire glucose metabolism following CB for normal development. PMID:28049690

Laboratory evaluation of a walleye (Sander vitreus) bioenergetics model

USGS Publications Warehouse

Madenjian, C.P.; Wang, C.; O'Brien, T. P.; Holuszko, M.J.; Ogilvie, L.M.; Stickel, R.G.

2010-01-01

Walleye (Sander vitreus) is an important game fish throughout much of North America. We evaluated the performance of the Wisconsin bioenergetics model for walleye in the laboratory. Walleyes were fed rainbow smelt (Osmerus mordax) in four laboratory tanks during a 126-day experiment. Based on a statistical comparison of bioenergetics model predictions of monthly consumption with the observed monthly consumption, we concluded that the bioenergetics model significantly underestimated food consumption by walleye in the laboratory. The degree of underestimation appeared to depend on the feeding rate. For the tank with the lowest feeding rate (1.4% of walleye body weight per day), the agreement between the bioenergetics model prediction of cumulative consumption over the entire 126-day experiment and the observed cumulative consumption was remarkably close, as the prediction was within 0.1% of the observed cumulative consumption. Feeding rates in the other three tanks ranged from 1.6% to 1.7% of walleye body weight per day, and bioenergetics model predictions of cumulative consumption over the 126-day experiment ranged between 11 and 15% less than the observed cumulative consumption. ?? 2008 Springer Science+Business Media B.V.

Bioenergetics in ecosystems

USGS Publications Warehouse

Madenjian, Charles P.; Farrell, Anthony P.

2011-01-01

A bioenergetics model for a fish can be defined as a quantitative description of the fish’s energy budget. Bioenergetics modeling can be applied to a fish population in a lake, river, or ocean to estimate the annual consumption of food by the fish population; such applications have proved to be useful in managing fisheries. In addition, bioenergetics models have been used to better understand fish growth and consumption in ecosystems, to determine the importance of the role of fish in cycling nutrients within ecosystems, and to identify the important factors regulating contaminant accumulation in fish from lakes, rivers, and oceans.

Development of a bioenergetics model for age-0 American Shad

USGS Publications Warehouse

Sauter, Sally T.

2011-01-01

Bioenergetics modeling can be used as a tool to investigate the impact of non-native age-0 American shad (Alosa sapidissima) on reservoir and estuary food webs. The model can increase our understanding of how these fish influence lower trophic levels as well as predatory fish populations that feed on juvenile salmonids. Bioenergetics modeling can be used to investigate ecological processes, evaluate alternative research hypotheses, provide decision support, and quantitative prediction. Bioenergetics modeling has proven to be extremely useful in fisheries research (Ney et al. 1993,Chips and Wahl 2008, Petersen et al. 2008). If growth and diet parameters are known, the bioenergetics model can be used to quantify the relative amount of zooplankton or insects consumed by age-0 American shad. When linked with spatial and temporal information on fish abundance, model output can guide inferential hypothesis development to demonstrate where the greatest impacts of age-0 American shad might occur.

Amino acid fermentation at the origin of the genetic code

PubMed Central

2012-01-01

There is evidence that the genetic code was established prior to the existence of proteins, when metabolism was powered by ribozymes. Also, early proto-organisms had to rely on simple anaerobic bioenergetic processes. In this work I propose that amino acid fermentation powered metabolism in the RNA world, and that this was facilitated by proto-adapters, the precursors of the tRNAs. Amino acids were used as carbon sources rather than as catalytic or structural elements. In modern bacteria, amino acid fermentation is known as the Stickland reaction. This pathway involves two amino acids: the first undergoes oxidative deamination, and the second acts as an electron acceptor through reductive deamination. This redox reaction results in two keto acids that are employed to synthesise ATP via substrate-level phosphorylation. The Stickland reaction is the basic bioenergetic pathway of some bacteria of the genus Clostridium. Two other facts support Stickland fermentation in the RNA world. First, several Stickland amino acid pairs are synthesised in abiotic amino acid synthesis. This suggests that amino acids that could be used as an energy substrate were freely available. Second, anticodons that have complementary sequences often correspond to amino acids that form Stickland pairs. The main hypothesis of this paper is that pairs of complementary proto-adapters were assigned to Stickland amino acids pairs. There are signatures of this hypothesis in the genetic code. Furthermore, it is argued that the proto-adapters formed double strands that brought amino acid pairs into proximity to facilitate their mutual redox reaction, structurally constraining the anticodon pairs that are assigned to these amino acid pairs. Significance tests which randomise the code are performed to study the extent of the variability of the energetic (ATP) yield. Random assignments can lead to a substantial yield of ATP and maintain enough variability, thus selection can act and refine the assignments into a proto-code that optimises the energetic yield. Monte Carlo simulations are performed to evaluate the establishment of these simple proto-codes, based on amino acid substitutions and codon swapping. In all cases, donor amino acids are assigned to anticodons composed of U+G, and have low redundancy (1-2 codons), whereas acceptor amino acids are assigned to the the remaining codons. These bioenergetic and structural constraints allow for a metabolic role for amino acids before their co-option as catalyst cofactors. Reviewers: this article was reviewed by Prof. William Martin, Prof. Eörs Szathmáry (nominated by Dr. Gáspár Jékely) and Dr. Ádám Kun (nominated by Dr. Sandor Pongor) PMID:22325238

Disruption of mitochondrial function as mechanism for anti-cancer activity of a novel mitochondriotropic menadione derivative.

PubMed

Teixeira, José; Amorim, Ricardo; Santos, Katia; Soares, Pedro; Datta, Sandipan; Cortopassi, Gino A; Serafim, Teresa L; Sardão, Vilma A; Garrido, Jorge; Borges, Fernanda; Oliveira, Paulo J

2018-01-15

Menadione, also known as vitamin K 3 , is a 2-methyl-1,4 naphthoquinone with a potent cytotoxic activity mainly resulting from its quinone redox-cycling with production of reactive oxygen species (ROS). Although increased ROS generation is considered a relevant mechanism in cancer cell death, it may not be sufficiently effective to kill cancer cells due to phenotypic adaptations. Therefore, combining ROS-generating agents with other molecules targeting important cancer cell phenotypes can be an effective therapeutic strategy. As mitochondrial dysfunction has been implicated in many human diseases, including cancer, we describe here the discovery of a mitochondrial-directed agent (MitoK 3 ), which was developed by conjugating a TPP cation to the C3 position of the menadione's naphthoquinone ring, increasing its selective accumulation in mitochondria, as well as led to alterations of its redox properties and consequent biological outcome. MitoK 3 disturbed the mitochondrial bioenergetic apparatus, with subsequent loss of mitochondrial ATP production. The combinatory strategy of MitoK 3 with anticancer agent doxorubicin (DOX) resulted in a degree of cytotoxicity higher than those of the individual molecules, as the combination triggered tumour apoptotic cell death evident by caspase 3/9 activities, probably through mitochondrial destabilization or by interference with mitochondrial redox processes. The results of this investigation support the importance of drug discovery process in developing molecules that can be use as adjuvant therapy in patients with specific cancer subtypes. Copyright © 2017 Elsevier B.V. All rights reserved.

Inositol trisphosphate receptor-mediated Ca2+ signalling stimulates mitochondrial function and gene expression in core myopathy patients.

PubMed

Suman, Matteo; Sharpe, Jenny A; Bentham, Robert B; Kotiadis, Vassilios N; Menegollo, Michela; Pignataro, Viviana; Molgó, Jordi; Muntoni, Francesco; Duchen, Michael R; Pegoraro, Elena; Szabadkai, Gyorgy

2018-07-01

Core myopathies are a group of childhood muscle disorders caused by mutations of the ryanodine receptor (RyR1), the Ca2+ release channel of the sarcoplasmic reticulum. These mutations have previously been associated with elevated inositol trisphosphate receptor (IP3R) levels in skeletal muscle myotubes derived from patients. However, the functional relevance and the relationship of IP3R mediated Ca2+ signalling with the pathophysiology of the disease is unclear. It has also been suggested that mitochondrial dysfunction underlies the development of central and diffuse multi-mini-cores, devoid of mitochondrial activity, which is a key pathological consequence of RyR1 mutations. Here we used muscle biopsies of central core and multi-minicore disease patients with RyR1 mutations, as well as cellular and in vivo mouse models of the disease to characterize global cellular and mitochondrial Ca2+ signalling, mitochondrial function and gene expression associated with the disease. We show that RyR1 mutations that lead to the depletion of the channel are associated with increased IP3-mediated nuclear and mitochondrial Ca2+ signals and increased mitochondrial activity. Moreover, western blot and microarray analysis indicated enhanced mitochondrial biogenesis at the transcriptional and protein levels and was reflected in increased mitochondrial DNA content. The phenotype was recapitulated by RYR1 silencing in mouse cellular myotube models. Altogether, these data indicate that remodelling of skeletal muscle Ca2+ signalling following loss of functional RyR1 mediates bioenergetic adaptation.

Prospects for therapeutic mitochondrial transplantation.

PubMed

Gollihue, Jenna L; Rabchevsky, Alexander G

2017-07-01

Mitochondrial dysfunction has been implicated in a multitude of diseases and pathological conditions- the organelles that are essential for life can also be major players in contributing to cell death and disease. Because mitochondria are so well established in our existence, being present in all cell types except for red blood cells and having the responsibility of providing most of our energy needs for survival, then dysfunctional mitochondria can elicit devastating cellular pathologies that can be widespread across the entire organism. As such, the field of "mitochondrial medicine" is emerging in which disease states are being targeted therapeutically at the level of the mitochondrion, including specific antioxidants, bioenergetic substrate additions, and membrane uncoupling agents. New and compelling research investigating novel techniques for mitochondrial transplantation to replace damaged or dysfunctional mitochondria with exogenous healthy mitochondria has shown promising results, including tissue sparing accompanied by increased energy production and decreased oxidative damage. Various experimental techniques have been attempted and each has been challenged to accomplish successful transplantation. The purpose of this review is to present the history of mitochondrial transplantation, the different techniques used for both in vitro and in vivo delivery, along with caveats and pitfalls that have been discovered along the way. Results from such pioneering studies are promising and could be the next big wave of "mitochondrial medicine" once technical hurdles are overcome. Copyright © 2017 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

Reevaluation of lake trout and lake whitefish bioenergetics models

USGS Publications Warehouse

Madenjian, Charles P.; Pothoven, Steve A.; Kao, Yu-Chun

2013-01-01

Using a corrected algorithm for balancing the energy budget, we reevaluated the Wisconsin bioenergetics model for lake trout (Salvelinus namaycush) in the laboratory and for lake whitefish (Coregonus clupeaformis) in the laboratory and in the field. For lake trout, results showed that the bioenergetics model slightly overestimated food consumption by the lake trout when they were fed low and intermediate rations, whereas the model predicted food consumption by lake trout fed ad libitum without any detectable bias. The slight bias in model predictions for lake trout on restricted rations may have been an artifact of the feeding schedule for these fish, and we would therefore recommend application of the Wisconsin lake trout bioenergetics model to lake trout populations in the field without any revisions to the model. Use of the Wisconsin bioenergetics model for coregonids resulted in overestimation of food consumption by lake whitefish both in the laboratory and in the field by between 20 and 30%, on average. This overestimation of food consumption was most likely due to overestimation of respiration rate. We therefore adjusted the respiration component of the bioenergetics model to obtain a good fit to the observed consumption in our laboratory tanks. The adjusted model predicted the consumption in the laboratory and the field without any detectable bias. Until a detailed lake whitefish respiration study can be conducted, we recommend application of our adjusted version of the Wisconsin generalized coregonid bioenergetics model to lake whitefish populations in the field.

Tafenoquine, an Antiplasmodial 8-Aminoquinoline, Targets Leishmania Respiratory Complex III and Induces Apoptosis ▿

PubMed Central

Carvalho, Luis; Luque-Ortega, Juan Román; Manzano, José Ignacio; Castanys, Santiago; Rivas, Luis; Gamarro, Francisco

2010-01-01

Tafenoquine (TFQ), an 8-aminoquinoline analogue of primaquine, which is currently under clinical trial (phase IIb/III) for the treatment and prevention of malaria, may represent an alternative treatment for leishmaniasis. In this work, we have studied the mechanism of action of TFQ against Leishmania parasites. TFQ impaired the overall bioenergetic metabolism of Leishmania promastigotes, causing a rapid drop in intracellular ATP levels without affecting plasma membrane permeability. TFQ induced mitochondrial dysfunction through the inhibition of cytochrome c reductase (respiratory complex III) with a decrease in the oxygen consumption rate and depolarization of mitochondrial membrane potential. This was accompanied by ROS production, elevation of intracellular Ca2+ levels and concomitant nuclear DNA fragmentation. We conclude that TFQ targets Leishmania mitochondria, leading to an apoptosis-like death process. PMID:20837758

Tafenoquine, an antiplasmodial 8-aminoquinoline, targets leishmania respiratory complex III and induces apoptosis.

PubMed

Carvalho, Luis; Luque-Ortega, Juan Román; Manzano, José Ignacio; Castanys, Santiago; Rivas, Luis; Gamarro, Francisco

2010-12-01

Tafenoquine (TFQ), an 8-aminoquinoline analogue of primaquine, which is currently under clinical trial (phase IIb/III) for the treatment and prevention of malaria, may represent an alternative treatment for leishmaniasis. In this work, we have studied the mechanism of action of TFQ against Leishmania parasites. TFQ impaired the overall bioenergetic metabolism of Leishmania promastigotes, causing a rapid drop in intracellular ATP levels without affecting plasma membrane permeability. TFQ induced mitochondrial dysfunction through the inhibition of cytochrome c reductase (respiratory complex III) with a decrease in the oxygen consumption rate and depolarization of mitochondrial membrane potential. This was accompanied by ROS production, elevation of intracellular Ca(2+) levels and concomitant nuclear DNA fragmentation. We conclude that TFQ targets Leishmania mitochondria, leading to an apoptosis-like death process.

Modelling and interpreting fish bioenergetics: a role for behaviour, life-history traits and survival trade-offs

PubMed Central

Jørgensen, C; Enberg, K; Mangel, M

2016-01-01

Bioenergetics is used as the mechanistic foundation of many models of fishes. As the context of a model gradually extends beyond pure bioenergetics to include behaviour, life-history traits and function and performance of the entire organism, so does the need for complementing bioenergetic measurements with trade-offs, particularly those dealing with survival. Such a broadening of focus revitalized and expanded the domain of behavioural ecology in the 1980s. This review makes the case that a similar change of perspective is required for physiology to contribute to the types of predictions society currently demands, e.g. regarding climate change and other anthropogenic stressors. PMID:26768979

Bioenergetics of the Archaea

PubMed Central

Schäfer, Günter; Engelhard, Martin; Müller, Volker

1999-01-01

In the late 1970s, on the basis of rRNA phylogeny, Archaea (archaebacteria) was identified as a distinct domain of life besides Bacteria (eubacteria) and Eucarya. Though forming a separate domain, archaea display an enormous diversity of lifestyles and metabolic capabilities. Many archaeal species are adapted to extreme environments with respect to salinity, temperatures around the boiling point of water, and/or extremely alkaline or acidic pH. This has posed the challenge of studying the molecular and mechanistic bases on which these organisms can cope with such adverse conditions. This review considers our cumulative knowledge on archaeal mechanisms of primary energy conservation, in relationship to those of bacteria and eucarya. Although the universal principle of chemiosmotic energy conservation also holds for Archaea, distinct features have been discovered with respect to novel ion-transducing, membrane-residing protein complexes and the use of novel cofactors in bioenergetics of methanogenesis. From aerobically respiring archaea, unusual electron-transporting supercomplexes could be isolated and functionally resolved, and a proposal on the organization of archaeal electron transport chains has been presented. The unique functions of archaeal rhodopsins as sensory systems and as proton or chloride pumps have been elucidated on the basis of recent structural information on the atomic scale. Whereas components of methanogenesis and of phototrophic energy transduction in halobacteria appear to be unique to archaea, respiratory complexes and the ATP synthase exhibit some chimeric features with respect to their evolutionary origin. Nevertheless, archaeal ATP synthases are to be considered distinct members of this family of secondary energy transducers. A major challenge to future investigations is the development of archaeal genetic transformation systems, in order to gain access to the regulation of bioenergetic systems and to overproducers of archaeal membrane proteins as a prerequisite for their crystallization. PMID:10477309

Age- and Brain Region-Specific Differences in Mitochondrial Bioenergetics in Brown Norway Rats

EPA Pesticide Factsheets

Differences in various mitochondrial bioenergetics parameters in different brain regions in different age groups.This dataset is associated with the following publication:Pandya, J.D., J. Royland , R.C. McPhail, P.G. Sullivan, and P. Kodavanti. Age-and Brain Region-Specific Differences in Mitochondrial Bioenergetics in Brown Norway Rats. NEUROBIOLOGY OF AGING. Elsevier Science Ltd, New York, NY, USA, 42: 25-34, (2016).

A cannabinoid link between mitochondria and memory.

PubMed

Hebert-Chatelain, Etienne; Desprez, Tifany; Serrat, Román; Bellocchio, Luigi; Soria-Gomez, Edgar; Busquets-Garcia, Arnau; Pagano Zottola, Antonio Christian; Delamarre, Anna; Cannich, Astrid; Vincent, Peggy; Varilh, Marjorie; Robin, Laurie M; Terral, Geoffrey; García-Fernández, M Dolores; Colavita, Michelangelo; Mazier, Wilfrid; Drago, Filippo; Puente, Nagore; Reguero, Leire; Elezgarai, Izaskun; Dupuy, Jean-William; Cota, Daniela; Lopez-Rodriguez, Maria-Luz; Barreda-Gómez, Gabriel; Massa, Federico; Grandes, Pedro; Bénard, Giovanni; Marsicano, Giovanni

2016-11-24

Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces amnesia in humans and animals, and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB 1 ) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB 1 receptors. Genetic exclusion of CB 1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB 1 receptors signal through intra-mitochondrial Gα i protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects of cannabinoids. Thus, the G protein-coupled mtCB 1 receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.

Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis.

PubMed

Andrabi, Shaida A; Umanah, George K E; Chang, Calvin; Stevens, Daniel A; Karuppagounder, Senthilkumar S; Gagné, Jean-Philippe; Poirier, Guy G; Dawson, Valina L; Dawson, Ted M

2014-07-15

Excessive poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) activation kills cells via a cell-death process designated "parthanatos" in which PAR induces the mitochondrial release and nuclear translocation of apoptosis-inducing factor to initiate chromatinolysis and cell death. Accompanying the formation of PAR are the reduction of cellular NAD(+) and energetic collapse, which have been thought to be caused by the consumption of cellular NAD(+) by PARP-1. Here we show that the bioenergetic collapse following PARP-1 activation is not dependent on NAD(+) depletion. Instead PARP-1 activation initiates glycolytic defects via PAR-dependent inhibition of hexokinase, which precedes the NAD(+) depletion in N-methyl-N-nitroso-N-nitroguanidine (MNNG)-treated cortical neurons. Mitochondrial defects are observed shortly after PARP-1 activation and are mediated largely through defective glycolysis, because supplementation of the mitochondrial substrates pyruvate and glutamine reverse the PARP-1-mediated mitochondrial dysfunction. Depleting neurons of NAD(+) with FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, does not alter glycolysis or mitochondrial function. Hexokinase, the first regulatory enzyme to initiate glycolysis by converting glucose to glucose-6-phosphate, contains a strong PAR-binding motif. PAR binds to hexokinase and inhibits hexokinase activity in MNNG-treated cortical neurons. Preventing PAR formation with PAR glycohydrolase prevents the PAR-dependent inhibition of hexokinase. These results indicate that bioenergetic collapse induced by overactivation of PARP-1 is caused by PAR-dependent inhibition of glycolysis through inhibition of hexokinase.

Loss of Pink1 modulates synaptic mitochondrial bioenergetics in the rat striatum prior to motor symptoms: concomitant complex I respiratory defects and increased complex II-mediated respiration.

PubMed

Stauch, Kelly L; Villeneuve, Lance M; Purnell, Phillip R; Ottemann, Brendan M; Emanuel, Katy; Fox, Howard S

2016-12-01

Mutations in PTEN-induced putative kinase 1 (Pink1), a mitochondrial serine/threonine kinase, cause a recessive inherited form of Parkinson's disease (PD). Pink1 deletion in rats results in a progressive PD-like phenotype, characterized by significant motor deficits starting at 4 months of age. Despite the evidence of mitochondrial dysfunction, the pathogenic mechanism underlying disease due to Pink1-deficiency remains obscure. Striatal synaptic mitochondria from 3-month-old Pink1-deficient rats were characterized using bioenergetic and mass spectroscopy (MS)-based proteomic analyses. Striatal synaptic mitochondria from Pink1-deficient rats exhibit decreased complex I-driven respiration and increased complex II-mediated respiration compared with wild-type rats. MS-based proteomics revealed 69 of the 811 quantified mitochondrial proteins were differentially expressed between Pink1-deficient rats and controls. Down-regulation of several electron carrier proteins, which shuttle electrons to reduce ubiquinone at complex III, in the Pink1-knockouts suggests disruption of the linkage between fatty acid, amino acid, and choline metabolism and the mitochondrial respiratory system. These results suggest that complex II activity is increased to compensate for loss of electron transfer mechanisms due to reduced complex I activity and loss of electron carriers within striatal nerve terminals early during disease progression. This may contribute to the pathogenesis of PD. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Metagenomic study of red biofilms from Diamante Lake reveals ancient arsenic bioenergetics in haloarchaea.

PubMed

Rascovan, Nicolás; Maldonado, Javier; Vazquez, Martín P; Eugenia Farías, María

2016-02-01

Arsenic metabolism is proposed to be an ancient mechanism in microbial life. Different bacteria and archaea use detoxification processes to grow under high arsenic concentration. Some of them are also able to use arsenic as a bioenergetic substrate in either anaerobic arsenate respiration or chemolithotrophic growth on arsenite. However, among the archaea, bioenergetic arsenic metabolism has only been found in the Crenarchaeota phylum. Here we report the discovery of haloarchaea (Euryarchaeota phylum) biofilms forming under the extreme environmental conditions such as high salinity, pH and arsenic concentration at 4589 m above sea level inside a volcano crater in Diamante Lake, Argentina. Metagenomic analyses revealed a surprisingly high abundance of genes used for arsenite oxidation (aioBA) and respiratory arsenate reduction (arrCBA) suggesting that these haloarchaea use arsenic compounds as bioenergetics substrates. We showed that several haloarchaea species, not only from this study, have all genes required for these bioenergetic processes. The phylogenetic analysis of aioA showed that haloarchaea sequences cluster in a novel and monophyletic group, suggesting that the origin of arsenic metabolism in haloarchaea is ancient. Our results also suggest that arsenite chemolithotrophy likely emerged within the archaeal lineage. Our results give a broad new perspective on the haloarchaea metabolism and shed light on the evolutionary history of arsenic bioenergetics.

Application of a bioenergetics model for hatchery production: Largemouth bass fed commercial diets

USGS Publications Warehouse

Csargo, Isak J.; Michael L. Brown,; Chipps, Steven R.

2012-01-01

Fish bioenergetics models based on natural prey items have been widely used to address research and management questions. However, few attempts have been made to evaluate and apply bioenergetics models to hatchery-reared fish receiving commercial feeds that contain substantially higher energy densities than natural prey. In this study, we evaluated a bioenergetics model for age-0 largemouth bass Micropterus salmoidesreared on four commercial feeds. Largemouth bass (n ≈ 3,504) were reared for 70 d at 25°C in sixteen 833-L circular tanks connected in parallel to a recirculation system. Model performance was evaluated using error components (mean, slope, and random) derived from decomposition of the mean square error obtained from regression of observed on predicted values. Mean predicted consumption was only 8.9% lower than mean observed consumption and was similar to error rates observed for largemouth bass consuming natural prey. Model evaluation showed that the 97.5% joint confidence region included the intercept of 0 (−0.43 ± 3.65) and slope of 1 (1.08 ± 0.20), which indicates the model accurately predicted consumption. Moreover model error was similar among feeds (P = 0.98), and most error was probably attributable to sampling error (unconsumed feed), underestimated predator energy densities, or consumption-dependent error, which is common in bioenergetics models. This bioenergetics model could provide a valuable tool in hatchery production of largemouth bass. Furthermore, we believe that bioenergetics modeling could be useful in aquaculture production, particularly for species lacking historical hatchery constants or conventional growth models.

The bioenergetic signature of isogenic colon cancer cells predicts the cell death response to treatment with 3-bromopyruvate, iodoacetate or 5-fluorouracil.

PubMed

Sánchez-Aragó, María; Cuezva, José M

2011-02-08

Metabolic reprogramming resulting in enhanced glycolysis is a phenotypic trait of cancer cells, which is imposed by the tumor microenvironment and is linked to the down-regulation of the catalytic subunit of the mitochondrial H+-ATPase (β-F1-ATPase). The bioenergetic signature is a protein ratio (β-F1-ATPase/GAPDH), which provides an estimate of glucose metabolism in tumors and serves as a prognostic indicator for cancer patients. Targeting energetic metabolism could be a viable alternative to conventional anticancer chemotherapies. Herein, we document that the bioenergetic signature of isogenic colon cancer cells provides a gauge to predict the cell-death response to the metabolic inhibitors, 3-bromopyruvate (3BrP) and iodoacetate (IA), and the anti-metabolite, 5-fluorouracil (5-FU). The bioenergetic signature of the cells was determined by western blotting. Aerobic glycolysis was determined from lactate production rates. The cell death was analyzed by fluorescence microscopy and flow cytometry. Cellular ATP concentrations were determined using bioluminiscence. Pearson's correlation coefficient was applied to assess the relationship between the bioenergetic signature and the cell death response. In vivo tumor regression activities of the compounds were assessed using a xenograft mouse model injected with the highly glycolytic HCT116 colocarcinoma cells. We demonstrate that the bioenergetic signature of isogenic HCT116 cancer cells inversely correlates with the potential to execute necrosis in response to 3BrP or IA treatment. Conversely, the bioenergetic signature directly correlates with the potential to execute apoptosis in response to 5-FU treatment in the same cells. However, despite the large differences observed in the in vitro cell-death responses associated with 3BrP, IA and 5-FU, the in vivo tumor regression activities of these agents were comparable. Overall, we suggest that the determination of the bioenergetic signature of colon carcinomas could provide a tool for predicting the therapeutic response to various chemotherapeutic strategies aimed at combating tumor progression.

Early Immune Function and Duration of Organ Dysfunction in Critically Ill Septic Children.

PubMed

Muszynski, Jennifer A; Nofziger, Ryan; Moore-Clingenpeel, Melissa; Greathouse, Kristin; Anglim, Larissa; Steele, Lisa; Hensley, Josey; Hanson-Huber, Lisa; Nateri, Jyotsna; Ramilo, Octavio; Hall, Mark W

2018-02-22

Late immune suppression is associated with nosocomial infection and mortality in septic adults and children. Relationships between early immune suppression and outcomes in septic children remain unclear. Prospective observational study to test the hypothesis that early innate and adaptive immune suppression are associated with longer duration of organ dysfunction in children with severe sepsis/septic shock. Methods, Measurements and Main Results: Children aged < 18 years meeting consensus criteria for severe sepsis or septic shock were sampled within 48 hours of sepsis onset. Healthy controls were sampled once. Innate immune function was quantified by whole blood ex vivo lipopolysaccharide-induced TNFα production capacity. Adaptive immune function was quantified by ex vivo phytohemagglutinin-induced IFNγ production capacity. 102 septic children and 35 healthy children were enrolled. Compared to healthy children, septic children demonstrated lower LPS-induced TNFα production (p < 0.0001) and lower PHA-induced IFNγ production (p<0.0001). Among septic children, early innate and adaptive immune suppression were associated with greater number of days with multiple organ dysfunction (MODS) and greater number of days with any organ dysfunction. On multivariable analyses, early innate immune suppression remained independently associated with increased MODS days [aRR 1.2 (1.03, 1.5)] and organ dysfunction days [aRR 1.2 (1.1, 1.3)]. Critically ill children with severe sepsis or septic shock demonstrate early innate and adaptive immune suppression. Early suppression of both innate and adaptive immunity are associated with longer duration of organ dysfunction and may be useful markers to guide investigations of immunomodulatory therapies in septic children.

Adaptation of Microplate-based Respirometry for Hippocampal Slices and Analysis of Respiratory Capacity

PubMed Central

Schuh, Rosemary A.; Clerc, Pascaline; Hwang, Hyehyun; Mehrabian, Zara; Bittman, Kevin; Chen, Hegang; Polster, Brian M.

2011-01-01

Multiple neurodegenerative disorders are associated with altered mitochondrial bioenergetics. Although mitochondrial O2 consumption is frequently measured in isolated mitochondria, isolated synaptic nerve terminals (synaptosomes), or cultured cells, the absence of mature brain circuitry is a remaining limitation. Here we describe the development of a method that adapts the Seahorse Extracellular Flux Analyzer (XF24) for the microplate-based measurement of hippocampal slice O2 consumption. As a first evaluation of the technique, we compared whole slice bioenergetics to previous measurements made with synaptosomes or cultured neurons. We found that mitochondrial respiratory capacity and O2 consumption coupled to ATP synthesis could be estimated in cultured or acute hippocampal slices with preserved neural architecture. Mouse organotypic hippocampal slices oxidizing glucose displayed mitochondrial O2 consumption that was well-coupled, as determined by the sensitivity to the ATP synthase inhibitor oligomycin. However stimulation of respiration by uncoupler was modest (<120% of basal respiration) compared to previous measurements in cells or synaptosomes, although enhanced slightly (to ~150% of basal respiration) by the acute addition of the mitochondrial complex I-linked substrate pyruvate. These findings suggest a high basal utilization of respiratory capacity in slices and a limitation of glucose-derived substrate for maximal respiration. The improved throughput of microplate-based hippocampal respirometry over traditional O2 electrode-based methods is conducive to neuroprotective drug screening. When coupled with cell type-specific pharmacology or genetic manipulations, the ability to efficiently measure O2 consumption from whole slices should advance our understanding of mitochondrial roles in physiology and neuropathology. PMID:21520220

Yeast mitochondria: an overview of mitochondrial biology and the potential of mitochondrial systems biology.

PubMed

Malina, Carl; Larsson, Christer; Nielsen, Jens

2018-08-01

Mitochondria are dynamic organelles of endosymbiotic origin that are essential components of eukaryal cells. They contain their own genetic machinery, have multicopy genomes and like their bacterial ancestors they consist of two membranes. However, the majority of the ancestral genome has been lost or transferred to the nuclear genome of the host, preserving only a core set of genes involved in oxidative phosphorylation. Mitochondria perform numerous biological tasks ranging from bioenergetics to production of protein co-factors, including heme and iron-sulfur clusters. Due to the importance of mitochondria in many cellular processes, mitochondrial dysfunction is implicated in a wide variety of human disorders. Much of our current knowledge on mitochondrial function and dysfunction comes from studies using Saccharomyces cerevisiae. This yeast has good fermenting capacity, rendering tolerance to mutations that inactivate oxidative phosphorylation and complete loss of mitochondrial DNA. Here, we review yeast mitochondrial metabolism and function with focus on S. cerevisiae and its contribution in understanding mitochondrial biology. We further review how systems biology studies, including mathematical modeling, has allowed gaining new insight into mitochondrial function, and argue that this approach may enable us to gain a holistic view on how mitochondrial function interacts with different cellular processes.

The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes

PubMed Central

Indrieri, Alessia; Conte, Ivan; Chesi, Giancarlo; Romano, Alessia; Quartararo, Jade; Tatè, Rosarita; Ghezzi, Daniele; Zeviani, Massimo; Goffrini, Paola; Ferrero, Ileana; Bovolenta, Paola; Franco, Brunella

2013-01-01

Mitochondrial-dependent (intrinsic) programmed cell death (PCD) is an essential homoeostatic mechanism that selects bioenergetically proficient cells suitable for tissue/organ development. However, the link between mitochondrial dysfunction, intrinsic apoptosis and developmental anomalies has not been demonstrated to date. Now we provide the evidence that non-canonical mitochondrial-dependent apoptosis explains the phenotype of microphthalmia with linear skin lesions (MLS), an X-linked developmental disorder caused by mutations in the holo-cytochrome c-type synthase (HCCS) gene. By taking advantage of a medaka model that recapitulates the MLS phenotype we demonstrate that downregulation of hccs, an essential player of the mitochondrial respiratory chain (MRC), causes increased cell death via an apoptosome-independent caspase-9 activation in brain and eyes. We also show that the unconventional activation of caspase-9 occurs in the mitochondria and is triggered by MRC impairment and overproduction of reactive oxygen species (ROS). We thus propose that HCCS plays a key role in central nervous system (CNS) development by modulating a novel non-canonical start-up of cell death and provide the first experimental evidence for a mechanistic link between mitochondrial dysfunction, intrinsic apoptosis and developmental disorders. PMID:23239471

Investigation of Mitochondrial Dysfunction by Sequential Microplate-Based Respiration Measurements from Intact and Permeabilized Neurons

PubMed Central

Clerc, Pascaline; Polster, Brian M.

2012-01-01

Mitochondrial dysfunction is a component of many neurodegenerative conditions. Measurement of oxygen consumption from intact neurons enables evaluation of mitochondrial bioenergetics under conditions that are more physiologically realistic compared to isolated mitochondria. However, mechanistic analysis of mitochondrial function in cells is complicated by changing energy demands and lack of substrate control. Here we describe a technique for sequentially measuring respiration from intact and saponin-permeabilized cortical neurons on single microplates. This technique allows control of substrates to individual electron transport chain complexes following permeabilization, as well as side-by-side comparisons to intact cells. To illustrate the utility of the technique, we demonstrate that inhibition of respiration by the drug KB-R7943 in intact neurons is relieved by delivery of the complex II substrate succinate, but not by complex I substrates, via acute saponin permeabilization. In contrast, methyl succinate, a putative cell permeable complex II substrate, failed to rescue respiration in intact neurons and was a poor complex II substrate in permeabilized cells. Sequential measurements of intact and permeabilized cell respiration should be particularly useful for evaluating indirect mitochondrial toxicity due to drugs or cellular signaling events which cannot be readily studied using isolated mitochondria. PMID:22496810

Genomic integration of ERRγ-HNF1β regulates renal bioenergetics and prevents chronic kidney disease.

PubMed

Zhao, Juanjuan; Lupino, Katherine; Wilkins, Benjamin J; Qiu, Chengxiang; Liu, Jian; Omura, Yasuhiro; Allred, Amanda L; McDonald, Caitlin; Susztak, Katalin; Barish, Grant D; Pei, Liming

2018-05-22

Mitochondrial dysfunction is increasingly recognized as a critical determinant of both hereditary and acquired kidney diseases. However, it remains poorly understood how mitochondrial metabolism is regulated to support normal kidney function and how its dysregulation contributes to kidney disease. Here, we show that the nuclear receptor estrogen-related receptor gamma (ERRγ) and hepatocyte nuclear factor 1 beta (HNF1β) link renal mitochondrial and reabsorptive functions through coordinated epigenomic programs. ERRγ directly regulates mitochondrial metabolism but cooperatively controls renal reabsorption via convergent binding with HNF1β. Deletion of ERRγ in renal epithelial cells (RECs), in which it is highly and specifically expressed, results in severe renal energetic and reabsorptive dysfunction and progressive renal failure that recapitulates phenotypes of animals and patients with HNF1β loss-of-function gene mutations. Moreover, ERRγ expression positively correlates with renal function and is decreased in patients with chronic kidney disease (CKD). REC-ERRγ KO mice share highly overlapping renal transcriptional signatures with human patients with CKD. Together these findings reveal a role for ERRγ in directing independent and HNF1β-integrated programs for energy production and use essential for normal renal function and the prevention of kidney disease.

Rewiring of embryonic glucose metabolism via suppression of PFK-1 and aldolase during mouse chorioallantoic branching.

PubMed

Miyazawa, Hidenobu; Yamaguchi, Yoshifumi; Sugiura, Yuki; Honda, Kurara; Kondo, Koki; Matsuda, Fumio; Yamamoto, Takehiro; Suematsu, Makoto; Miura, Masayuki

2017-01-01

Adapting the energy metabolism state to changing bioenergetic demands is essential for mammalian development accompanying massive cell proliferation and cell differentiation. However, it remains unclear how developing embryos meet the changing bioenergetic demands during the chorioallantoic branching (CB) stage, when the maternal-fetal exchange of gases and nutrients is promoted. In this study, using metabolome analysis with mass-labeled glucose, we found that developing embryos redirected glucose carbon flow into the pentose phosphate pathway via suppression of the key glycolytic enzymes PFK-1 and aldolase during CB. Concomitantly, embryos exhibited an increase in lactate pool size and in the fractional contribution of glycolysis to lactate biosynthesis. Imaging mass spectrometry visualized lactate-rich tissues, such as the dorsal or posterior neural tube, somites and head mesenchyme. Furthermore, we found that the heterochronic gene Lin28a could act as a regulator of the metabolic changes observed during CB. Perturbation of glucose metabolism rewiring by suppressing Lin28a downregulation resulted in perinatal lethality. Thus, our work demonstrates that developing embryos rewire glucose metabolism following CB for normal development. © 2017. Published by The Company of Biologists Ltd.

Genome Analysis of Structure–Function Relationships in Respiratory Complex I, an Ancient Bioenergetic Enzyme

PubMed Central

Degli Esposti, Mauro

2016-01-01

Respiratory complex I (NADH:ubiquinone oxidoreductase) is a ubiquitous bioenergetic enzyme formed by over 40 subunits in eukaryotes and a minimum of 11 subunits in bacteria. Recently, crystal structures have greatly advanced our knowledge of complex I but have not clarified the details of its reaction with ubiquinone (Q). This reaction is essential for bioenergy production and takes place in a large cavity embedded within a conserved module that is homologous to the catalytic core of Ni–Fe hydrogenases. However, how a hydrogenase core has evolved into the protonmotive Q reductase module of complex I has remained unclear. This work has exploited the abundant genomic information that is currently available to deduce structure–function relationships in complex I that indicate the evolutionary steps of Q reactivity and its adaptation to natural Q substrates. The results provide answers to fundamental questions regarding various aspects of complex I reaction with Q and help re-defining the old concept that this reaction may involve two Q or inhibitor sites. The re-definition leads to a simplified classification of the plethora of complex I inhibitors while throwing a new light on the evolution of the enzyme function. PMID:26615219

Adaptive Inferential Feedback Partner Training for Depression: A Pilot Study

ERIC Educational Resources Information Center

Dobkin, Roseanne DeFronzo; Allen, Lesley A.; Alloy, Lauren B.; Menza, Matthew; Gara, Michael A.; Panzarella, Catherine

2007-01-01

Adaptive inferential feedback (AIF) partner training is a cognitive technique that teaches the friends and family members of depressed patients to respond to the patients' dysfunctional thoughts in a targeted manner. These dysfunctional attributions, which AIF addresses, are a common residual feature of depression amongst remitted patients, and…

Evaluation of a lake whitefish bioenergetics model

USGS Publications Warehouse

Madenjian, Charles P.; O'Connor, Daniel V.; Pothoven, Steven A.; Schneeberger, Philip J.; Rediske, Richard R.; O'Keefe, James P.; Bergstedt, Roger A.; Argyle, Ray L.; Brandt, Stephen B.

2006-01-01

We evaluated the Wisconsin bioenergetics model for lake whitefish Coregonus clupeaformis in the laboratory and in the field. For the laboratory evaluation, lake whitefish were fed rainbow smelt Osmerus mordax in four laboratory tanks during a 133-d experiment. Based on a comparison of bioenergetics model predictions of lake whitefish food consumption and growth with observed consumption and growth, we concluded that the bioenergetics model furnished significantly biased estimates of both food consumption and growth. On average, the model overestimated consumption by 61% and underestimated growth by 16%. The source of the bias was probably an overestimation of the respiration rate. We therefore adjusted the respiration component of the bioenergetics model to obtain a good fit of the model to the observed consumption and growth in our laboratory tanks. Based on the adjusted model, predictions of food consumption over the 133-d period fell within 5% of observed consumption in three of the four tanks and within 9% of observed consumption in the remaining tank. We used polychlorinated biphenyls (PCBs) as a tracer to evaluate model performance in the field. Based on our laboratory experiment, the efficiency with which lake whitefish retained PCBs from their food (I?) was estimated at 0.45. We applied the bioenergetics model to Lake Michigan lake whitefish and then used PCB determinations of both lake whitefish and their prey from Lake Michigan to estimate p in the field. Application of the original model to Lake Michigan lake whitefish yielded a field estimate of 0.28, implying that the original formulation of the model overestimated consumption in Lake Michigan by 61%. Application of the bioenergetics model with the adjusted respiration component resulted in a field I? estimate of 0.56, implying that this revised model underestimated consumption by 20%.

No consistent bioenergetic defects in presynaptic nerve terminals isolated from mouse models of Alzheimer’s disease

PubMed Central

Choi, Sung W.; Gerencser, Akos A.; Ng, Ryan; Flynn, James M.; Melov, Simon; Danielson, Steven R.; Gibson, Bradford W.; Nicholls, David G.; Bredesen, Dale E.; Brand, Martin D.

2012-01-01

Depressed cortical energy supply and impaired synaptic function are predominant associations of Alzheimer’s disease (AD). To test the hypothesis that presynaptic bioenergetic deficits are associated with the progression of AD pathogenesis, we compared bioenergetic variables of cortical and hippocampal presynaptic nerve terminals (synaptosomes) from commonly used mouse models with AD-like phenotypes (J20 age 6 months, Tg2576 age 16 months and APP/PS age 9 and 14 months) to age-matched controls. No consistent bioenergetic deficiencies were detected in synaptosomes from the three models, only APP/PS cortical synaptosomes from 14 month old mice showed an increase in respiration associated with proton leak. J20 mice were chosen for a highly stringent investigation of mitochondrial function and content. There were no significant differences in the quality of the synaptosomal preparations or the mitochondrial volume fraction. Furthermore, respiratory variables, calcium handling, and membrane potentials of synaptosomes from symptomatic J20 mice under calcium-imposed stress were not consistently impaired. The recovery of marker proteins during synaptosome preparation was the same, ruling out the possibility that the lack of functional bioenergetic defects in synaptosomes from J20 mice was due to the selective loss of damaged synaptosomes during sample preparation. Our results support the conclusion that the intrinsic bioenergetic capacities of presynaptic nerve terminals are maintained in these symptomatic AD mouse models. PMID:23175831

Respiratory syncytial virus increases lung cellular bioenergetics in neonatal C57BL/6 mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alsuwaidi, Ahmed R., E-mail: alsuwaidia@uaeu.ac.ae; Albawardi, Alia, E-mail: alia.albawardi@uaeu.ac.ae; Almarzooqi, Saeeda, E-mail: saeeda.almarzooqi@uaeu.ac.ae

2014-04-15

We have previously reported that lung cellular bioenergetics (cellular respiration and ATP) increased in 4–10 week-old BALB/c mice infected with respiratory syncytial virus (RSV). This study examined the kinetics and changes in cellular bioenergetics in ≤2-week-old C57BL/6 mice following RSV infection. Mice (5–14 days old) were inoculated intranasally with RSV and the lungs were examined on days 1–10 post-infection. Histopathology and electron microscopy revealed preserved pneumocyte architectures and organelles. Increased lung cellular bioenergetics was noted from days 1–10 post-infection. Cellular GSH remained unchanged. These results indicate that the increased lung cellular respiration (measured by mitochondrial O{sub 2} consumption) and ATPmore » following RSV infection is independent of either age or genetic background of the host. - Highlights: • RSV infection increases lung cellular respiration and ATP in neonatal C57BL/6 mice. • Increased lung cellular bioenergetics is a biomarker of RSV infection. • Lung cellular glutathione remains unchanged in RSV infection.« less

Predation rates by North Sea cod (Gadus morhua) - Predictions from models on gastric evacuation and bioenergetics

USGS Publications Warehouse

Hansson, S.; Rudstam, L. G.; Kitchell, J.F.; Hilden, M.; Johnson, B.L.; Peppard, P.E.

1996-01-01

We compared four different methods for estimating predation rates by North Sea cod (Gadus moi hua). Three estimates, based on gastric evacuation rates, came from an ICES multispecies working group and the fourth from a bioenergetics model. The bioenergetics model was developed from a review of literature on cod physiology. The three gastric evacuation rate models produced very different prey consumption estimates for small (2 kg) fish. For most size and age classes, the bioenergetics model predicted food consumption rates intermediate to those predicted by the gastric evacuation models. Using the standard ICES model and the average population abundance and age structure for 1974-1989, annual, prey consumption by the North Sea cod population (age greater than or equal to 1) was 840 kilotons. The other two evacuation rate models produced estimates of 1020 and 1640 kilotons, respectively. The bioenergetics model estimate was 1420 kilotons. The major differences between models were due to consumption rate estimates for younger age groups of cod. (C) 1996 International Council for the Exploration of the Sea

Bone Cell Bioenergetics and Skeletal Energy Homeostasis

PubMed Central

Riddle, Ryan C.; Clemens, Thomas L.

2017-01-01

The rising incidence of metabolic diseases worldwide has prompted renewed interest in the study of intermediary metabolism and cellular bioenergetics. The application of modern biochemical methods for quantitating fuel substrate metabolism with advanced mouse genetic approaches has greatly increased understanding of the mechanisms that integrate energy metabolism in the whole organism. Examination of the intermediary metabolism of skeletal cells has been sparked by a series of unanticipated observations in genetically modified mice that suggest the existence of novel endocrine pathways through which bone cells communicate their energy status to other centers of metabolic control. The recognition of this expanded role of the skeleton has in turn led to new lines of inquiry directed at defining the fuel requirements and bioenergetic properties of bone cells. This article provides a comprehensive review of historical and contemporary studies on the metabolic properties of bone cells and the mechanisms that control energy substrate utilization and bioenergetics. Special attention is devoted to identifying gaps in our current understanding of this new area of skeletal biology that will require additional research to better define the physiological significance of skeletal cell bioenergetics in human health and disease. PMID:28202599

Chronic Obstructive Pulmonary Disease heterogeneity: challenges for health risk assessment, stratification and management.

PubMed

Roca, Josep; Vargas, Claudia; Cano, Isaac; Selivanov, Vitaly; Barreiro, Esther; Maier, Dieter; Falciani, Francesco; Wagner, Peter; Cascante, Marta; Garcia-Aymerich, Judith; Kalko, Susana; De Mas, Igor; Tegnér, Jesper; Escarrabill, Joan; Agustí, Alvar; Gomez-Cabrero, David

2014-11-28

Heterogeneity in clinical manifestations and disease progression in Chronic Obstructive Pulmonary Disease (COPD) lead to consequences for patient health risk assessment, stratification and management. Implicit with the classical "spill over" hypothesis is that COPD heterogeneity is driven by the pulmonary events of the disease. Alternatively, we hypothesized that COPD heterogeneities result from the interplay of mechanisms governing three conceptually different phenomena: 1) pulmonary disease, 2) systemic effects of COPD and 3) co-morbidity clustering, each of them with their own dynamics. To explore the potential of a systems analysis of COPD heterogeneity focused on skeletal muscle dysfunction and on co-morbidity clustering aiming at generating predictive modeling with impact on patient management. To this end, strategies combining deterministic modeling and network medicine analyses of the Biobridge dataset were used to investigate the mechanisms of skeletal muscle dysfunction. An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was performed using a large dataset (ICD9-CM data from Medicare, 13 million people). Finally, a targeted network analysis using the outcomes of the two approaches (skeletal muscle dysfunction and co-morbidity clustering) explored shared pathways between these phenomena. (1) Evidence of abnormal regulation of skeletal muscle bioenergetics and skeletal muscle remodeling showing a significant association with nitroso-redox disequilibrium was observed in COPD; (2) COPD patients presented higher risk for co-morbidity clustering than non-COPD patients increasing with ageing; and, (3) the on-going targeted network analyses suggests shared pathways between skeletal muscle dysfunction and co-morbidity clustering. The results indicate the high potential of a systems approach to address COPD heterogeneity. Significant knowledge gaps were identified that are relevant to shape strategies aiming at fostering 4P Medicine for patients with COPD.

Mitochondria-targeted nutraceuticals in sports medicine: a new perspective.

PubMed

Ostojic, Sergej M

2017-01-01

Since mitochondria have been recognized as the cells' key organelles involved in the energy utilization during exercise, targeting the organelle with specifically designed compounds (mitochondria-targeted nutraceuticals, MTNs) may have a great promise in the prevention and treatment of heavy exercise-related mitochondrial dysfunction. In vitro studies suggested that MTNs have antioxidant effects at the molecular level, and might boost mitochondrial biogenesis and organelle bioenergetics, with both processes are known to positively affect exercise performance and recovery. However, while there are a number of different MTNs evaluated for a potential benefit as a therapy for mitochondria-related diseases and conditions, only few human studies evaluated the possible impact of novel MTNs in the field of sports medicine. This mini review summarizes recent research findings regarding the efficacy of different mitochondria-targeted nutritional agents, emphasizing their roles in sports medicine.

Higher Vulnerability of Menadione-Exposed Cortical Astrocytes of Glutaryl-CoA Dehydrogenase Deficient Mice to Oxidative Stress, Mitochondrial Dysfunction, and Cell Death: Implications for the Neurodegeneration in Glutaric Aciduria Type I.

PubMed

Rodrigues, Marília Danyelle Nunes; Seminotti, Bianca; Zanatta, Ângela; de Mello Gonçalves, Aline; Bellaver, Bruna; Amaral, Alexandre Umpierrez; Quincozes-Santos, André; Goodman, Stephen Irwin; Woontner, Michael; Souza, Diogo Onofre; Wajner, Moacir

2017-08-01

Patients affected by glutaric aciduria type I (GA-I) show progressive cortical leukoencephalopathy whose pathogenesis is poorly known. In the present work, we exposed cortical astrocytes of wild-type (Gcdh +/+ ) and glutaryl-CoA dehydrogenase knockout (Gcdh -/- ) mice to the oxidative stress inducer menadione and measured mitochondrial bioenergetics, redox homeostasis, and cell viability. Mitochondrial function (MTT and JC1-mitochondrial membrane potential assays), redox homeostasis (DCFH oxidation, nitrate and nitrite production, GSH concentrations and activities of the antioxidant enzymes SOD and GPx), and cell death (propidium iodide incorporation) were evaluated in primary cortical astrocyte cultures of Gcdh +/+ and Gcdh -/- mice unstimulated and stimulated by menadione. We also measured the pro-inflammatory response (TNFα levels, IL1-β and NF-ƙB) in unstimulated astrocytes obtained from these mice. Gcdh -/- mice astrocytes were more vulnerable to menadione-induced oxidative stress (decreased GSH concentrations and altered activities of the antioxidant enzymes), mitochondrial dysfunction (decrease of MTT reduction and JC1 values), and cell death as compared with Gcdh +/+ astrocytes. A higher inflammatory response (TNFα, IL1-β and NF-ƙB) was also observed in Gcdh -/- mice astrocytes. These data indicate a higher susceptibility of Gcdh -/- cortical astrocytes to oxidative stress and mitochondrial dysfunction, probably leading to cell death. It is presumed that these pathomechanisms may contribute to the cortical leukodystrophy observed in GA-I patients.

Cardiac-specific inactivation of LPP3 in mice leads to myocardial dysfunction and heart failure.

PubMed

Chandra, Mini; Escalante-Alcalde, Diana; Bhuiyan, Md Shenuarin; Orr, Anthony Wayne; Kevil, Christopher; Morris, Andrew J; Nam, Hyung; Dominic, Paari; McCarthy, Kevin J; Miriyala, Sumitra; Panchatcharam, Manikandan

2018-04-01

Lipid Phosphate phosphatase 3 (LPP3), encoded by the Plpp3 gene, is an enzyme that dephosphorylates the bioactive lipid mediator lysophosphatidic acid (LPA). To study the role of LPP3 in the myocardium, we generated a cardiac specific Plpp3 deficient mouse strain. Although these mice were viable at birth in contrast to global Plpp3 knockout mice, they showed increased mortality ~ 8 months. LPP3 deficient mice had enlarged hearts with reduced left ventricular performance as seen by echocardiography. Cardiac specific Plpp3 deficient mice had longer ventricular effective refractory periods compared to their Plpp3 littermates. We observed that lack of Lpp3 enhanced cardiomyocyte hypertrophy based on analysis of cell surface area. We found that lack of Lpp3 signaling was mediated through the activation of Rho and phospho-ERK pathways. There are increased levels of fetal genes Natriuretic Peptide A and B (Nppa and Nppb) expression indicating myocardial dysfunction. These mice also demonstrate mitochondrial dysfunction as evidenced by a significant decrease (P < 0.001) in the basal oxygen consumption rate, mitochondrial ATP production, and spare respiratory capacity as measured through mitochondrial bioenergetics. Histology and transmission electron microscopy of these hearts showed disrupted sarcomere organization and intercalated disc, with a prominent disruption of the cristae and vacuole formation in the mitochondria. Our findings suggest that LPA/LPP3-signaling nexus plays an important role in normal function of cardiomyocytes. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Emerging (and converging) pathways in Parkinson's disease: keeping mitochondrial wellness

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cieri, Domenico; Brini, Marisa; Calì, Tito

The selective cell loss in the ventral component of the substantia nigra pars compacta and the presence of alpha-synuclein (α-syn)-rich intraneuronal inclusions called Lewy bodies are the pathological hallmarks of Parkinson's disease (PD), the most common motor system disorder whose aetiology remains largely elusive. Although most cases of PD are idiopathic, there are rare familial forms of the disease that can be traced to single gene mutations that follow Mendelian inheritance pattern. The study of several nuclear encoded proteins whose mutations are linked to the development of autosomal recessive and dominant forms of familial PD enhanced our understanding of biochemicalmore » and cellular mechanisms contributing to the disease and suggested that many signs of neurodegeneration result from compromised mitochondrial function. Here we present an overview of the current understanding of PD-related mitochondrial dysfunction including defects in bioenergetics and Ca{sup 2+} homeostasis, mitochondrial DNA mutations, altered mitochondrial dynamics and autophagy. We emphasize, in particular, the convergence of many “apparently” different pathways towards a common route involving mitochondria. Understanding whether mitochondrial dysfunction in PD represents the cause or the consequence of the disease is challenging and will help to define the pathogenic processes at the basis of the PD onset and progression. - Highlights: • Mitochondrial dysfunctions are a common feature of neurodegenerative diseases. • Many familial PD related proteins ensure mitochondrial function. • Mutations in PD genes differently affect mitochondria related activities.« less

Mitochondrial Dynamics in Diabetic Cardiomyopathy

PubMed Central

Galloway, Chad A.

2015-01-01

Abstract Significance: Cardiac function is energetically demanding, reliant on efficient well-coupled mitochondria to generate adenosine triphosphate and fulfill the cardiac demand. Predictably then, mitochondrial dysfunction is associated with cardiac pathologies, often related to metabolic disease, most commonly diabetes. Diabetic cardiomyopathy (DCM), characterized by decreased left ventricular function, arises independently of coronary artery disease and atherosclerosis. Dysregulation of Ca2+ handling, metabolic changes, and oxidative stress are observed in DCM, abnormalities reflected in alterations in mitochondrial energetics. Cardiac tissue from DCM patients also presents with altered mitochondrial morphology, suggesting a possible role of mitochondrial dynamics in its pathological progression. Recent Advances: Abnormal mitochondrial morphology is associated with pathologies across diverse tissues, suggesting that this highly regulated process is essential for proper cell maintenance and physiological homeostasis. Highly structured cardiac myofibers were hypothesized to limit alterations in mitochondrial morphology; however, recent work has identified morphological changes in cardiac tissue, specifically in DCM. Critical Issues: Mitochondrial dysfunction has been reported independently from observations of altered mitochondrial morphology in DCM. The temporal relationship and causative nature between functional and morphological changes of mitochondria in the establishment/progression of DCM is unclear. Future Directions: Altered mitochondrial energetics and morphology are not only causal for but also consequential to reactive oxygen species production, hence exacerbating oxidative damage through reciprocal amplification, which is integral to the progression of DCM. Therefore, targeting mitochondria for DCM will require better mechanistic characterization of morphological distortion and bioenergetic dysfunction. Antioxid. Redox Signal. 22, 1545–1562. PMID:25738230

Dynamic area telethermometry and its clinical applications

NASA Astrophysics Data System (ADS)

Anbar, Michael

1995-03-01

Dynamic area telethermometry (DAT) is a recent development in thermology, the science of biological heat generation and dissipation. DAT is based on monitoring changes in infrared emission, deriving from them information on the kinetics and mechanisms of biological thermoregulation. Remotely monitoring infrared emission is the most reliable technique to study bioenergetics, because it minimally perturbs the investigated system. Area monitoring of heat dissipating surfaces is needed because temporal changes in the spatial distribution of temperature conveys information on mechanisms of thermoregulation. DAT can be applied to biological systems ranging from single cells (microtelecalorimetry) to large areas of human skin (clinical thermology). DAT requires the accumulation of many (hundreds to thousands) thermal images followed by analysis of the thermokinetics of each pixel or group of pixels. In clinical thermology this analysis uses FFT to extract systemic, regional and local thermoregulatory frequencies (TRFs). DAT also extracts information on local thermoregulation from the temporal behavior of homogeneity of skin temperature (HST). Analysis of the relative contributions (FFT amplitudes) of the different frequencies allows distinction between vascular, neurological, and immunological thermoregulatory dysfunctions. This analysis, which can reveal the mechanism of the dysfunction, can be very useful in the diagnosis and staging of various disorders, ranging from diabetes mellitus and liver cirrhosis to breast cancer and malignant melanoma. From the engineering standpoint DAT requires highly stable imaging systems and effective display of the spatial distribution of TRFs to allow identification of thermoregulatory pathways and their dysfunction.

The bioenergetic signature of isogenic colon cancer cells predicts the cell death response to treatment with 3-bromopyruvate, iodoacetate or 5-fluorouracil

PubMed Central

2011-01-01

Background Metabolic reprogramming resulting in enhanced glycolysis is a phenotypic trait of cancer cells, which is imposed by the tumor microenvironment and is linked to the down-regulation of the catalytic subunit of the mitochondrial H+-ATPase (β-F1-ATPase). The bioenergetic signature is a protein ratio (β-F1-ATPase/GAPDH), which provides an estimate of glucose metabolism in tumors and serves as a prognostic indicator for cancer patients. Targeting energetic metabolism could be a viable alternative to conventional anticancer chemotherapies. Herein, we document that the bioenergetic signature of isogenic colon cancer cells provides a gauge to predict the cell-death response to the metabolic inhibitors, 3-bromopyruvate (3BrP) and iodoacetate (IA), and the anti-metabolite, 5-fluorouracil (5-FU). Methods The bioenergetic signature of the cells was determined by western blotting. Aerobic glycolysis was determined from lactate production rates. The cell death was analyzed by fluorescence microscopy and flow cytometry. Cellular ATP concentrations were determined using bioluminiscence. Pearson's correlation coefficient was applied to assess the relationship between the bioenergetic signature and the cell death response. In vivo tumor regression activities of the compounds were assessed using a xenograft mouse model injected with the highly glycolytic HCT116 colocarcinoma cells. Results We demonstrate that the bioenergetic signature of isogenic HCT116 cancer cells inversely correlates with the potential to execute necrosis in response to 3BrP or IA treatment. Conversely, the bioenergetic signature directly correlates with the potential to execute apoptosis in response to 5-FU treatment in the same cells. However, despite the large differences observed in the in vitro cell-death responses associated with 3BrP, IA and 5-FU, the in vivo tumor regression activities of these agents were comparable. Conclusions Overall, we suggest that the determination of the bioenergetic signature of colon carcinomas could provide a tool for predicting the therapeutic response to various chemotherapeutic strategies aimed at combating tumor progression. PMID:21303518

Winter to summer change in vitamin D status reduces systemic inflammation and bioenergetic activity of human peripheral blood mononuclear cells.

PubMed

Calton, Emily K; Keane, Kevin N; Raizel, Raquel; Rowlands, Jordan; Soares, Mario J; Newsholme, Philip

2017-08-01

Vitamin D status [25(OH)D] has recently been reported to be associated with altered cellular bioenergetic profiles of peripheral blood mononuclear cells (PBMCs). No study has tracked the seasonal variation of 25(OH)D and its putative influence on whole body energy metabolism, cellular bioenergetic profiles, inflammatory markers and clinical chemistry. Whole body energy metabolism and substrate utilisation were measured by indirect calorimetry. PBMCs obtained from the same subjects were isolated from whole blood, counted and freshly seeded. Bioenergetic analysis (mitochondrial stress test and glycolysis stress test) was performed using the Seahorse XF e 96 flux analyser. 25(OH)D was assessed using the Architect immunoassay method. 25(OH)D increased by a median (IQR) of 14.40 (20.13)nmol/L (p<0.001) from winter to summer and was accompanied by significant improvements in indices of insulin sensitivity, McAuley's index (p=0.019) and quantitative insulin sensitivity check index (p=0.028). PBMC mitochondrial parameters basal respiration, non-mitochondrial respiration, ATP production, proton leak, and maximal respiration decreased in summer compared to winter. Similarly, PBMC glycolytic parameters glycolytic activity, glucose response, and glycolytic capacity were all reduced in summer compared to winter. There was also a trend for absolute resting metabolic rate (RMR) to decrease (p=0.066). Markers of systemic inflammation MCP-1, IL-6, IL-8, IL-10, and IL-12p70 decreased significantly in summer compared to winter. Participants who entered winter with a low 25(OH)D (<50nmol/L), had the greatest alteration in bioenergetic parameters in summer, relative to those with winter 25(OH)D concentrations of 50-75nmol/L or >75nmol/L. The absolute change in 25(OH)D was not associated with altered bioenergetics. Seasonal improvements in 25(OH)D was associated with reduced systemic inflammation, PBMC bioenergetic profiles and whole body energy metabolism. These observational changes in PBMC bioenergetics were most pronounced in those who had insufficient 25(OH)D in winter. The data warrants confirmation through cause and effect study designs. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

The bioenergetics of inflammation: insights into obesity and type 2 diabetes.

PubMed

Keane, K N; Calton, E K; Carlessi, R; Hart, P H; Newsholme, P

2017-07-01

Diabetes mellitus is one of the most common chronic metabolic disorders worldwide, and its incidence in Asian countries is alarmingly high. Type 2 diabetes (T2DM) is closely associated with obesity, and the staggering rise in obesity is one of the primary factors related to the increased frequency of T2DM. Low-grade chronic inflammation is also accepted as an integral metabolic adaption in obesity and T2DM, and is believed to be a major player in the onset of insulin resistance. However, the exact mechanism(s) that cause a persistent chronic low-grade infiltration of leukocytes into insulin-target tissues such as adipose, skeletal muscle and liver are not entirely known. Recent developments in the understanding of leukocyte metabolism have revealed that the inflammatory polarization of immune cells, and consequently their immunological function, are strongly connected to their metabolic profile. Therefore, it is hypothesized that dysfunctional immune cell metabolism is a central cellular mechanism that prevents the resolution of inflammation in chronic metabolic conditions such as that observed in obesity and T2DM. The purpose of this review is to explore the metabolic demands of different immune cell types, and identify the molecular switches that control immune cell metabolism and ultimately function. Understanding of these concepts may allow the development of interventions that can correct immune function and may possibly decrease chronic low-grade inflammation in humans suffering from obesity and T2DM. We also review the latest clinical techniques used to measure metabolic flux in primary leukocytes isolated from obese and T2DM patients.

Modeling of Mitochondria Bioenergetics Using a Composable Chemiosmotic Energy Transduction Rate Law: Theory and Experimental Validation

PubMed Central

Chang, Ivan; Heiske, Margit; Letellier, Thierry; Wallace, Douglas; Baldi, Pierre

2011-01-01

Mitochondrial bioenergetic processes are central to the production of cellular energy, and a decrease in the expression or activity of enzyme complexes responsible for these processes can result in energetic deficit that correlates with many metabolic diseases and aging. Unfortunately, existing computational models of mitochondrial bioenergetics either lack relevant kinetic descriptions of the enzyme complexes, or incorporate mechanisms too specific to a particular mitochondrial system and are thus incapable of capturing the heterogeneity associated with these complexes across different systems and system states. Here we introduce a new composable rate equation, the chemiosmotic rate law, that expresses the flux of a prototypical energy transduction complex as a function of: the saturation kinetics of the electron donor and acceptor substrates; the redox transfer potential between the complex and the substrates; and the steady-state thermodynamic force-to-flux relationship of the overall electro-chemical reaction. Modeling of bioenergetics with this rate law has several advantages: (1) it minimizes the use of arbitrary free parameters while featuring biochemically relevant parameters that can be obtained through progress curves of common enzyme kinetics protocols; (2) it is modular and can adapt to various enzyme complex arrangements for both in vivo and in vitro systems via transformation of its rate and equilibrium constants; (3) it provides a clear association between the sensitivity of the parameters of the individual complexes and the sensitivity of the system's steady-state. To validate our approach, we conduct in vitro measurements of ETC complex I, III, and IV activities using rat heart homogenates, and construct an estimation procedure for the parameter values directly from these measurements. In addition, we show the theoretical connections of our approach to the existing models, and compare the predictive accuracy of the rate law with our experimentally fitted parameters to those of existing models. Finally, we present a complete perturbation study of these parameters to reveal how they can significantly and differentially influence global flux and operational thresholds, suggesting that this modeling approach could help enable the comparative analysis of mitochondria from different systems and pathological states. The procedures and results are available in Mathematica notebooks at http://www.igb.uci.edu/tools/sb/mitochondria-modeling.html. PMID:21931590

Piscivorous fish exhibit temperature-influenced binge feeding during an annual prey pulse.

PubMed

Furey, Nathan B; Hinch, Scott G; Mesa, Matthew G; Beauchamp, David A

2016-09-01

Understanding the limits of consumption is important for determining trophic influences on ecosystems and predator adaptations to inconsistent prey availability. Fishes have been observed to consume beyond what is sustainable (i.e. digested on a daily basis), but this phenomenon of hyperphagia (or binge-feeding) is largely overlooked. We expect hyperphagia to be a short-term (1-day) event that is facilitated by gut volume providing capacity to store consumed food during periods of high prey availability to be later digested. We define how temperature, body size and food availability influence the degree of binge-feeding by comparing field observations with laboratory experiments of bull trout (Salvelinus confluentus), a large freshwater piscivore that experiences highly variable prey pulses. We also simulated bull trout consumption and growth during salmon smolt outmigrations under two scenarios: 1) daily consumption being dependent upon bioenergetically sustainable rates and 2) daily consumption being dependent upon available gut volume (i.e. consumption is equal to gut volume when empty and otherwise 'topping off' based on sustainable digestion rates). One-day consumption by laboratory-held bull trout during the first day of feeding experiments after fasting exceeded bioenergetically sustainable rates by 12- to 87-fold at low temperatures (3 °C) and by  ˜1·3-fold at 20 °C. The degree of binge-feeding by bull trout in the field was slightly reduced but largely in agreement with laboratory estimates, especially when prey availability was extremely high [during a sockeye salmon (Oncorhynchus nerka) smolt outmigration and at a counting fence where smolts are funnelled into high densities]. Consumption by bull trout at other settings were lower and more variable, but still regularly hyperphagic. Simulations demonstrated the ability to binge-feed increased cumulative consumption (16-32%) and cumulative growth (19-110%) relative to only feeding at bioenergetically sustainable rates during the  ˜1-month smolt outmigration period. Our results indicate the ability for predators to maximize short-term consumption when prey are available can be extreme and is limited primarily by gut volume, then mediated by temperature; thus, predator-prey relationships may be more dependent upon prey availability than traditional bioenergetic models suggest. Binge-feeding has important implications for energy budgets of consumers as well as acute predation impacts on prey. © 2016 The Authors. Journal of Animal Ecology © 2016 British Ecological Society.

Piscivorous fish exhibit temperature-influenced binge feeding during an annual prey pulse

USGS Publications Warehouse

Furey, Nathan B.; Hinch, Scott G.; Mesa, Matthew G.; Beauchamp, David A.

2016-01-01

Understanding the limits of consumption is important for determining trophic influences on ecosystems and predator adaptations to inconsistent prey availability. Fishes have been observed to consume beyond what is sustainable (i.e. digested on a daily basis), but this phenomenon of hyperphagia (or binge-feeding) is largely overlooked. We expect hyperphagia to be a short-term (1-day) event that is facilitated by gut volume providing capacity to store consumed food during periods of high prey availability to be later digested.We define how temperature, body size and food availability influence the degree of binge-feeding by comparing field observations with laboratory experiments of bull trout (Salvelinus confluentus), a large freshwater piscivore that experiences highly variable prey pulses. We also simulated bull trout consumption and growth during salmon smolt outmigrations under two scenarios: 1) daily consumption being dependent upon bioenergetically sustainable rates and 2) daily consumption being dependent upon available gut volume (i.e. consumption is equal to gut volume when empty and otherwise ‘topping off’ based on sustainable digestion rates).One-day consumption by laboratory-held bull trout during the first day of feeding experiments after fasting exceeded bioenergetically sustainable rates by 12- to 87-fold at low temperatures (3 °C) and by  ˜1·3-fold at 20 °C. The degree of binge-feeding by bull trout in the field was slightly reduced but largely in agreement with laboratory estimates, especially when prey availability was extremely high [during a sockeye salmon (Oncorhynchus nerka) smolt outmigration and at a counting fence where smolts are funnelled into high densities]. Consumption by bull trout at other settings were lower and more variable, but still regularly hyperphagic.Simulations demonstrated the ability to binge-feed increased cumulative consumption (16–32%) and cumulative growth (19–110%) relative to only feeding at bioenergetically sustainable rates during the  ˜1-month smolt outmigration period.Our results indicate the ability for predators to maximize short-term consumption when prey are available can be extreme and is limited primarily by gut volume, then mediated by temperature; thus, predator–prey relationships may be more dependent upon prey availability than traditional bioenergetic models suggest. Binge-feeding has important implications for energy budgets of consumers as well as acute predation impacts on prey.

Modeling of mitochondria bioenergetics using a composable chemiosmotic energy transduction rate law: theory and experimental validation.

PubMed

Chang, Ivan; Heiske, Margit; Letellier, Thierry; Wallace, Douglas; Baldi, Pierre

2011-01-01

Mitochondrial bioenergetic processes are central to the production of cellular energy, and a decrease in the expression or activity of enzyme complexes responsible for these processes can result in energetic deficit that correlates with many metabolic diseases and aging. Unfortunately, existing computational models of mitochondrial bioenergetics either lack relevant kinetic descriptions of the enzyme complexes, or incorporate mechanisms too specific to a particular mitochondrial system and are thus incapable of capturing the heterogeneity associated with these complexes across different systems and system states. Here we introduce a new composable rate equation, the chemiosmotic rate law, that expresses the flux of a prototypical energy transduction complex as a function of: the saturation kinetics of the electron donor and acceptor substrates; the redox transfer potential between the complex and the substrates; and the steady-state thermodynamic force-to-flux relationship of the overall electro-chemical reaction. Modeling of bioenergetics with this rate law has several advantages: (1) it minimizes the use of arbitrary free parameters while featuring biochemically relevant parameters that can be obtained through progress curves of common enzyme kinetics protocols; (2) it is modular and can adapt to various enzyme complex arrangements for both in vivo and in vitro systems via transformation of its rate and equilibrium constants; (3) it provides a clear association between the sensitivity of the parameters of the individual complexes and the sensitivity of the system's steady-state. To validate our approach, we conduct in vitro measurements of ETC complex I, III, and IV activities using rat heart homogenates, and construct an estimation procedure for the parameter values directly from these measurements. In addition, we show the theoretical connections of our approach to the existing models, and compare the predictive accuracy of the rate law with our experimentally fitted parameters to those of existing models. Finally, we present a complete perturbation study of these parameters to reveal how they can significantly and differentially influence global flux and operational thresholds, suggesting that this modeling approach could help enable the comparative analysis of mitochondria from different systems and pathological states. The procedures and results are available in Mathematica notebooks at http://www.igb.uci.edu/tools/sb/mitochondria-modeling.html.

Mutations in the Caenorhabditis elegans orthologs of human genes required for mitochondrial tRNA modification cause similar electron transport chain defects but different nuclear responses.

PubMed

Navarro-González, Carmen; Moukadiri, Ismaïl; Villarroya, Magda; López-Pascual, Ernesto; Tuck, Simon; Armengod, M-Eugenia

2017-07-01

Several oxidative phosphorylation (OXPHOS) diseases are caused by defects in the post-transcriptional modification of mitochondrial tRNAs (mt-tRNAs). Mutations in MTO1 or GTPBP3 impair the modification of the wobble uridine at position 5 of the pyrimidine ring and cause heart failure. Mutations in TRMU affect modification at position 2 and cause liver disease. Presently, the molecular basis of the diseases and why mutations in the different genes lead to such different clinical symptoms is poorly understood. Here we use Caenorhabditis elegans as a model organism to investigate how defects in the TRMU, GTPBP3 and MTO1 orthologues (designated as mttu-1, mtcu-1, and mtcu-2, respectively) exert their effects. We found that whereas the inactivation of each C. elegans gene is associated with a mild OXPHOS dysfunction, mutations in mtcu-1 or mtcu-2 cause changes in the expression of metabolic and mitochondrial stress response genes that are quite different from those caused by mttu-1 mutations. Our data suggest that retrograde signaling promotes defect-specific metabolic reprogramming, which is able to rescue the OXPHOS dysfunction in the single mutants by stimulating the oxidative tricarboxylic acid cycle flux through complex II. This adaptive response, however, appears to be associated with a biological cost since the single mutant worms exhibit thermosensitivity and decreased fertility and, in the case of mttu-1, longer reproductive cycle. Notably, mttu-1 worms also exhibit increased lifespan. We further show that mtcu-1; mttu-1 and mtcu-2; mttu-1 double mutants display severe growth defects and sterility. The animal models presented here support the idea that the pathological states in humans may initially develop not as a direct consequence of a bioenergetic defect, but from the cell's maladaptive response to the hypomodification status of mt-tRNAs. Our work highlights the important association of the defect-specific metabolic rewiring with the pathological phenotype, which must be taken into consideration in exploring specific therapeutic interventions.

The energy blockers 3-bromopyruvate and lonidamine: effects on bioenergetics of brain mitochondria.

PubMed

Macchioni, Lara; Davidescu, Magdalena; Roberti, Rita; Corazzi, Lanfranco

2014-10-01

Tumor cells favor abnormal energy production via aerobic glycolysis and show resistance to apoptosis, suggesting the involvement of mitochondrial dysfunction. The differences between normal and cancer cells in their energy metabolism provide a biochemical basis for developing new therapeutic strategies. The energy blocker 3-bromopyruvate (3BP) can eradicate liver cancer in animals without associated toxicity, and is a potent anticancer towards glioblastoma cells. Since mitochondria are 3BP targets, in this work the effects of 3BP on the bioenergetics of normal rat brain mitochondria were investigated in vitro, in comparison with the anticancer agent lonidamine (LND). Whereas LND impaired oxygen consumption dependent on any complex of the respiratory chain, 3BP was inhibitory to malate/pyruvate and succinate (Complexes I and II), but preserved respiration from glycerol-3-phosphate and ascorbate (Complex IV). Accordingly, although electron flow along the respiratory chain and ATP levels were decreased by 3BP in malate/pyruvate- and succinate-fed mitochondria, they were not significantly influenced from glycerol-3-phosphate- or ascorbate-fed mitochondria. LND produced a decrease in electron flow from all substrates tested. No ROS were produced from any substrate, with the exception of 3BP-induced H(2)O(2) release from succinate, which suggests an antimycin-like action of 3BP as an inhibitor of Complex III. We can conclude that 3BP does not abolish completely respiration and ATP synthesis in brain mitochondria, and has a limited effect on ROS production, confirming that this drug may have limited harmful effects on normal cells.

Combined effects of aging and in vitro non-steroid anti-inflammatory drugs on kidney and liver mitochondrial physiology.

PubMed

Rocha-Rodrigues, Sílvia; Santos-Alves, Estela; Coxito, Pedro M; Marques-Aleixo, Inês; Passos, Emanuel; Guimarães, João T; Martins, Maria J; Oliveira, Paulo J; Magalhães, José; Ascensão, António

2013-09-03

Aging and drug-induced side effects may contribute to deteriorate mitochondrial bioenergetics in many tissues, including kidney and liver. One possibility is that the combination of both aging and drug toxicity accelerates the process of mitochondrial degradation, leading to progressive bioenergetic disruption. We therefore analyzed in vitro kidney (KM) and liver (LM) mitochondrial response to salicylate and diclofenac in old and adult animals. Male-Wistar adult (19-wks) and aged (106-wks) rats were used. In vitro endpoints of oxygen consumption and membrane potential were evaluated in non-treated conditions (vehicle) and in the presence of salicylate (0.5mM) and diclofenac (50μM). The susceptibility to calcium-induced permeability transition pore (MPTP) was assessed. Aconitase and C, -SH and MDA contents were measured. Apoptotic signaling was followed by measuring caspase 3, 8 and 9 activities, Bax, Bcl2 and CypD expression. ANT content was semi-quantified. In general, animal age alone compromised KM state 3 and LM ADP lag phase while resulting in decreased resistance to the MPTP. Aging decreased LM CypD and increased Mn-SOD. Kidney caspase 9-like activity was lower in aged group. Salicylate and diclofenac induced KM and LM dysfunction. ADP lag phase in KM was further increased in the aged group in the presence of diclofenac. No further impairments were observed regarding drug toxicity adding to the aging process. Aging impaired KM and LM function despite no detected alterations on oxidative stress and apoptosis. However, aging did not further exacerbate KM and LM frailty induced by salicylate and diclofenac. © 2013.

A high fat diet alters metabolic and bioenergetic function in the brain: A magnetic resonance spectroscopy study.

PubMed

Raider, Kayla; Ma, Delin; Harris, Janna L; Fuentes, Isabella; Rogers, Robert S; Wheatley, Joshua L; Geiger, Paige C; Yeh, Hung-Wen; Choi, In-Young; Brooks, William M; Stanford, John A

2016-07-01

Diet-induced obesity and associated metabolic effects can lead to neurological dysfunction and increase the risk of developing Alzheimer's disease (AD) and Parkinson's disease (PD). Despite these risks, the effects of a high-fat diet on the central nervous system are not well understood. To better understand the mechanisms underlying the effects of high fat consumption on brain regions affected by AD and PD, we used proton magnetic resonance spectroscopy ((1)H-MRS) to measure neurochemicals in the hippocampus and striatum of rats fed a high fat diet vs. normal low fat chow. We detected lower concentrations of total creatine (tCr) and a lower glutamate-to-glutamine ratio in the hippocampus of high fat rats. Additional effects observed in the hippocampus of high fat rats included higher N-acetylaspartylglutamic acid (NAAG), and lower myo-inositol (mIns) and serine (Ser) concentrations. Post-mortem tissue analyses revealed lower phosphorylated AMP-activated protein kinase (pAMPK) in the striatum but not in the hippocampus of high fat rats. Hippocampal pAMPK levels correlated significantly with tCr, aspartate (Asp), phosphoethanolamine (PE), and taurine (Tau), indicating beneficial effects of AMPK activation on brain metabolic and energetic function, membrane turnover, and edema. A negative correlation between pAMPK and glucose (Glc) indicates a detrimental effect of brain Glc on cellular energy response. Overall, these changes indicate alterations in neurotransmission and in metabolic and bioenergetic function in the hippocampus and in the striatum of rats fed a high fat diet. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mitochondrial quality control and communications with the nucleus are important in maintaining mitochondrial function and cell health☆☆☆

PubMed Central

Kotiadis, Vassilios N.; Duchen, Michael R.; Osellame, Laura D.

2014-01-01

Background The maintenance of cell metabolism and homeostasis is a fundamental characteristic of living organisms. In eukaryotes, mitochondria are the cornerstone of these life supporting processes, playing leading roles in a host of core cellular functions, including energy transduction, metabolic and calcium signalling, and supporting roles in a number of biosynthetic pathways. The possession of a discrete mitochondrial genome dictates that the maintenance of mitochondrial ‘fitness’ requires quality control mechanisms which involve close communication with the nucleus. Scope of review This review explores the synergistic mechanisms that control mitochondrial quality and function and ensure cellular bioenergetic homeostasis. These include antioxidant defence mechanisms that protect against oxidative damage caused by reactive oxygen species, while regulating signals transduced through such free radicals. Protein homeostasis controls import, folding, and degradation of proteins underpinned by mechanisms that regulate bioenergetic capacity through the mitochondrial unfolded protein response. Autophagic machinery is recruited for mitochondrial turnover through the process of mitophagy. Mitochondria also communicate with the nucleus to exact specific transcriptional responses through retrograde signalling pathways. Major conclusions The outcome of mitochondrial quality control is not only reliant on the efficient operation of the core homeostatic mechanisms but also in the effective interaction of mitochondria with other cellular components, namely the nucleus. General significance Understanding mitochondrial quality control and the interactions between the organelle and the nucleus will be crucial in developing therapies for the plethora of diseases in which the pathophysiology is determined by mitochondrial dysfunction. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research. PMID:24211250

Uranium extremophily is an adaptive, rather than intrinsic, feature for extremely thermoacidophilic Metallosphaera species

PubMed Central

Mukherjee, Arpan; Wheaton, Garrett H.; Blum, Paul H.; Kelly, Robert M.

2012-01-01

Thermoacidophilic archaea are found in heavy metal-rich environments, and, in some cases, these microorganisms are causative agents of metal mobilization through cellular processes related to their bioenergetics. Given the nature of their habitats, these microorganisms must deal with the potentially toxic effect of heavy metals. Here, we show that two thermoacidophilic Metallosphaera species with nearly identical (99.99%) genomes differed significantly in their sensitivity and reactivity to uranium (U). Metallosphaera prunae, isolated from a smoldering heap on a uranium mine in Thüringen, Germany, could be viewed as a “spontaneous mutant” of Metallosphaera sedula, an isolate from Pisciarelli Solfatara near Naples. Metallosphaera prunae tolerated triuranium octaoxide (U3O8) and soluble uranium [U(VI)] to a much greater extent than M. sedula. Within 15 min following exposure to “U(VI) shock,” M. sedula, and not M. prunae, exhibited transcriptomic features associated with severe stress response. Furthermore, within 15 min post-U(VI) shock, M. prunae, and not M. sedula, showed evidence of substantial degradation of cellular RNA, suggesting that transcriptional and translational processes were aborted as a dynamic mechanism for resisting U toxicity; by 60 min post-U(VI) shock, RNA integrity in M. prunae recovered, and known modes for heavy metal resistance were activated. In addition, M. sedula rapidly oxidized solid U3O8 to soluble U(VI) for bioenergetic purposes, a chemolithoautotrophic feature not previously reported. M. prunae, however, did not solubilize solid U3O8 to any significant extent, thereby not exacerbating U(VI) toxicity. These results point to uranium extremophily as an adaptive, rather than intrinsic, feature for Metallosphaera species, driven by environmental factors. PMID:23010932

Constraints of bioenergetics on the ecology and distribution of vertebrate ectotherms: Progress report for period 1 January 1987 to 31 December 1987

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spotila, J.R.; Standora, E.A.

1987-09-01

We quantified the constraints of bioenergetics on the ecology and distribution of vertebrate ectotherms. We completed studies on the thermoregulation of largemouth bass, on the bioenergetics of the slider turtle, Trachemys scripta, and on the role of temperature dependent sex determination in the extinction of dinosaurs. We also began research to develop the three dimensional bioenergetic climate space for freshwater turtles, to determine the role of incubation temperature on the post hatching growth rate of the snapping turtle, Chelydra serpentina, to establish the rate of energy expenditure of the slider turtle, Trachemys scripta, in the field, to determine the fieldmore » metabolic rates, body temperatures and water flux rates of the box turtle, Terrapene carolina, and to measure the effect of diet type on the consumption rate, digestion rate and digestive efficiency of adult T. scripta. 60 refs., 9 figs.« less

An active lifestyle induces positive antioxidant enzyme modulation in peripheral blood mononuclear cells of overweight/obese postmenopausal women.

PubMed

Farinha, Juliano Boufleur; De Carvalho, Nélson Rodrigues; Steckling, Flávia Mariel; De Vargas, Liziane Da Silva; Courtes, Aline Alves; Stefanello, Sílvio Terra; Martins, Caroline Curry; Bresciani, Guilherme; Dos Santos, Daniela Lopes; Soares, Félix Alexandre Antunes

2015-01-15

The aim of this study was to investigate the effects of an active lifestyle on mitochondrial functioning, viability, bioenergetics, and redox status markers in peripheral blood mononuclear cells (PBMC) of overweight/ obese postmenopausal women. We performed a cross-sectional study with postmenopausal women aged 45–64 years and body mass index N 25 kg/m2, divided into physically active (n = 23) and sedentary (n = 12) groups. Mitochondria functioning and viability, bioenergetics and redox status parameters were assessed in PBMC with spectrophotometric and fluorometric assays. No differences were found in the enzyme activity of complexes I and II of the electron transport chain (ETC), mitochondrial superoxide dismutase (MnSOD) activity, methyl-tetrazolium reduction levels and reduced glutathione and oxidized glutathione levels between the groups. However, the physically active group presented higher levels of reactive oxygen species (ROS) (P= 0.04) and increased catalase (CAT) (P= 0.029), total (P= 0.011) and cytosolic SOD (CuZnSOD) (P= 0.009) activities. An active lifestyle that includes aerobic exercise for at least 30 min, three times per week may improve antioxidant enzyme activities in PBMC in overweight/obese postmenopausal women, without changes in the activity of the ETC enzymes. However, this low intensity physical activity is not able to induce relevant mitochondrial adaptations.

Growth and food consumption by tiger muskellunge: Effects of temperature and ration level on bioenergetic model predictions

USGS Publications Warehouse

Chipps, S.R.; Einfalt, L.M.; Wahl, David H.

2000-01-01

We measured growth of age-0 tiger muskellunge as a function of ration size (25, 50, 75, and 100% C(max))and water temperature (7.5-25??C) and compared experimental results with those predicted from a bioenergetic model. Discrepancies between actual and predicted values varied appreciably with water temperature and growth rate. On average, model output overestimated winter consumption rates at 10 and 7.5??C by 113 to 328%, respectively, whereas model predictions in summer and autumn (20-25??C) were in better agreement with actual values (4 to 58%). We postulate that variation in model performance was related to seasonal changes in esocid metabolic rate, which were not accounted for in the bioenergetic model. Moreover, accuracy of model output varied with feeding and growth rate of tiger muskellunge. The model performed poorly for fish fed low rations compared with estimates based on fish fed ad libitum rations and was attributed, in part, to the influence of growth rate on the accuracy of bioenergetic predictions. Based on modeling simulations, we found that errors associated with bioenergetic parameters had more influence on model output when growth rate was low, which is consistent with our observations. In addition, reduced conversion efficiency at high ration levels may contribute to variable model performance, thereby implying that waste losses should be modeled as a function of ration size for esocids. Our findings support earlier field tests of the esocid bioenergetic model and indicate that food consumption is generally overestimated by the model, particularly in winter months and for fish exhibiting low feeding and growth rates.

A longitudinal analysis of cognitive dysfunction, coping, and depression in multiple sclerosis.

PubMed

Rabinowitz, Amanda R; Arnett, Peter A

2009-09-01

Using a longitudinal design, the authors examined coping and cognitive functioning in the development of depression in individuals with multiple sclerosis (MS). Coping style was evaluated in 2 conceptually distinct roles: as moderator and mediator of the impact of cognitive dysfunction on depression. Using indices derived from the COPE (C. S. Carver, M. F. Scheier, & J. K. Weintraub, 1989), the authors operationalized coping in 3 ways-as active, avoidant, and an index accounting for relative levels of both. Coping both moderated and partially mediated the relationship between cognitive dysfunction and depression. Moderation results suggest that the relationship between cognitive dysfunction and depression is dependent on coping style-adaptive coping protects individuals from experiencing depression related to their cognitive deficits; however, when individuals use maladaptive coping, cognitive dysfunction puts them at risk for depression. Mediational results suggest that cognitive dysfunction leads to depression partially due to cognitive dysfunction's effects on coping. That is, cognitive deficits may impair individuals' ability to use adaptive coping strategies, leaving them more likely to use maladaptive strategies. Clinical and theoretical implications of these findings are discussed.

Poly(ADP-ribose) polymerase inhibition reveals a potential mechanism to promote neuroprotection and treat neuropathic pain.

PubMed

Komirishetty, Prashanth; Areti, Aparna; Gogoi, Ranadeep; Sistla, Ramakrishna; Kumar, Ashutosh

2016-10-01

Neuropathic pain is triggered by the lesions to peripheral nerves which alter their structure and function. Neuroprotective approaches that limit the pathological changes and improve the behavioral outcome have been well explained in different experimental models of neuropathy but translation of such strategies to clinics has been disappointing. Experimental evidences revealed the role of free radicals, especially peroxynitrite after the nerve injury. They provoke oxidative DNA damage and consequent over-activation of the poly(ADP-ribose) polymerase (PARP) upregulates pro-inflammatory pathways, causing bioenergetic crisis and neuronal death. Along with these changes, it causes mitochondrial dysfunction leading to neuronal apoptosis. In related preclinical studies agents that neutralize the free radicals and pharmacological inhibitors of PARP have shown benefits in treating experimental neuropathy. This article reviews the involvement of PARP over-activation in trauma induced neuropathy and therapeutic significance of PARP inhibitors in the experimental neuropathy and neuropathic pain.

Mitochondrial oxidative stress and cardiac ageing.

PubMed

Martín-Fernández, Beatriz; Gredilla, Ricardo

According with different international organizations, cardiovascular diseases are becoming the first cause of death in western countries. Although exposure to different risk factors, particularly those related to lifestyle, contribute to the etiopathogenesis of cardiac disorders, the increase in average lifespan and aging are considered major determinants of cardiac diseases events. Mitochondria and oxidative stress have been pointed out as relevant factors both in heart aging and in the development of cardiac diseases such as heart failure, cardiac hypertrophy and diabetic cardiomyopathy. During aging, cellular processes related with mitochondrial function, such as bioenergetics, apoptosis and inflammation are altered leading to cardiac dysfunction. Increasing our knowledge about the mitochondrial mechanisms related with the aging process, will provide new strategies in order to improve this process, particularly the cardiovascular ones. Copyright © 2017 Sociedad Española de Arteriosclerosis. Publicado por Elsevier España, S.L.U. All rights reserved.

A systems biology approach identifies molecular networks defining skeletal muscle abnormalities in chronic obstructive pulmonary disease.

PubMed

Turan, Nil; Kalko, Susana; Stincone, Anna; Clarke, Kim; Sabah, Ayesha; Howlett, Katherine; Curnow, S John; Rodriguez, Diego A; Cascante, Marta; O'Neill, Laura; Egginton, Stuart; Roca, Josep; Falciani, Francesco

2011-09-01

Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory process of the lung inducing persistent airflow limitation. Extensive systemic effects, such as skeletal muscle dysfunction, often characterize these patients and severely limit life expectancy. Despite considerable research efforts, the molecular basis of muscle degeneration in COPD is still a matter of intense debate. In this study, we have applied a network biology approach to model the relationship between muscle molecular and physiological response to training and systemic inflammatory mediators. Our model shows that failure to co-ordinately activate expression of several tissue remodelling and bioenergetics pathways is a specific landmark of COPD diseased muscles. Our findings also suggest that this phenomenon may be linked to an abnormal expression of a number of histone modifiers, which we discovered correlate with oxygen utilization. These observations raised the interesting possibility that cell hypoxia may be a key factor driving skeletal muscle degeneration in COPD patients.

Acidosis overrides oxygen deprivation to maintain mitochondrial function and cell survival

PubMed Central

Khacho, Mireille; Tarabay, Michelle; Patten, David; Khacho, Pamela; MacLaurin, Jason G.; Guadagno, Jennifer; Bergeron, Richard; Cregan, Sean P.; Harper, Mary-Ellen; Park, David S.; Slack, Ruth S.

2014-01-01

Sustained cellular function and viability of high-energy demanding post-mitotic cells rely on the continuous supply of ATP. The utilization of mitochondrial oxidative phosphorylation for efficient ATP generation is a function of oxygen levels. As such, oxygen deprivation, in physiological or pathological settings, has profound effects on cell metabolism and survival. Here we show that mild extracellular acidosis, a physiological consequence of anaerobic metabolism, can reprogramme the mitochondrial metabolic pathway to preserve efficient ATP production regardless of oxygen levels. Acidosis initiates a rapid and reversible homeostatic programme that restructures mitochondria, by regulating mitochondrial dynamics and cristae architecture, to reconfigure mitochondrial efficiency, maintain mitochondrial function and cell survival. Preventing mitochondrial remodelling results in mitochondrial dysfunction, fragmentation and cell death. Our findings challenge the notion that oxygen availability is a key limiting factor in oxidative metabolism and brings forth the concept that mitochondrial morphology can dictate the bioenergetic status of post-mitotic cells. PMID:24686499

A COMPUTATIONAL MODEL OF MOTOR NEURON DEGENERATION

PubMed Central

Le Masson, Gwendal; Przedborski, Serge; Abbott, L.F.

2014-01-01

SUMMARY To explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting in a chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortage is confined to the distal part of the axon, the ensuing local ionic instability eventually spreads to the whole neuron and involves fasciculation-like spiking events. A shortage of ATP also causes a rise in intracellular calcium. Our modeling work supports the notion that mitochondrial dysfunction can account for salient features of the paralytic disorder amyotrophic lateral sclerosis, including motor neuron hyperexcitability, fasciculation, and differential vulnerability of motor neuron subpopulations. PMID:25088365

A computational model of motor neuron degeneration.

PubMed

Le Masson, Gwendal; Przedborski, Serge; Abbott, L F

2014-08-20

To explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting in a chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortage is confined to the distal part of the axon, the ensuing local ionic instability eventually spreads to the whole neuron and involves fasciculation-like spiking events. A shortage of ATP also causes a rise in intracellular calcium. Our modeling work supports the notion that mitochondrial dysfunction can account for salient features of the paralytic disorder amyotrophic lateral sclerosis, including motor neuron hyperexcitability, fasciculation, and differential vulnerability of motor neuron subpopulations. Copyright © 2014 Elsevier Inc. All rights reserved.

Antioxidant dietary approach in treatment of fatty liver: New insights and updates

PubMed Central

Ferramosca, Alessandra; Di Giacomo, Mariangela; Zara, Vincenzo

2017-01-01

Non-alcoholic fatty liver disease (NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols (i.e., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids (i.e., lycopene, astaxanthin and fucoxanthin) and glucosinolates (i.e., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver. PMID:28694655

Antioxidant dietary approach in treatment of fatty liver: New insights and updates.

PubMed

Ferramosca, Alessandra; Di Giacomo, Mariangela; Zara, Vincenzo

2017-06-21

Non-alcoholic fatty liver disease (NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols ( i.e ., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids ( i.e ., lycopene, astaxanthin and fucoxanthin) and glucosinolates ( i.e ., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver.

Translation and cross-cultural adaptation of the Sexual Function Questionnaire (SFQ) into Brazilian Portuguese.

PubMed

Lapa, Clara de Oliveira; Rocha, Gibsi Possapp; Marques, Tiago Reis; Howes, Oliver; Smith, Shubulade; Monteiro, Ricardo Tavares; Zorzetti, Roberta; Spanemberg, Lucas

2017-01-01

Sexual dysfunction is common in patients with psychotic illness. This article describes the translation and cross-cultural adaptation of the Sexual Function Questionnaire (SFQ) into Brazilian Portuguese. The translation and cross-cultural adaptation followed the guidelines for adapting self-report instruments proposed by the Task Force of the International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Briefly, ISPOR steps include: preparation, forward translation, reconciliation, back-translation, back-translation review, harmonization, cognitive debriefing, review of cognitive debriefing and finalization, before proofreading and final version. The original authors authorized the translation and participated in the study. There was good agreement between translations and between the back-translation and the original English version of the SFQ. The final version was prepared with certificated evaluators in the original language and in Portuguese. Few changes were necessary to the new version in Portuguese. The translated and adapted Brazilian Portuguese version of the SFQ is reliable and semantically equivalent to the original version. Studies on psychotropic-related sexual dysfunction may now test the validity of the instrument and can investigate sexual dysfunction in Portuguese-speaking patients.

Life-stage and organ specific changes in mitochondrial bioenergetics in Brown Norway Rats

EPA Science Inventory

Mitochondria are central regulators of energy homeostasis and play a pivotal role in mechanisms of cellular senescence and age-related neurodegenerative and metabolic disorders. However, mitochondrial bioenergetic parameters have not been systematically evaluated under identical ...

Mitochondrial bioenergetics in young, adult, middle-age and senescent brown Norway rats

EPA Science Inventory

Mitochondria are central regulators of energy homeostasis and may play a pivotal role in mechanisms of cellular senescence and age-related neurodegenerative and metabolic disorders. However, mitochondrial bioenergetic parameters have not been systematically evaluated under identi...

Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy

PubMed Central

Boyd, Penelope J.; Shorrock, Hannah K.; Carter, Roderick N.; Powis, Rachael A.; Thomson, Sophie R.; Thomson, Derek; Graham, Laura C.; Motyl, Anna A. L.; Highley, J. Robin; Becker, Thomas; Becker, Catherina G.; Heath, Paul R.

2017-01-01

Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo. PMID:28426667

Forecasting consequences of changing sea ice availability for Pacific walruses

USGS Publications Warehouse

Udevitz, Mark S.; Jay, Chadwick V.; Taylor, Rebecca; Fischbach, Anthony S.; Beatty, William S.; Noren, Shawn R.

2017-01-01

The accelerating rate of anthropogenic alteration and disturbance of environments has increased the need for forecasting effects of environmental change on fish and wildlife populations. Models linking projections of environmental change with behavioral responses and bioenergetic effects can provide a basis for these forecasts. There is particular interest in forecasting effects of projected reductions in sea ice availability on Pacific walruses (Odobenus rosmarus divergens). Declining extent of summer sea ice in the Chukchi Sea has caused Pacific walruses to increase use of coastal haulouts and decrease use of more productive offshore feeding areas. Such climate-induced changes in distribution and behavior could ultimately affect the status of the population. We developed behavioral models to relate changes in sea ice availability to adult female walrus movements and activity levels, and adapted previously developed bioenergetics models to relate those activity levels to energy requirements and the ability to meet those requirements. We then linked these models to general circulation model projections of future ice availability to forecast autumn body condition for female walruses during mid- and late-century time periods. Our results suggest that as sea ice becomes less available in the Chukchi Sea, female walruses will spend more time in the southwestern region of that sea, less time resting, and less time foraging. Median forecasted autumn body masses were 7–12% lower in future scenarios than during recent times, but posterior distributions broadly overlapped and median forecasted seasonal mass losses (15–34%) were comparable to seasonal mass losses routinely experienced by other pinnipeds. These seasonal reductions in body condition would be unlikely to result in demographic effects, but if walruses were unable to rebuild endogenous reserves while wintering in the Bering Sea, cumulative effects could have implications for reproduction and survival, ultimately affecting the status of the Pacific walrus population. Our approach provides a general framework for forecasting consequences of the broad range of environmental changes and anthropogenic disturbances that may affect bioenergetics through behavioral responses or changes in prey availability.

Preservice Teacher Education about Drug or Alcohol-Impaired Dysfunctional Families.

ERIC Educational Resources Information Center

Burke, Robert W.

2003-01-01

This article provides an overview of family systems theory, with a particular focus on the roles adapted by children in dysfunctional families. In addition, analyses of narratives about dysfunctional families, written by 125 preservice teachers, provide implications for new directions in teacher education. (Contains references.) (Author/CR)

MITOCHONDRIAL BIOENERGETICS FOLLOWING OZONE EXPOSURE IN SEDENTARY VERSUS ACTIVE LIFESTYLE OF FEMALE LONG-EVANS RATS

EPA Science Inventory

Mitochondria are key regulators of cellular energy homeostasis and may play a key role in the mechanisms of neurodegenerative disorders and chemical induced neurotoxicity. However, mitochondrial bioenergetic parameters have not been systematically evaluated within multiple brain ...

Functional Abdominal Pain Patient Subtypes in Childhood Predict Functional Gastrointestinal Disorders with Chronic Pain and Psychiatric Comorbidities in Adolescence and Adulthood

PubMed Central

Walker, Lynn S.; Sherman, Amanda L.; Bruehl, Stephen; Garber, Judy; Smith, Craig A.

2012-01-01

Although pediatric functional abdominal pain (FAP) has been linked to abdominal pain later in life, childhood predictors of long-term outcomes have not been identified. This study evaluated whether distinct FAP profiles based on patterns of pain and adaptation in childhood could be identified and whether these profiles predicted differences in clinical outcomes and central sensitization (wind-up) on average 9 years later. In 843 pediatric FAP patients, cluster analysis was used to identify subgroups at initial FAP evaluation based on profiles of pain severity, gastrointestinal (GI) and non-GI symptoms, pain threat appraisal, pain coping efficacy, catastrophizing, negative affect, and activity impairment. Three profiles were identified: High Pain Dysfunctional, High Pain Adaptive, and Low Pain Adaptive. Logistic regression analyses controlling for age and sex showed that, compared to pediatric patients with the Low Pain Adaptive profile, those with the High Pain Dysfunctional profile were significantly more likely at long-term follow-up to meet criteria for pain-related functional gastrointestinal disorder (FGID) (OR: 3.45; CI: 1.95–6.11), FGID with comorbid non-abdominal chronic pain (OR: 2.6; CI:1.45–4.66), and FGID with comorbid anxiety or depressive psychiatric disorder (OR: 2.84; CI: 1.35–6.00). Pediatric patients with the High Pain Adaptive profile had baseline pain severity comparable to the High Pain Dysfunctional profile, but had outcomes as favorable as the Low Pain Adaptive profile. In laboratory pain testing at follow-up, High Pain Dysfunctional patients exhibited significantly greater thermal wind-up than Low Pain Adaptive patients, suggesting that a subgroup of FAP patients has outcomes consistent with widespread effects of heightened central sensitization. PMID:22721910

[The mechanism of phenoptosis: I. Age-dependent decrease of the overall rate of protein synthesis is caused by the programmed attenuation of bio-energetics].

PubMed

Trubitsyn, A G

2009-01-01

The age-dependent degradation of all vital processes of an organism can be result of influences of destructive factors (the stochastic mechanism of aging), or effect of realizations of the genetic program (phenoptosis). The stochastic free-radical theory of aging dominating now contradicts the set of empirical data, and the semicentenial attempts to create the means to slow down aging did not give any practical results. It makes obvious that the stochastic mechanism of aging is incorrect. At the same time, the alternative mechanism of the programmed aging is not developed yet but preconditions for it development have already been created. It is shown that the genes controlling process of aging exist (contrary to the customary opinion) and the increase in the level of damaged macromolecules (basic postulate of the free-radical theory) can be explained by programmed attenuation of bio-energetics. As the bio-energetics is a driving force of all vital processes, decrease of its level is capable to cause degradation of all functions of an organism. However to transform this postulate into a basis of the theory of phenoptosis it is necessary to show, that attenuation of bio-energetics predetermines such fundamental processes accompanying aging as decrease of the overall rate of protein biosynthesis, restriction of cellular proliferations (Hayflick limit), loss of telomeres etc. This article is the first step in this direction: the natural mechanism of interaction of overall rate of protein synthesis with a level of cellular bio-energetics is shown. This is built-in into the translation machine and based on dependence of recirculation rate of eukaryotic initiation factor 2 (elF2) from ATP/ADP value that is created by mitochondrial bio-energetic machine.

A randomized, double-blind, placebo-controlled, proof-of-concept trial of creatine monohydrate as adjunctive treatment for bipolar depression.

PubMed

Toniolo, Ricardo Alexandre; Silva, Michelle; Fernandes, Francy de Brito Ferreira; Amaral, José Antonio de Mello Siqueira; Dias, Rodrigo da Silva; Lafer, Beny

2018-02-01

Depressive episodes are a major cause of morbidity and dysfunction in individuals suffering from bipolar disorder. Currently available treatments for this condition have limited efficacy and new therapeutic options are needed. Extensive research in the pathophysiology of bipolar disorder points to the existence of mitochondrial and bioenergetic dysfunction. We hypothesized that creatine monohydrate, a nutraceutical that works as a mitochondrial modulator, would be effective as an adjunctive therapy for bipolar depression. We conducted a double-blind trial in which 35 patients with bipolar disorder type I or II in a depressive episode by DSM-IV criteria and in use of regular medication for the treatment of this phase of the disease were randomly allocated into two adjunctive treatment groups for 6 weeks: creatine monohydrate 6 g daily (N = 17) or placebo (N = 18). Primary efficacy was assessed by the change in the Montgomery-Åsberg Depression Rating Scale (MADRS). We did not find a statistically significant difference in the comparison between groups for the change in score on the MADRS after 6 weeks in an intention-to-treat (ITT) analysis (p = 0.560; Cohen's d = 0.231). However, we found significant superiority of creatine add-on vs. placebo when we considered the remission criterion of a MADRS score ≤ 12 at week 6 analyzing the outcome of the 35 randomized patients on ITT (52.9% remission in the creatine group vs. 11.1% remission in the placebo group) and of the 23 completers (66.7% remission in the creatine group vs. 18.2% remission in the placebo group) (p = 0.012; OR = 9.0 and p = 0.036; OR = 9.0, respectively). Two patients who received creatine switched to hypomania/mania early in the trial. No clinically relevant physical side-effects were reported or observed. This proof-of-concept study, aiming to restore brain bioenergetics using an adjunctive mitochondrial modulator, is not conclusive on the efficacy of creatine add-on for bipolar depression, but suggests that this compound may have a role in the adjunctive treatment of this phase of the illness. Further investigation through randomized controlled trials with larger samples should be conducted to verify the efficacy of creatine supplementation for bipolar depression and also for subsyndromal depressive symptoms.

Adaptive Benefits of Storage Strategy and Dual AMPK/TOR Signaling in Metabolic Stress Response

PubMed Central

Pfeuty, Benjamin; Thommen, Quentin

2016-01-01

Cellular metabolism must ensure that supply of nutrient meets the biosynthetic and bioenergetic needs. Cells have therefore developed sophisticated signaling and regulatory pathways in order to cope with dynamic fluctuations of both resource and demand and to regulate accordingly diverse anabolic and catabolic processes. Intriguingly, these pathways are organized around a relatively small number of regulatory hubs, such as the highly conserved AMPK and TOR kinase families in eukaryotic cells. Here, the global metabolic adaptations upon dynamic environment are investigated using a prototypical model of regulated metabolism. In this model, the optimal enzyme profiles as well as the underlying regulatory architecture are identified by combining perturbation and evolutionary methods. The results reveal the existence of distinct classes of adaptive strategies, which differ in the management of storage reserve depending on the intensity of the stress and in the regulation of ATP-producing reaction depending on the nature of the stress. The regulatory architecture that optimally implements these adaptive features is characterized by a crosstalk between two specialized signaling pathways, which bears close similarities with the sensing and regulatory properties of AMPK and TOR pathways. PMID:27505075

Translation, Adaptation, and Validation of the Brazilian Version of the Dickman Impulsivity Inventory (Br-DII).

PubMed

Gomes, Áurea K V; Diniz, Leandro F M; Lage, Guilherme M; de Miranda, Débora M; de Paula, Jonas J; Costa, Danielle; Albuquerque, Maicon R

2017-01-01

Impulsivity has mainly been described as a negative or dysfunctional characteristic associated with several disorders. However, impulsivity is not only related to dysfunctional outcomes and may explain individual differences in optimal human functioning as well. The Dickman Impulsivity Inventory (DII) is a self-report instrument measuring both the dysfunctional and the functional aspects of impulsivity. In this study, we performed the translation and cultural adaptation of the DII to the Brazilian context and analyzed its psychometric properties. Translation and cultural adaptation followed a rigorous process, which relied on an expert panel in the cross-cultural adaptation of psychological instruments. Data from 405 undergraduate students were obtained for the Brazilian version of the DII (Br-DII). The 23 items of the Br-DII was considered unsuitable according to model fit indices of the Confirmatory Factor Analysis (both for Oblique and Orthogonal models). Exploratory Factor Analysis showed an 18 items version of the Br-DII to be suitable (CFI = 0.92; TLI = 0.90, and RMSEA = 0.057). The DII's 18 items version also showed adequate Cronbach's alpha, intraclass correlation coefficient, and convergent and discriminant validity with the BIS-11. Therefore, the Br-DII demonstrated reliability and validity in the measurement of functional and dysfunctional impulsivity.

Constraints of bioenergetics on the ecology and distribution of vertebrate ectotherms: Progress report, 1 January 1988-31 December 1988

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spotila, J.R.

1988-08-01

The constraints of bioenergetics on the ecology and distribution of vertebrate ectotherms were quantified. During 1988, we conducted studies: (1) to determine the role of incubation temperature on the post-hatching growth rate of the snapping turtle, Chelydra serpentina, (2) to establish the rate of energy expenditure of the slider turtle, Trachemys scripta, in the field, (3) to determine the field metabolic rates, body temperatures and selected microclimates of the box turtle, Terrapene carolina, and (4) to measure the effect of diet type on the consumption rate, digestion rate and digestive efficiency of adult T. scripta. We also continued our researchmore » on the three-dimensional bioenergetic climate space for freshwater turtles. In addition, we completed editing the symposium volume from our symposium on Constraints of Bioenergetics on Animal Population Dynamics that was held at the last meeting of the American Society of Zoologists. 43 refs., 1 fig., 1 tab.« less

Bioenergetics and synaptic plasticity as potential targets for individualizing treatment for depression.

PubMed

Price, J Blair; Bronars, Carrie; Erhardt, Sophie; Cullen, Kathyrn R; Schwieler, Lilly; Berk, Michael; Walder, Ken; McGee, Sean L; Frye, Mark A; Tye, Susannah J

2018-04-12

Disruptions of bioenergetic signaling and neurogenesis are hallmarks of depression physiology and are often the product of dysregulation of the inflammatory, stress-response, and metabolic systems. These systems are extensively interrelated at the physiological level, yet the bulk of the literature to date addresses pathophysiological mechanisms in isolation. A more integrated understanding of the etiology, progression, and treatment response profiles of depression is possible through wider consideration of relevant preclinical and clinical studies that examine the result of disruptions in these systems. Here, we review recent data demonstrating the critical effects of bioenergetic disruption on neuroplasticity and the development and progression of depressive illness. We further highlight the interactive and dynamic nature of the inflammatory and stress response systems and how disruption of these systems influences bioenergetic signaling pathways critical to treatment outcomes. In so doing, we underscore the pressing need to reconsider the implications of treatment resistance and present a framework for developing novel, personalized treatment approaches for depression. Copyright © 2018 Elsevier Ltd. All rights reserved.

Ergothioneine maintains redox and bioenergetic homeostasis essential for drug susceptibility and virulence of Mycobacterium tuberculosis

PubMed Central

Saini, Vikram; Cumming, Bridgette M.; Guidry, Loni; Lamprecht, Dirk; Adamson, John H.; Reddy, Vineel P.; Chinta, Krishna C.; Mazorodzo, James; Glasgow, Joel N.; Richard-Greenblatt, Melissa; Gomez-Velasco, Anaximandro; Bach, Horacio; Av-Gay, Yossef; Eoh, Hyungjin; Rhee, Kyu; Steyn, Adrie J.C.

2016-01-01

SUMMARY The mechanisms by which Mycobacterium tuberculosis (Mtb) maintains metabolic equilibrium to survive during infection and upon exposure to antimycobacterial drugs are poorly characterized. Ergothioneine (EGT) and mycothiol (MSH) are the major redox buffers present in Mtb, but the contribution of EGT to Mtb redox homeostasis and virulence remains unknown. We report that Mtb WhiB3, a 4Fe-4S redox sensor protein, regulates EGT production and maintains bioenergetic homeostasis. We show that central carbon metabolism and lipid precursors regulate EGT production and that EGT modulates drug sensitivity. Notably, EGT and MSH are both essential for redox and bioenergetic homeostasis. Transcriptomic analyses of EGT and MSH mutants indicate overlapping, but distinct functions of EGT and MSH. Lastly, we show that EGT is critical for Mtb survival in both macrophages and mice. This study has uncovered a dynamic balance between Mtb redox and bioenergetic homeostasis, which critically influences Mtb drug susceptibility and pathogenicity. PMID:26774486

2-Deoxy-D-glucose treatment induces ketogenesis, sustains mitochondrial function, and reduces pathology in female mouse model of Alzheimer's disease.

PubMed

Yao, Jia; Chen, Shuhua; Mao, Zisu; Cadenas, Enrique; Brinton, Roberta Diaz

2011-01-01

Previously, we demonstrated that mitochondrial bioenergetic deficits preceded Alzheimer's disease (AD) pathology in the female triple-transgenic AD (3xTgAD) mouse model. In parallel, 3xTgAD mice exhibited elevated expression of ketogenic markers, indicating a compensatory mechanism for energy production in brain. This compensatory response to generate an alternative fuel source was temporary and diminished with disease progression. To determine whether this compensatory alternative fuel system could be sustained, we investigated the impact of 2-deoxy-D-glucose (2-DG), a compound known to induce ketogenesis, on bioenergetic function and AD pathology burden in brain. 6-month-old female 3xTgAD mice were fed either a regular diet (AIN-93G) or a diet containing 0.04% 2-DG for 7 weeks. 2-DG diet significantly increased serum ketone body level and brain expression of enzymes required for ketone body metabolism. The 2-DG-induced maintenance of mitochondrial bioenergetics was paralleled by simultaneous reduction in oxidative stress. Further, 2-DG treated mice exhibited a significant reduction of both amyloid precursor protein (APP) and amyloid beta (Aβ) oligomers, which was paralleled by significantly increased α-secretase and decreased γ-secretase expression, indicating that 2-DG induced a shift towards a non-amyloidogenic pathway. In addition, 2-DG increased expression of genes involved in Aβ clearance pathways, degradation, sequestering, and transport. Concomitant with increased bioenergetic capacity and reduced β-amyloid burden, 2-DG significantly increased expression of neurotrophic growth factors, BDNF and NGF. Results of these analyses demonstrate that dietary 2-DG treatment increased ketogenesis and ketone metabolism, enhanced mitochondrial bioenergetic capacity, reduced β-amyloid generation and increased mechanisms of β-amyloid clearance. Further, these data link bioenergetic capacity with β-amyloid generation and demonstrate that β-amyloid burden was dynamic and reversible, as 2-DG reduced activation of the amyloidogenic pathway and increased mechanisms of β-amyloid clearance. Collectively, these data provide preclinical evidence for dietary 2-DG as a disease-modifying intervention to delay progression of bioenergetic deficits in brain and associated β-amyloid burden.

Balance of autonomic nervous system in children having signs of endothelial dysfunction, that were born and are domiciled in contaminated territories.

PubMed

Kondrashova, V G; Kolpakov, I E; Vdovenko, V Yu; Leonovych, O S; Lytvynets, O M; Stepanova, E I

2014-09-01

Objective. The study examined the features of functional state of the autonomic nervous system in children having endothelial dysfunction and permanently residing in contaminated areas. Materials and methods. Clinical and instrumental examination of 101 children aged 7-18 years that were born and are domiciled in contaminated territories, including 37 persons with signs of endothelial dysfunction (subgroup IA) and 64 ones with no signs of endothelial dysfunction (IB subgroup) was conducted. The control group being comparable to the subgroups IA and IB by age, gender and clinical examination results included 37 children neither been domiciled in contaminated areas nor were belonging to the contingent of Chornobyl accident survivors. There were 20 apparently healthy children also examined. Results. Due to peculiarities of physiological pathways providing adaptive responses the children having signs of endothelial dysfunction are characterized by a more pronounced dysregulation of autonomous nervous system both in a resting state and under a functional load simulation, and also by a high strain of adaptation pathways. The lack of autonomous support of cardiovascular system is caused by inadequate adaptive responses of both central regulatory bodies (hypothalamus, vasomotor center) and peripheral receptors. Mainly the failure of segmental autonomous (parasympathetic) structures was revealed. The mode of their response to stress in this case corresponds to that in healthy individuals but at a lower functional level. There is a reduced aerobic capacity of the organism by the Robinson index, contributing to low adaptive range to non-specific stress in children being domiciled on contaminated territories including children having the endothelial dysfunction. Conclusions. Endothelial dysfunction was associated with more pronounced manifestations of autonomic dysregulation and reduced aerobic capacity of the organism being the risk factors of development of a range of somatic diseases requiring the development of prevention measures in children permanently residing in contaminated areas. autonomous nervous system balance, endothelial dysfunction, children, Chornobyl accident. V. G. Kondrashova, I. E. Kolpakov, V. Yu. Vdovenko, O. S. Leonovych, O. M. Lytvynets, E. I. Stepanova.

A Bioenergetics Systems Evaluation of Ketogenic Diet Liver Effects

PubMed Central

Hutfles, Lewis J.; Wilkins, Heather M.; Koppel, Scott J.; Weidling, Ian W.; Selfridge, J. Eva; Tan, Eephie; Thyfault, John P.; Slawson, Chad; Fenton, Aron W.; Zhu, Hao; Swerdlow, Russell H.

2018-01-01

Ketogenic diets induce hepatocyte fatty acid oxidation and ketone body production. To further evaluate how ketogenic diets affect hepatocyte bioenergetic infrastructure, we analyzed livers from C57Bl/6J male mice maintained for one month on a ketogenic or standard chow diet. Compared to the standard diet, the ketogenic diet increased cytosolic and mitochondrial protein acetylation and also altered protein succinylation patterns. SIRT3 protein decreased while SIRT5 protein increased, and gluconeogenesis, oxidative phosphorylation, and mitochondrial biogenesis pathway proteins were variably and likely strategically altered. The pattern of changes observed can be used to inform a broader systems overview of how ketogenic diets affect liver bioenergetics. PMID:28514599

A bioenergetics systems evaluation of ketogenic diet liver effects.

PubMed

Hutfles, Lewis J; Wilkins, Heather M; Koppel, Scott J; Weidling, Ian W; Selfridge, J Eva; Tan, Eephie; Thyfault, John P; Slawson, Chad; Fenton, Aron W; Zhu, Hao; Swerdlow, Russell H

2017-09-01

Ketogenic diets induce hepatocyte fatty acid oxidation and ketone body production. To further evaluate how ketogenic diets affect hepatocyte bioenergetic infrastructure, we analyzed livers from C57Bl/6J male mice maintained for 1 month on a ketogenic or standard chow diet. Compared with the standard diet, the ketogenic diet increased cytosolic and mitochondrial protein acetylation and also altered protein succinylation patterns. SIRT3 protein decreased while SIRT5 protein increased, and gluconeogenesis, oxidative phosphorylation, and mitochondrial biogenesis pathway proteins were variably and likely strategically altered. The pattern of changes observed can be used to inform a broader systems overview of how ketogenic diets affect liver bioenergetics.

A structured approach to the study of metabolic control principles in intact and impaired mitochondria.

PubMed

Huber, Heinrich J; Connolly, Niamh M C; Dussmann, Heiko; Prehn, Jochen H M

2012-03-01

We devised an approach to extract control principles of cellular bioenergetics for intact and impaired mitochondria from ODE-based models and applied it to a recently established bioenergetic model of cancer cells. The approach used two methods for varying ODE model parameters to determine those model components that, either alone or in combination with other components, most decisively regulated bioenergetic state variables. We found that, while polarisation of the mitochondrial membrane potential (ΔΨ(m)) and, therefore, the protomotive force were critically determined by respiratory complex I activity in healthy mitochondria, complex III activity was dominant for ΔΨ(m) during conditions of cytochrome-c deficiency. As a further important result, cellular bioenergetics in healthy, ATP-producing mitochondria was regulated by three parameter clusters that describe (1) mitochondrial respiration, (2) ATP production and consumption and (3) coupling of ATP-production and respiration. These parameter clusters resembled metabolic blocks and their intermediaries from top-down control analyses. However, parameter clusters changed significantly when cells changed from low to high ATP levels or when mitochondria were considered to be impaired by loss of cytochrome-c. This change suggests that the assumption of static metabolic blocks by conventional top-down control analyses is not valid under these conditions. Our approach is complementary to both ODE and top-down control analysis approaches and allows a better insight into cellular bioenergetics and its pathological alterations.

Re-estimating temperature-dependent consumption parameters in bioenergetics models for juvenile Chinook salmon

USGS Publications Warehouse

Plumb, John M.; Moffitt, Christine M.

2015-01-01

Researchers have cautioned against the borrowing of consumption and growth parameters from other species and life stages in bioenergetics growth models. In particular, the function that dictates temperature dependence in maximum consumption (Cmax) within the Wisconsin bioenergetics model for Chinook Salmon Oncorhynchus tshawytscha produces estimates that are lower than those measured in published laboratory feeding trials. We used published and unpublished data from laboratory feeding trials with subyearling Chinook Salmon from three stocks (Snake, Nechako, and Big Qualicum rivers) to estimate and adjust the model parameters for temperature dependence in Cmax. The data included growth measures in fish ranging from 1.5 to 7.2 g that were held at temperatures from 14°C to 26°C. Parameters for temperature dependence in Cmax were estimated based on relative differences in food consumption, and bootstrapping techniques were then used to estimate the error about the parameters. We found that at temperatures between 17°C and 25°C, the current parameter values did not match the observed data, indicating that Cmax should be shifted by about 4°C relative to the current implementation under the bioenergetics model. We conclude that the adjusted parameters for Cmax should produce more accurate predictions from the bioenergetics model for subyearling Chinook Salmon.

Cisplatin Induces a Mitochondrial-ROS Response That Contributes to Cytotoxicity Depending on Mitochondrial Redox Status and Bioenergetic Functions

PubMed Central

Marullo, Rossella; Werner, Erica; Degtyareva, Natalya; Moore, Bryn; Altavilla, Giuseppe; Ramalingam, Suresh S.; Doetsch, Paul W.

2013-01-01

Cisplatin is one of the most effective and widely used anticancer agents for the treatment of several types of tumors. The cytotoxic effect of cisplatin is thought to be mediated primarily by the generation of nuclear DNA adducts, which, if not repaired, cause cell death as a consequence of DNA replication and transcription blockage. However, the ability of cisplatin to induce nuclear DNA (nDNA) damage per se is not sufficient to explain its high degree of effectiveness nor the toxic effects exerted on normal, post-mitotic tissues. Oxidative damage has been observed in vivo following exposure to cisplatin in several tissues, suggesting a role for oxidative stress in the pathogenesis of cisplatin-induced dose-limiting toxicities. However, the mechanism of cisplatin-induced generation of ROS and their contribution to cisplatin cytotoxicity in normal and cancer cells is still poorly understood. By employing a panel of normal and cancer cell lines and the budding yeast Saccharomyces cerevisiae as model system, we show that exposure to cisplatin induces a mitochondrial-dependent ROS response that significantly enhances the cytotoxic effect caused by nDNA damage. ROS generation is independent of the amount of cisplatin-induced nDNA damage and occurs in mitochondria as a consequence of protein synthesis impairment. The contribution of cisplatin-induced mitochondrial dysfunction in determining its cytotoxic effect varies among cells and depends on mitochondrial redox status, mitochondrial DNA integrity and bioenergetic function. Thus, by manipulating these cellular parameters, we were able to enhance cisplatin cytotoxicity in cancer cells. This study provides a new mechanistic insight into cisplatin-induced cell killing and may lead to the design of novel therapeutic strategies to improve anticancer drug efficacy. PMID:24260552

Bioenergetic Profile Experiment using C2C12 Myoblast Cells

PubMed Central

Nicholls, David G.; Darley-Usmar, Victor M.; Wu, Min; Jensen, Per Bo; Rogers, George W.; Ferrick, David A.

2010-01-01

The ability to measure cellular metabolism and understand mitochondrial dysfunction, has enabled scientists worldwide to advance their research in understanding the role of mitochondrial function in obesity, diabetes, aging, cancer, cardiovascular function and safety toxicity. Cellular metabolism is the process of substrate uptake, such as oxygen, glucose, fatty acids, and glutamine, and subsequent energy conversion through a series of enzymatically controlled oxidation and reduction reactions. These intracellular biochemical reactions result in the production of ATP, the release of heat and chemical byproducts, such as lactate and CO2 into the extracellular environment. Valuable insight into the physiological state of cells, and the alteration of the state of those cells, can be gained through measuring the rate of oxygen consumed by the cells, an indicator of mitochondrial respiration - the Oxygen Consumption Rate - or OCR. Cells also generate ATP through glycolysis, i.e.: the conversion of glucose to lactate, independent of oxygen. In cultured wells, lactate is the primary source of protons. Measuring the lactic acid produced indirectly via protons released into the extracellular medium surrounding the cells, which causes acidification of the medium provides the Extra-Cellular Acidification Rate - or ECAR. In this experiment, C2C12 myoblast cells are seeded at a given density in Seahorse cell culture plates. The basal oxygen consumption (OCR) and extracellular acidification (ECAR) rates are measured to establish baseline rates. The cells are then metabolically perturbed by three additions of different compounds (in succession) that shift the bioenergetic profile of the cell. This assay is derived from a classic experiment to assess mitochondria and serves as a framework with which to build more complex experiments aimed at understanding both physiologic and pathophysiologic function of mitochondria and to predict the ability of cells to respond to stress and/or insults. PMID:21189469

Paraquat affects mitochondrial bioenergetics, dopamine system expression, and locomotor activity in zebrafish (Danio rerio).

PubMed

Wang, Xiao H; Souders, Christopher L; Zhao, Yuan H; Martyniuk, Christopher J

2018-01-01

The dipyridyl herbicide paraquat induces oxidative stress in cells and is implicated in adult neurodegenerative diseases. However, less is known about paraquat toxicity in early stages of vertebrate development. To address this gap, zebrafish (Danio rerio) embryos were exposed to 1, 10 and 100 μM paraquat for 96 h. Paraquat did not induce significant mortality nor deformity in embryos and larvae, but it did accelerate time to hatch. To evaluate whether mitochondrial respiration was related to earlier hatch times, oxygen consumption rate was measured in whole embryos. Maximal respiration of embryos exposed to 100 μM paraquat for 24 h was reduced by more than 70%, suggesting that paraquat negatively impacts mitochondrial bioenergetics in early development. Based upon this evidence for mitochondrial dysfunction, transcriptional responses of oxidative stress- and apoptosis-related genes were measured. Fish exposed to 1 μM paraquat showed higher expression levels of superoxide dismutase 2, heat shock protein 70, Bcl-2-associated X protein, and B-cell CLL/lymphoma 2a compared to control fish. No differences among groups were detected in larvae exposed to 10 and 100 μM paraquat, suggesting a non-monotonic response. We also measured endpoints related to larval behavior and dopaminergic signaling as paraquat is associated with degeneration of dopamine neurons. Locomotor activity was stimulated with 100 μM paraquat and dopamine transporter and dopamine receptor 3 mRNA levels were increased in larvae exposed to 1 μM paraquat, interpreted to be a compensatory response at lower concentrations. This study improves mechanistic understanding into the toxic actions of paraquat on early developmental stages. Copyright © 2017 Elsevier Ltd. All rights reserved.

Altered Bioenergetics in Primary Dermal Fibroblasts from Adult Carriers of the FMR1 Premutation Before the Onset of the Neurodegenerative Disease Fragile X-Associated Tremor/Ataxia Syndrome.

PubMed

Napoli, Eleonora; Song, Gyu; Wong, Sarah; Hagerman, Randi; Giulivi, Cecilia

2016-10-01

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder, characterized by tremors, ataxia, impaired coordination, and cognitive decline. While all FXTAS individuals are carriers of a 55-200 CGG expansion at the 5'-UTR of the fragile X mental retardation gene (FMR1), also known as premutation, not all carriers develop FXTAS symptoms and some display other types of psychological/emotional disorders (e.g., autism, anxiety). The goal of this study was to investigate whether the mitochondrial dysfunction previously observed in fibroblasts from older premutation individuals (>60 years) was already present in younger (17-48 years), non-FXTAS-affected carriers and to identify the type and severity of the bioenergetic deficit. Since FXTAS affects mostly males, while females account for a small part of the FXTAS-affected population displaying less severe symptoms, only fibroblasts from males were evaluated in this study. Based on polarographic and enzymatic measurements, a generalized OXPHOS deficit was noted accompanied by increases in the matrix biomarker citrate synthase, oxidative stress (as increased mtDNA copy number and deletions), and mitochondrial network disruption/disorganization. Some of the outcomes (ATP-linked oxygen uptake, coupling, citrate synthase activity, and mitochondrial network organization) strongly correlated with the extent of the CGG expansion, with more severe deficits observed in cell lines carrying higher CGG number. Furthermore, mitochondrial outcomes can identify endophenotypes among carriers and are robust predictors of the premutation diagnosis before the onset of FXTAS, with the potential to be used as markers of prognosis and/or as readouts of pharmacological interventions.

Lipidomics Characterization of Biosynthetic and Remodeling Pathways of Cardiolipins in Genetically and Nutritionally Manipulated Yeast Cells.

PubMed

Tyurina, Yulia Y; Lou, Wenjia; Qu, Feng; Tyurin, Vladimir A; Mohammadyani, Dariush; Liu, Jenney; Hüttemann, Maik; Frasso, Michael A; Wipf, Peter; Bayir, Hülya; Greenberg, Miriam L; Kagan, Valerian E

2017-01-20

Cardioipins (CLs) are unique tetra-acylated phospholipids of mitochondria and define the bioenergetics and regulatory functions of these organelles. An unresolved paradox is the high uniformity of CL molecular species (tetra-linoleoyl-CL) in the heart, liver, and skeletal muscles-in contrast to their high diversification in the brain. Here, we combined liquid chromatography-mass-spectrometry-based phospholipidomics with genetic and nutritional manipulations to explore CLs' biosynthetic vs postsynthetic remodeling processes in S. cerevisiae yeast cells. By applying the differential phospholipidomics analysis, we evaluated the contribution of Cld1 (CL-specific phospholipase A) and Taz1 (acyl-transferase) as the major regulatory mechanisms of the remodeling process. We further established that nutritional "pressure" by high levels of free fatty acids triggered a massive synthesis of homoacylated molecular species in all classes of phospholipids, resulting in the preponderance of the respective homoacylated CLs. We found that changes in molecular speciation of CLs induced by exogenous C18-fatty acids (C18:1 and C18:2) in wild-type (wt) cells did not occur in any of the remodeling mutant cells, including cld1Δ, taz1Δ, and cld1Δtaz1Δ. Interestingly, molecular speciation of CLs in wt and double mutant cells cld1Δtaz1Δ was markedly different. Given that the bioenergetics functions are preserved in the double mutant, this suggests that the accumulated MLCL-rather than the changed CL speciation-are the likely major contributors to the mitochondrial dysfunction in taz1Δ mutant cells (also characteristic of Barth syndrome). Biochemical studies of Cld1 specificity and computer modeling confirmed the hydrolytic selectivity of the enzyme toward C16-CL substrates and the preservation of C18:1-containing CL species.

Curcumin prevents mitochondrial dynamics disturbances in early 5/6 nephrectomy: Relation to oxidative stress and mitochondrial bioenergetics.

PubMed

Aparicio-Trejo, Omar Emiliano; Tapia, Edilia; Molina-Jijón, Eduardo; Medina-Campos, Omar Noel; Macías-Ruvalcaba, Norma Angélica; León-Contreras, Juan Carlos; Hernández-Pando, Rogelio; García-Arroyo, Fernando E; Cristóbal, Magdalena; Sánchez-Lozada, Laura Gabriela; Pedraza-Chaverri, José

2017-03-01

Five-sixths nephrectomy (5/6NX) is a widely used model to study the mechanisms leading to renal damage in chronic kidney disease (CKD). However, early alterations on renal function, mitochondrial dynamics, and oxidative stress have not been explored yet. Curcumin is an antioxidant that has shown nephroprotection in 5/6NX-induced renal damage. The aim of this study was to explore the effect of curcumin on early mitochondrial alterations induced by 5/6NX in rats. In isolated mitochondria, 5/6NX-induced hydrogen peroxide production was associated with decreased activity of complexes I and V, decreased activity of antioxidant enzymes, alterations in oxygen consumption and increased MDA-protein adducts. In addition, it was found that 5/6NX shifted mitochondrial dynamics to fusion, which was evidenced by increased optic atrophy 1 and mitofusin 1 (Mfn1) and decreased fission 1 and dynamin-related protein 1 expressions. These data were confirmed by morphological analysis and immunoelectron microscopy of Mfn-1. All the above-described mechanisms were prevented by curcumin. Also, it was found that curcumin prevented renal dysfunction by improving renal blood flow and the total antioxidant capacity induced by 5/6NX. Moreover, in glomeruli and proximal tubules 5/6NX-induced superoxide anion production by uncoupled nitric oxide synthase (NOS) and nicotinamide adenine dinucleotide phosphate oxidase (NOX) dependent way, this latter was associated with increased phosphorylation of serine 304 of p47phox subunit of NOX. In conclusion, this study shows that curcumin pretreatment decreases early 5/6NX-induced altered mitochondrial dynamics, bioenergetics, and oxidative stress, which may be associated with the preservation of renal function. © 2016 BioFactors, 43(2):293-310, 2017. © 2016 International Union of Biochemistry and Molecular Biology.

Long-Term Skeletal Muscle Mitochondrial Dysfunction is Associated with Hypermetabolism in Severely Burned Children.

PubMed

Porter, Craig; Herndon, David N; Børsheim, Elisabet; Bhattarai, Nisha; Chao, Tony; Reidy, Paul T; Rasmussen, Blake B; Andersen, Clark R; Suman, Oscar E; Sidossis, Labros S

2016-01-01

The long-term impact of burn trauma on skeletal muscle bioenergetics remains unknown. Here, the authors determined respiratory capacity and function of skeletal muscle mitochondria in healthy individuals and in burn victims for up to 2 years postinjury. Biopsies were collected from the m. vastus lateralis of 16 healthy men (26 ± 4 years) and 69 children (8 ± 5 years) with burns encompassing ≥30% of their total BSA. Seventy-nine biopsies were collected from cohorts of burn victims at 2 weeks (n = 18), 6 months (n = 18), 12 months (n = 25), and 24 months (n = 18) postburn. Hypermetabolism was determined by the difference in predicted and measured metabolic rate. Mitochondrial respiration was determined in saponin-permeabilized myofiber bundles. Outcomes were modeled by analysis of variance, with differences in groups assessed by Tukey-adjusted contrasts. Burn patients were hypermetabolic for up to 2 years postinjury. Coupled mitochondrial respiration was lower at 2 weeks (17 [8] pmol/sec/mg; P < .001), 6 months (41 [30] pmol/sec/mg; P = .03), and 12 months (35 [14] pmol/sec/mg; P < .001) postburn compared with healthy controls (58 [13] pmol/sec/mg). Coupled respiration was greater at 6, 12, and 24 months postburn vs 2 weeks postburn (P < .001). Mitochondrial adenosine diphosphate and oligomycin sensitivity (measures of coupling control) were lower at all time-points postburn vs control (P < .05), but greater at 6, 12, and 24 months postburn vs 2 weeks postburn (P < .05). Muscle mitochondrial respiratory capacity remains significantly lower in burn victims for 1-year postinjury. Mitochondrial coupling control is diminished for up to 2 years postinjury in burn victims, resulting in greater mitochondrial thermogenesis. These quantitative and qualitative derangements in skeletal muscle bioenergetics likely contribute to the long-term pathophysiological stress response to burn trauma.

Minnelide/Triptolide Impairs Mitochondrial Function by Regulating SIRT3 in P53-Dependent Manner in Non-Small Cell Lung Cancer.

PubMed

Kumar, Ajay; Corey, Catherine; Scott, Iain; Shiva, Sruti; D'Cunha, Jonathan

2016-01-01

Minnelide/Triptolide (TL) has recently emerged as a potent anticancer drug in non-small cell lung cancer (NSCLC). However, the precise mechanism of its action remains ambiguous. In this study, we elucidated the molecular basis for TL-induced cell death in context to p53 status. Cell death was attributed to dysfunction of mitochondrial bioenergetics in p53-deficient cells, which was characterized by decreased mitochondrial respiration, steady-state ATP level and membrane potential, but augmented reactive oxygen species (ROS). Increased ROS production resulted in oxidative stress in TL-treated cells. This was exhibited by elevated nuclear levels of a redox-sensitive transcriptional factor, NF-E2-related factor-2 (NRF2), along with diminished cellular glutathione (GSH) content. We further demonstrated that in the absence of p53, TL blunted the expression of mitochondrial SIRT3 triggering increased acetylation of NDUAF9 and succinate dehydrogenase, components of complexes I and II of the electron transport chain (ETC). TL-mediated hyperacetylation of complexes I and II proteins and these complexes displayed decreased enzymatic activities. We also provide the evidence that P53 regulate steady-state level of SIRT3 through Proteasome-Pathway. Finally, forced overexpression of Sirt3, but not deacetylase-deficient mutant of Sirt3 (H243Y), restored the deleterious effect of TL on p53-deficient cells by rescuing mitochondrial bioenergetics. On contrary, Sirt3 deficiency in the background of wild-type p53 triggered TL-induced mitochondrial impairment that echoed TL effect in p53-deficeint cells. These findings illustrate a novel mechanism by which TL exerts its potent effects on mitochondrial function and ultimately the viability of NSCLC tumor.

Building a Foundation for Bioenergetics

ERIC Educational Resources Information Center

Hamori, Eugene

2002-01-01

To give students a lasting comprehension of bioenergetics, first such basics as heat, work, equilibrium, entropy, free energy, closed "versus" open systems, steady state, and reversibility should be explained to them in a meticulous manner, albeit with a minimal use of mathematical formulae. The unique feature of thermodynamics, that it does not…

Elementary School Teachers' Vocal Dose: Muscle Bioenergetics and Training Implications

ERIC Educational Resources Information Center

Smith, Audrey G.; Sandage, Mary J.; Pascoe, David D.; Plexico, Laura W.; Lima, Italo R.; Cao, Guanqun

2017-01-01

Purpose: Translating exercise-science methodology for determination of muscle bioenergetics, we hypothesized that the temporal voice-use patterns for classroom and music teachers would indicate a reliance on the immediate energy system for laryngeal skeletal-muscle metabolism. It was hypothesized that the music-teacher group would produce longer…

Constraints of bioenergetics on the ecology and distribution of vertebrate ectotherms

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spotila, J.R.

1992-11-01

The constraints of bioenergetics on the ecology and distribution of vertebrate ectotherms were quantified. During this project we conducted studies: to determine the role of incubation temperature on the post-hatching growth rate of the snapping turtle, Chelydra serpentina; to establish the rate of energy expenditure of the slider turtle, Trachemys scripta, in the field; to determine the field metabolic rates, body temperatures and selected microclimates of the box turtle, Terrapene carolina, and to measure the effect of diet type on the consumption rate, digestion rate and digestive efficiency of adult T. scripta. We also completed our research on the three-dimensionalmore » bioenergetic climate space for freshwater turtles.« less

Effects of Metabolic Programming on Juvenile Play Behavior and Gene Expression in the Prefrontal Cortex of Rats.

PubMed

Hehar, Harleen; Ma, Irene; Mychasiuk, Richelle

2016-01-01

Early developmental processes, such as metabolic programming, can provide cues to an organism, which allow it to make modifications that are predicted to be beneficial for survival. Similarly, social play has a multifaceted role in promoting survival and fitness of animals. Play is a complex behavior that is greatly influenced by motivational and reward circuits, as well as the energy reserves and metabolism of an organism. This study examined the association between metabolic programming and juvenile play behavior in an effort to further elucidate insight into the consequences that early adaptions have on developmental trajectories. The study also examined changes in expression of four genes (Drd2, IGF1, Opa1, and OxyR) in the prefrontal cortex known to play significant roles in reward, bioenergetics, and social-emotional functioning. Using four distinct variations in developmental programming (high-fat diet, caloric restriction, exercise, or high-fat diet combined with exercise), we found that dietary programming (high-fat diet vs. caloric restriction) had the greatest impact on play behavior and gene expression. However, exercise also induced changes in both measures. This study demonstrates that metabolic programming can alter neural circuits and bioenergetics involved in play behavior, thus providing new insights into mechanisms that allow programming to influence the evolutionary success of an organism. © 2016 S. Karger AG, Basel.

Stressor-induced NMDAR dysfunction as a unifying hypothesis for the aetiology, pathogenesis and comorbidity of clinical depression.

PubMed

Marsden, W N

2011-10-01

Typically the monoamine system has been the central focus of neurobiological research into depression and represents the major target of modern antidepressant medications; although the extent to which monoamines such as serotonin play a role in the pathogenesis of depression is still not clear. Recent research advancements have expanded the neurotransmitter-level focus of mood disorders to incorporate intracellular pathways and regional brain circuitry. As such the importance of other systems has emerged including those related to neuroplastic signal transduction and gene transcription cascades within cortico-limbic circuits. Indeed mounting evidence suggests interaction with these pathways is required for the chronic therapeutic effect of current clinical antidepressants. Dysfunction of the glutamatergic system has also emerged as a major pathological feature in depression, and glutamatergic agents have demonstrated rapid and robust antidepressant activity in humans. In particular, the glutamate receptors (AMPAR, NMDAR & mGluR) are intrinsically connected to neuronal efficiency and inefficiency cascades, so their dysfunction may account for alterations to multiple signal transduction pathways in depression. This article presents concepts supporting a NMDA hypothesis of depression, whereby the pathogenesis of depression may arise from stressors inducing excessive NMDAR activity which acts heterogeneously at both cellular and regional levels to disrupt normal neurobiological function and induce the depressive phenotype. In this hypothesis multiple psychological and environmental stressors are united in their capacity to potentiate excessive tonic and phasic NMDAR activation on neurons and glia. Such NMDAR dysfunction may lead to: disruption of glia processes and tripartite signalling; potentiation of extrasynaptic inefficiency/LTD pathways in some regions (e.g. prefrontal cortex & hippocampus); potentiation of synaptic efficiency/LTP pathways in other regions (e.g. amygdala); and regional disruption of cortico-limbic circuits and dopaminergic reward pathways (e.g. nucleus accumbens). This model unites depression with a variety of stressors including glucocorticoids, inflammation, oxidative stress, magnesium deficiency, hyperhomocysteinemia, and bio-energetic dysfunction; and also helps explain comorbidity with other neurological and affective disorders. In particular, a neurometabolic contribution to the aetiology of depressive as well as other neurological and affective disorders is explored. Copyright © 2011 Elsevier Ltd. All rights reserved.

Increased mtDNA mutations with aging promotes amyloid accumulation and brain atrophy in the APP/Ld transgenic mouse model of Alzheimer’s disease

PubMed Central

2014-01-01

Background The role of mitochondrial dysfunction has long been implicated in age-related brain pathology, including Alzheimer’s disease (AD). However, the mechanism by which mitochondrial dysfunction may cause neurodegeneration in AD is unclear. To model mitochondrial dysfunction in vivo, we utilized mice that harbor a knockin mutation that inactivates the proofreading function of mitochondrial DNA polymerase γ (PolgA D257A), so that these mice accumulate mitochondrial DNA mutations with age. PolgA D257A mice develop a myriad of mitochondrial bioenergetic defects and physical phenotypes that mimic premature ageing, with subsequent death around one year of age. Results We crossed the D257A mice with a well-established transgenic AD mouse model (APP/Ld) that develops amyloid plaques. We hypothesized that mitochondrial dysfunction would affect Aβ synthesis and/or clearance, thus contributing to amyloidogenesis and triggering neurodegeneration. Initially, we discovered that Aβ42 levels along with Aβ42 plaque density were increased in D257A; APP/Ld bigenic mice compared to APP/Ld monogenic mice. Elevated Aβ production was not responsible for increased amyloid pathology, as levels of BACE1, PS1, C99, and C83 were unchanged in D257A; APP/Ld compared to APP/Ld mice. However, the levels of a major Aβ clearance enzyme, insulin degrading enzyme (IDE), were reduced in mice with the D257A mutation, suggesting this as mechanism for increased amyloid load. In the presence of the APP transgene, D257A mice also exhibited significant brain atrophy with apparent cortical thinning but no frank neuron loss. D257A; APP/Ld mice had increased levels of 17 kDa cleaved caspase-3 and p25, both indicative of neurodegeneration. Moreover, D257A; APP/Ld neurons appeared morphologically disrupted, with swollen and vacuolated nuclei. Conclusions Overall, our results implicate synergism between the effects of the PolgA D257A mutation and Aβ in causing neurodegeneration. These findings provide insight into mechanisms of mitochondrial dysfunction that may contribute to the pathogenesis of AD via decreased clearance of Aβ. PMID:24885175

Self-eating and self-defense: autophagy controls innate immunity and adaptive immunity.

PubMed

Liu, Guangwei; Bi, Yujing; Wang, Ruoning; Wang, Xianghui

2013-04-01

Autophagy (macroautophagy; "self-eating") is a degradation process, in which cytoplasmic content is engulfed and degraded by the lysosome. And, immunity is an important mechanism of the "self-defense" system. Autophagy has long been recognized as a stress response to nutrient deprivation. This will provide energy and anabolic building blocks to maintain cellular bioenergetic homeostasis. Thus, autophagy plays critical roles in regulating a wide variety of pathophysiological processes, including tumorigenesis, embryo development, tissue remodeling, and most recently, immunity. The latter shows that a self-eating (autophagy) process could regulate a self-defense (immune) system. In this review, we summarize the recent findings regarding the regulatory and mechanistic insights of the autophagy pathway in immunity.

Assessment of phytoplankton resources suitable for bigheaded carps in Lake Michigan derived from remote sensing and bioenergetics

USGS Publications Warehouse

Anderson, Karl R.; Chapman, Duane C.; Wynne, Tim T.; Paukert, Craig P.

2017-01-01

We used bioenergetic simulations combined with satellite-measured water temperature and estimates of algal food availability to predict the habitat suitability of Lake Michigan for adult silver carp (Hypophthalmichthys molitrix) and bighead carp (H. nobilis). Depending on water temperature, we found that bigheaded carp require ambient algal concentrations between 1 and 7 μg chlorophyll/L or between 0.25 × 105 and 1.20 × 105 cells/mL Microcystis to maintain body weight. When the bioenergetics model is forced with the observed average annual temperature cycle, our simulations predicted silver carp bioenergetics predicted annual weight change ranging from 9% weight loss to 23% gain; bighead carp ranged from 68 to 177% weight gain. Algal concentrations b4 μg chlorophyll/L and b200,000 cells/mL were below the detection limits of the remote sensing method. However, all areas with detectable algae have sufficient concentrations of algal foods for bigheaded carp weight-maintenance and growth. Those areas are predominately along the nearshore areas.

Comparative bioenergetics modeling of two Lake Trout morphotypes

USGS Publications Warehouse

Kepler, Megan V.; Wagner, Tyler; Sweka, John A.

2014-01-01

Efforts to restore Lake Trout Salvelinus namaycush in the Laurentian Great Lakes have been hampered for decades by several factors, including overfishing and invasive species (e.g., parasitism by Sea Lampreys Petromyzon marinus and reproductive deficiencies associated with consumption of Alewives Alosa pseudoharengus). Restoration efforts are complicated by the presence of multiple body forms (i.e., morphotypes) of Lake Trout that differ in habitat utilization, prey consumption, lipid storage, and spawning preferences. Bioenergetics models constitute one tool that is used to help inform management and restoration decisions; however, bioenergetic differences among morphotypes have not been evaluated. The goal of this research was to investigate bioenergetic differences between two actively stocked morphotypes: lean and humper Lake Trout. We measured consumption and respiration rates across a wide range of temperatures (4–22°C) and size-classes (5–100 g) to develop bioenergetics models for juvenile Lake Trout. Bayesian estimation was used so that uncertainty could be propagated through final growth predictions. Differences between morphotypes were minimal, but when present, the differences were temperature and weight dependent. Basal respiration did not differ between morphotypes at any temperature or size-class. When growth and consumption differed between morphotypes, the differences were not consistent across the size ranges tested. Management scenarios utilizing the temperatures presently found in the Great Lakes (e.g., predicted growth at an average temperature of 11.7°C and 14.4°C during a 30-d period) demonstrated no difference in growth between the two morphotypes. Due to a lack of consistent differences between lean and humper Lake Trout, we developed a model that combined data from both morphotypes. The combined model yielded results similar to those of the morphotype-specific models, suggesting that accounting for morphotype differences may not be necessary in bioenergetics modeling of lean and humper Lake Trout.

Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model

PubMed Central

Brunetti, Dario; Dusi, Sabrina; Giordano, Carla; Lamperti, Costanza; Morbin, Michela; Fugnanesi, Valeria; Marchet, Silvia; Fagiolari, Gigliola; Sibon, Ody; Moggio, Maurizio; d’Amati, Giulia

2014-01-01

Pantothenate kinase-associated neurodegeneration, caused by mutations in the PANK2 gene, is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration and brain iron accumulation. PANK2 encodes the mitochondrial enzyme pantothenate kinase type 2, responsible for the phosphorylation of pantothenate or vitamin B5 in the biosynthesis of co-enzyme A. A Pank2 knockout (Pank2−/−) mouse model did not recapitulate the human disease but showed azoospermia and mitochondrial dysfunctions. We challenged this mouse model with a low glucose and high lipid content diet (ketogenic diet) to stimulate lipid use by mitochondrial beta-oxidation. In the presence of a shortage of co-enzyme A, this diet could evoke a general impairment of bioenergetic metabolism. Only Pank2−/− mice fed with a ketogenic diet developed a pantothenate kinase-associated neurodegeneration-like syndrome characterized by severe motor dysfunction, neurodegeneration and severely altered mitochondria in the central and peripheral nervous systems. These mice also showed structural alteration of muscle morphology, which was comparable with that observed in a patient with pantothenate kinase-associated neurodegeneration. We here demonstrate that pantethine administration can prevent the onset of the neuromuscular phenotype in mice suggesting the possibility of experimental treatment in patients with pantothenate kinase-associated neurodegeneration. PMID:24316510

Dietary fat overload reprograms brown fat mitochondria.

PubMed

Lettieri Barbato, Daniele; Tatulli, Giuseppe; Vegliante, Rolando; Cannata, Stefano M; Bernardini, Sergio; Ciriolo, Maria R; Aquilano, Katia

2015-01-01

Chronic nutrient overload accelerates the onset of several aging-related diseases reducing life expectancy. Although the mechanisms by which overnutrition affects metabolic processes in many tissues are known, its role on BAT physiology is still unclear. Herein, we investigated the mitochondrial responses in BAT of female mice exposed to high fat diet (HFD) at different steps of life. Although adult mice showed an unchanged mitochondrial amount, both respiration and OxPHOS subunits were strongly affected. Differently, offspring pups exposed to HFD during pregnancy and lactation displayed reduced mitochondrial mass but high oxidative efficiency that, however, resulted in increased bioenergetics state of BAT rather than augmented uncoupling respiration. Interestingly, the metabolic responses triggered by HFD were accompanied by changes in mitochondrial dynamics characterized by decreased content of the fragmentation marker Drp1 both in mothers and offspring pups. HFD-induced inactivation of the FoxO1 transcription factor seemed to be the up-stream modulator of Drp1 levels in brown fat cells. Furthermore, HFD offspring pups weaned with normal diet only partially reverted the mitochondrial dysfunctions caused by HFD. Finally these mice failed in activating the thermogenic program upon cold exposure. Collectively our findings suggest that maternal dietary fat overload irreversibly commits BAT unresponsiveness to physiological stimuli such as cool temperature and this dysfunction in the early stage of life might negatively modulate health and lifespan.

Cellular stress induced by resazurin leads to autophagy and cell death via production of reactive oxygen species and mitochondrial impairment.

PubMed

Erikstein, Bjarte S; Hagland, Hanne R; Nikolaisen, Julie; Kulawiec, Mariola; Singh, Keshav K; Gjertsen, Bjørn T; Tronstad, Karl J

2010-10-15

Mitochondrial bioenergetics and reactive oxygen species (ROS) often play important roles in cellular stress mechanisms. In this study we investigated how these factors are involved in the stress response triggered by resazurin (Alamar Blue) in cultured cancer cells. Resazurin is a redox reactive compound widely used as reporter agent in assays of cell biology (e.g. cell viability and metabolic activity) due to its colorimetric and fluorimetric properties. In order to investigate resazurin-induced stress mechanisms we employed cells affording different metabolic and regulatory phenotypes. In HL-60 and Jurkat leukemia cells resazurin caused mitochondrial disintegration, respiratory dysfunction, reduced proliferation, and cell death. These effects were preceded by a burst of ROS, especially in HL-60 cells which were also more sensitive and contained autophagic vesicles. Studies in Rho(0) cells (devoid of mitochondrial DNA) indicated that the stress response does not depend on the rates of mitochondrial respiration. The anti-proliferative effect of resazurin was confirmed in native acute myelogenous leukemia (AML) blasts. In conclusion, the data suggest that resazurin triggers cellular ROS production and thereby initiates a stress response leading to mitochondrial dysfunction, reduced proliferation, autophagy, and cell degradation. The ability of cells to tolerate this type of stress may be important in toxicity and chemoresistance. © 2010 Wiley-Liss, Inc.

Mitochondria-targeted antioxidant mitotempo protects mitochondrial function against amyloid beta toxicity in primary cultured mouse neurons.

PubMed

Hu, Hongtao; Li, Mo

2016-09-09

Mitochondrial defects including excess reactive oxygen species (ROS) production and compromised ATP generation are featured pathology in Alzheimer's disease (AD). Amyloid beta (Aβ)-mediated mitochondrial ROS overproduction disrupts intra-neuronal Redox balance, in turn exacerbating mitochondrial dysfunction leading to neuronal injury. Previous studies have found the beneficial effects of mitochondria-targeted antioxidants in preventing mitochondrial dysfunction and neuronal injury in AD animal and cell models, suggesting that mitochondrial ROS scavengers hold promise for the treatment of this neurological disorder. In this study, we have determined that mitotempo, a novel mitochondria-targeted antioxidant protects mitochondrial function from the toxicity of Aβ in primary cultured neurons. Our results showed that Aβ-promoted mitochondrial superoxide production and neuronal lipid oxidation were significantly suppressed by the application of mitotempo. Moreover, mitotempo also demonstrated protective effects on mitochondrial bioenergetics evidenced by preserved mitochondrial membrane potential, cytochrome c oxidase activity as well as ATP production. In addition, the Aβ-induced mitochondrial DNA (mtDNA) depletion and decreased expression levels of mtDNA replication-related DNA polymerase gamma (DNA pol γ) and Twinkle were substantially mitigated by mitotempo. Therefore, our study suggests that elimination of excess mitochondrial ROS rescues mitochondrial function in Aβ-insulted neruons; and mitotempo has the potential to be a promising therapeutic agent to protect mitochondrial and neuronal function in AD. Copyright © 2016 Elsevier Inc. All rights reserved.

Aldehydic load and aldehyde dehydrogenase 2 profile during the progression of post-myocardial infarction cardiomyopathy: benefits of Alda-1

PubMed Central

Gomes, Katia M.S.; Bechara, Luiz R.G.; Lima, Vanessa M.; Ribeiro, Márcio A.C.; Campos, Juliane C.; Dourado, Paulo M.; Kowaltowski, Alicia J.; Mochly-Rosen, Daria; Ferreira, Julio C.B.

2015-01-01

Background/Objectives We previously demonstrated that reducing cardiac aldehydic load by aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme responsible for metabolizing the major lipid peroxidation product, protects against acute ischemia/reperfusion injury and chronic heart failure. However, time-dependent changes in ALDH2 profile, aldehydic load and mitochondrial bioenergetics during progression of post-myocardial infarction (post-MI) cardiomyopathy is unknown and should be established to determine the optimal time window for drug treatment. Methods Here we characterized cardiac ALDH2 activity and expression, lipid peroxidation, 4-hydroxy-2-nonenal (4-HNE) adduct formation, glutathione pool and mitochondrial energy metabolism and H2O2 release during the 4 weeks after permanent left anterior descending (LAD) coronary artery occlusion in rats. Results We observed a sustained disruption of cardiac mitochondrial function during the progression of post-MI cardiomyopathy, characterized by >50% reduced mitochondrial respiratory control ratios and up to 2 fold increase in H2O2 release. Mitochondrial dysfunction was accompanied by accumulation of cardiac and circulating lipid peroxides and 4-HNE protein adducts and down-regulation of electron transport chain complexes I and V. Moreover, increased aldehydic load was associated with a 90% reduction in cardiac ALDH2 activity and increased glutathione pool. Further supporting an ALDH2 mechanism, sustained Alda-1 treatment (starting 24hrs after permanent LAD occlusion surgery) prevented aldehydic overload, mitochondrial dysfunction and improved ventricular function in post-MI cardiomyopathy rats. Conclusion Taken together, our findings demonstrate a disrupted mitochondrial metabolism along with an insufficient cardiac ALDH2-mediated aldehyde clearance during the progression of ventricular dysfunction, suggesting a potential therapeutic value of ALDH2 activators during the progression of post-myocardial infarction cardiomyopathy. PMID:25464432

Carvedilol prevents functional deficits in peripheral nerve mitochondria of rats with oxaliplatin-evoked painful peripheral neuropathy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Areti, Aparna; Komirishetty, Prashanth; Kumar, Ash

Oxaliplatin use as chemotherapeutic agent is frequently limited by cumulative neurotoxicity which may compromise quality of life. Reports relate this neurotoxic effect to oxidative stress and mitochondrial dysfunction in peripheral nerves and dorsal root ganglion (DRG). Carvedilol is an antihypertensive drug, has also been appreciated for its antioxidant and mitoprotective properties. Carvedilol co-treatment did not reduce the anti-tumor effects of oxaliplatin in human colon cancer cells (HT-29), but exhibited free radical scavenging activity against oxaliplatin-induced oxidative stress in neuronal cells (Neuro-2a). Hence, the present study was designed to investigate the effect of carvedilol in the experimental model of oxaliplatin-induced peripheralmore » neuropathy (OIPN) in Sprague-Dawley rats. Oxaliplatin reduced the sensory nerve conduction velocity and produced the thermal and mechanical nociception. Carvedilol significantly (P < 0.001) attenuated these functional and sensorimotor deficits. It also counteracted oxidative/nitrosative stress by reducing the levels of nitrotyrosine and improving the mitochondrial superoxide dismutase expression in both sciatic nerve and DRG tissues. It improved the mitochondrial function and prevented the oxaliplatin-induced alteration in mitochondrial membrane potential in sciatic nerve thus prevented loss of intra epidermal nerve fiber density in the foot pads. Together the results prompt the use of carvedilol along with chemotherapy with oxaliplatin to prevent the peripheral neuropathy. - Graphical abstract: Schematic representation neuroprotective mechanisms of carvedilol in oxaliplatin-induced peripheral neuropathy. - Highlights: • Oxaliplatin-induced mitochondrial dysfunction causes neurotoxicity. • Mitochondrial dysfunction leads to bioenergetic and functional deficits. • Carvedilol alleviated oxaliplatin-induced behavioural and functional changes. • Targeting mitochondria with carvedilol attenuated neuropathic pain.« less

Defects in mitochondrial localization and ATP synthesis in the mdx mouse model of Duchenne muscular dystrophy are not alleviated by PDE5 inhibition

PubMed Central

Percival, Justin M.; Siegel, Michael P.; Knowels, Gary; Marcinek, David J.

2013-01-01

Given the crucial roles for mitochondria in ATP energy supply, Ca2+ handling and cell death, mitochondrial dysfunction has long been suspected to be an important pathogenic feature in Duchenne muscular dystrophy (DMD). Despite this foresight, mitochondrial function in dystrophin-deficient muscles has remained poorly defined and unknown in vivo. Here, we used the mdx mouse model of DMD and non-invasive spectroscopy to determine the impact of dystrophin-deficiency on skeletal muscle mitochondrial localization and oxidative phosphorylation function in vivo. Mdx mitochondria exhibited significant uncoupling of oxidative phosphorylation (reduced P/O) and a reduction in maximal ATP synthesis capacity that together decreased intramuscular ATP levels. Uncoupling was not driven by increased UCP3 or ANT1 expression. Dystrophin was required to maintain subsarcolemmal mitochondria (SSM) pool density, implicating it in the spatial control of mitochondrial localization. Given that nitric oxide-cGMP pathways regulate mitochondria and that sildenafil-mediated phosphodiesterase 5 inhibition ameliorates dystrophic pathology, we tested whether sildenafil's benefits result from decreased mitochondrial dysfunction in mdx mice. Unexpectedly, sildenafil treatment did not affect mitochondrial content or oxidative phosphorylation defects in mdx mice. Rather, PDE5 inhibition decreased resting levels of ATP, phosphocreatine and myoglobin, suggesting that sildenafil improves dystrophic pathology through other mechanisms. Overall, these data indicate that dystrophin-deficiency disrupts SSM localization, promotes mitochondrial inefficiency and restricts maximal mitochondrial ATP-generating capacity. Together these defects decrease intramuscular ATP and the ability of mdx muscle mitochondria to meet ATP demand. These findings further understanding of how mitochondrial bioenergetic dysfunction contributes to disease pathogenesis in dystrophin-deficient skeletal muscle in vivo. PMID:23049075

A Mitochondrial-Targeted Coenzyme Q Analog Prevents Weight Gain and Ameliorates Hepatic Dysfunction in High-Fat–Fed Mice

PubMed Central

Fink, Brian D.; Herlein, Judith A.; Guo, Deng Fu; Kulkarni, Chaitanya; Weidemann, Benjamin J.; Yu, Liping; Grobe, Justin L.; Rahmouni, Kamal; Kerns, Robert J.

2014-01-01

We hypothesized that the mitochondrial-targeted antioxidant, mitoquinone (mitoQ), known to have mitochondrial uncoupling properties, might prevent the development of obesity and mitigate liver dysfunction by increasing energy expenditure, as opposed to reducing energy intake. We administered mitoQ or vehicle (ethanol) to obesity-prone C57BL/6 mice fed high-fat (HF) or normal-fat (NF) diets. MitoQ (500 µM) or vehicle (ethanol) was added to the drinking water for 28 weeks. MitoQ significantly reduced total body mass and fat mass in the HF-fed mice but had no effect on these parameters in NF mice. Food intake was reduced by mitoQ in the HF-fed but not in the NF-fed mice. Average daily water intake was reduced by mitoQ in both the NF- and HF-fed mice. Hypothalamic expression of neuropeptide Y, agouti-related peptide, and the long form of the leptin receptor were reduced in the HF but not in the NF mice. Hepatic total fat and triglyceride content did not differ between the mitoQ-treated and control HF-fed mice. However, mitoQ markedly reduced hepatic lipid hydroperoxides and reduced circulating alanine aminotransferase, a marker of liver function. MitoQ did not alter whole-body oxygen consumption or liver mitochondrial oxygen utilization, membrane potential, ATP production, or production of reactive oxygen species. In summary, mitoQ added to drinking water mitigated the development of obesity. Contrary to our hypothesis, the mechanism involved decreased energy intake likely mediated at the hypothalamic level. MitoQ also ameliorated HF-induced liver dysfunction by virtue of its antioxidant properties without altering liver fat or mitochondrial bioenergetics. PMID:25301169

A mitochondrial-targeted coenzyme q analog prevents weight gain and ameliorates hepatic dysfunction in high-fat-fed mice.

PubMed

Fink, Brian D; Herlein, Judith A; Guo, Deng Fu; Kulkarni, Chaitanya; Weidemann, Benjamin J; Yu, Liping; Grobe, Justin L; Rahmouni, Kamal; Kerns, Robert J; Sivitz, William I

2014-12-01

We hypothesized that the mitochondrial-targeted antioxidant, mitoquinone (mitoQ), known to have mitochondrial uncoupling properties, might prevent the development of obesity and mitigate liver dysfunction by increasing energy expenditure, as opposed to reducing energy intake. We administered mitoQ or vehicle (ethanol) to obesity-prone C57BL/6 mice fed high-fat (HF) or normal-fat (NF) diets. MitoQ (500 µM) or vehicle (ethanol) was added to the drinking water for 28 weeks. MitoQ significantly reduced total body mass and fat mass in the HF-fed mice but had no effect on these parameters in NF mice. Food intake was reduced by mitoQ in the HF-fed but not in the NF-fed mice. Average daily water intake was reduced by mitoQ in both the NF- and HF-fed mice. Hypothalamic expression of neuropeptide Y, agouti-related peptide, and the long form of the leptin receptor were reduced in the HF but not in the NF mice. Hepatic total fat and triglyceride content did not differ between the mitoQ-treated and control HF-fed mice. However, mitoQ markedly reduced hepatic lipid hydroperoxides and reduced circulating alanine aminotransferase, a marker of liver function. MitoQ did not alter whole-body oxygen consumption or liver mitochondrial oxygen utilization, membrane potential, ATP production, or production of reactive oxygen species. In summary, mitoQ added to drinking water mitigated the development of obesity. Contrary to our hypothesis, the mechanism involved decreased energy intake likely mediated at the hypothalamic level. MitoQ also ameliorated HF-induced liver dysfunction by virtue of its antioxidant properties without altering liver fat or mitochondrial bioenergetics. U.S. Government work not protected by U.S. copyright.

Monoamine Oxidase B Prompts Mitochondrial and Cardiac Dysfunction in Pressure Overloaded Hearts

PubMed Central

Kaludercic, Nina; Carpi, Andrea; Nagayama, Takahiro; Sivakumaran, Vidhya; Zhu, Guangshuo; Lai, Edwin W.; Bedja, Djahida; De Mario, Agnese; Chen, Kevin; Gabrielson, Kathleen L.; Lindsey, Merry L.; Pacak, Karel; Takimoto, Eiki; Shih, Jean C.; Kass, David A.; Di Lisa, Fabio

2014-01-01

Abstract Aims: Monoamine oxidases (MAOs) are mitochondrial flavoenzymes responsible for neurotransmitter and biogenic amines catabolism. MAO-A contributes to heart failure progression via enhanced norepinephrine catabolism and oxidative stress. The potential pathogenetic role of the isoenzyme MAO-B in cardiac diseases is currently unknown. Moreover, it is has not been determined yet whether MAO activation can directly affect mitochondrial function. Results: In wild type mice, pressure overload induced by transverse aortic constriction (TAC) resulted in enhanced dopamine catabolism, left ventricular (LV) remodeling, and dysfunction. Conversely, mice lacking MAO-B (MAO-B−/−) subjected to TAC maintained concentric hypertrophy accompanied by extracellular signal regulated kinase (ERK)1/2 activation, and preserved LV function, both at early (3 weeks) and late stages (9 weeks). Enhanced MAO activation triggered oxidative stress, and dropped mitochondrial membrane potential in the presence of ATP synthase inhibitor oligomycin both in neonatal and adult cardiomyocytes. The MAO-B inhibitor pargyline completely offset this change, suggesting that MAO activation induces a latent mitochondrial dysfunction, causing these organelles to hydrolyze ATP. Moreover, MAO-dependent aldehyde formation due to inhibition of aldehyde dehydrogenase 2 activity also contributed to alter mitochondrial bioenergetics. Innovation: Our study unravels a novel role for MAO-B in the pathogenesis of heart failure, showing that both MAO-driven reactive oxygen species production and impaired aldehyde metabolism affect mitochondrial function. Conclusion: Under conditions of chronic hemodynamic stress, enhanced MAO-B activity is a major determinant of cardiac structural and functional disarrangement. Both increased oxidative stress and the accumulation of aldehyde intermediates are likely liable for these adverse morphological and mechanical changes by directly targeting mitochondria. Antioxid. Redox Signal. 20, 267–280. PMID:23581564

Attempting to Compensate for Reduced Neuronal Nitric Oxide Synthase Protein with Nitrate Supplementation Cannot Overcome Metabolic Dysfunction but Rather Has Detrimental Effects in Dystrophin-Deficient mdx Muscle.

PubMed

Timpani, Cara A; Trewin, Adam J; Stojanovska, Vanesa; Robinson, Ainsley; Goodman, Craig A; Nurgali, Kulmira; Betik, Andrew C; Stepto, Nigel; Hayes, Alan; McConell, Glenn K; Rybalka, Emma

2017-04-01

Duchenne muscular dystrophy arises from the loss of dystrophin and is characterized by calcium dysregulation, muscular atrophy, and metabolic dysfunction. The secondary reduction of neuronal nitric oxide synthase (nNOS) from the sarcolemma reduces NO production and bioavailability. As NO modulates glucose uptake, metabolism, and mitochondrial bioenergetics, we investigated whether an 8-week nitrate supplementation regimen could overcome metabolic dysfunction in the mdx mouse. Dystrophin-positive control (C57BL/10) and dystrophin-deficient mdx mice were supplemented with sodium nitrate (85 mg/l) in drinking water. Following the supplementation period, extensor digitorum longus and soleus were excised and radioactive glucose uptake was measured at rest (basal) and during contraction. Gastrocnemius was excised and mitochondrial respiration was measured using the Oroboros Oxygraph. Tibialis anterior was analyzed immunohistochemically for the presence of dystrophin, nNOS, nitrotyrosine, IgG and CD45+ cells, and histologically to assess areas of damage and regeneration. Glucose uptake in the basal and contracting states was normal in unsupplemented mdx muscles but was reduced following nitrate supplementation in mdx muscles only. The mitochondrial utilization of substrates was also impaired in mdx gastrocnemius during phosphorylating and maximal uncoupled respiration, and nitrate could not improve respiration in mdx muscle. Although nitrate supplementation reduced mitochondrial hydrogen peroxide emission, it induced mitochondrial uncoupling in red gastrocnemius, increased muscle fiber peroxynitrite (nitrotyrosine), and promoted skeletal muscle damage. Our novel data suggest that despite lower nNOS protein expression and likely lower NO production in mdx muscle, enhancing NO production with nitrate supplementation in these mice has detrimental effects on skeletal muscle. This may have important relevance for those with DMD.

Effect of S-adenosyl-L-methionine (SAM), an allosteric activator of cystathionine-β-synthase (CBS) on colorectal cancer cell proliferation and bioenergetics in vitro.

PubMed

Módis, Katalin; Coletta, Ciro; Asimakopoulou, Antonia; Szczesny, Bartosz; Chao, Celia; Papapetropoulos, Andreas; Hellmich, Mark R; Szabo, Csaba

2014-09-15

Recent data show that colon cancer cells selectively overexpress cystathionine-β-synthase (CBS), which produces hydrogen sulfide (H2S), to maintain cellular bioenergetics, support tumor growth and stimulate angiogenesis and vasorelaxation in the tumor microenvironment. The purpose of the current study was to investigate the effect of the allosteric CBS activator S-adenosyl-L-methionine (SAM) on the proliferation and bioenergetics of the CBS-expressing colon cancer cell line HCT116. The non-transformed, non-tumorigenic colon epithelial cell line NCM356 was used as control. For assessment of cell proliferation, the xCELLigence system was used. Bioenergetic function was measured by Extracellular Flux Analysis. Experiments using human recombinant CBS or HCT116 homogenates complemented the cell-based studies. SAM markedly enhanced CBS-mediated H2S production in vitro, especially when a combination of cysteine and homocysteine was used as substrates. Addition of SAM (0.1-3 mM) to HCT116 cells induced a concentration-dependent increase H2S production. SAM exerted time- and concentration-dependent modulatory effects on cell proliferation. At 0.1-1 mM SAM increased HCT116 proliferation between 0 and 12 h, while the highest SAM concentration (3 mM) inhibited proliferation. Over a longer time period (12-24 h), only the lowest concentration of SAM used (0.1 mM) stimulated cell proliferation; higher SAM concentrations produced a concentration-dependent inhibition. The short-term stimulatory effects of SAM were attenuated by the CBS inhibitor aminooxyacetic acid (AOAA) or by stable silencing of CBS. In contrast, the inhibitory effects of SAM on cell proliferation was unaffected by CBS inhibition or CBS silencing. In contrast to HCT116 cells, the lower rate of proliferation of the low-CBS expressor NCM356 cells was unaffected by SAM. Short-term (1 h) exposure of HCT116 cells to SAM induced a concentration-dependent increase in oxygen consumption and bioenergetic function at 0.1-1 mM, while 3 mM was inhibitory. Longer-term (72 h) exposure of HCT116 cells to all concentrations of SAM tested suppressed mitochondrial oxygen consumption rate, cellular ATP content and cell viability. The stimulatory effect of SAM on bioenergetics was attenuated in cells with stable CBS silencing, while the inhibitory effects were unaffected. In NCM356 cells SAM exerted smaller effects on cellular bioenergetics than in HCT116 cells. We have also observed a downregulation of CBS in response to prolonged exposure of SAM both in HCT116 and NCM356 cells. Taken together, the results demonstrate that H2S production in HCT116 cells is stimulated by the allosteric CBS activator, SAM. At low-to intermediate levels and early time periods the resulting H2S serves as an endogenous cancer cell growth and bioenergetic factor. In contrast, the inhibition of cell proliferation and bioenergetic function by SAM does not appear to relate to adverse autocrine effects of H2S resulting from CBS over-stimulation but, rather to CBS-independent pharmacological effects. Copyright © 2014 Elsevier Inc. All rights reserved.

Constraints of bioenergetics on the ecology and distribution of vertebrate ectotherms. Final report, 1 September 1988--30 June 1990

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spotila, J.R.

1992-11-01

The constraints of bioenergetics on the ecology and distribution of vertebrate ectotherms were quantified. During this project we conducted studies: to determine the role of incubation temperature on the post-hatching growth rate of the snapping turtle, Chelydra serpentina; to establish the rate of energy expenditure of the slider turtle, Trachemys scripta, in the field; to determine the field metabolic rates, body temperatures and selected microclimates of the box turtle, Terrapene carolina, and to measure the effect of diet type on the consumption rate, digestion rate and digestive efficiency of adult T. scripta. We also completed our research on the three-dimensionalmore » bioenergetic climate space for freshwater turtles.« less

Development of a stress response therapy targeting aggressive prostate cancer.

PubMed

Nguyen, Hao G; Conn, Crystal S; Kye, Yae; Xue, Lingru; Forester, Craig M; Cowan, Janet E; Hsieh, Andrew C; Cunningham, John T; Truillet, Charles; Tameire, Feven; Evans, Michael J; Evans, Christopher P; Yang, Joy C; Hann, Byron; Koumenis, Constantinos; Walter, Peter; Carroll, Peter R; Ruggero, Davide

2018-05-02

Oncogenic lesions up-regulate bioenergetically demanding cellular processes, such as protein synthesis, to drive cancer cell growth and continued proliferation. However, the hijacking of these key processes by oncogenic pathways imposes onerous cell stress that must be mitigated by adaptive responses for cell survival. The mechanism by which these adaptive responses are established, their functional consequences for tumor development, and their implications for therapeutic interventions remain largely unknown. Using murine and humanized models of prostate cancer (PCa), we show that one of the three branches of the unfolded protein response is selectively activated in advanced PCa. This adaptive response activates the phosphorylation of the eukaryotic initiation factor 2-α (P-eIF2α) to reset global protein synthesis to a level that fosters aggressive tumor development and is a marker of poor patient survival upon the acquisition of multiple oncogenic lesions. Using patient-derived xenograft models and an inhibitor of P-eIF2α activity, ISRIB, our data show that targeting this adaptive brake for protein synthesis selectively triggers cytotoxicity against aggressive metastatic PCa, a disease for which presently there is no cure. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Adversity, Adaptive Calibration, and Health: The Case of Disadvantaged Families.

PubMed

de Baca, Tomás Cabeza; Wahl, Richard A; Barnett, Melissa A; Figueredo, Aurelio José; Ellis, Bruce J

2016-06-01

Epidemiologists and medical researchers often employ an allostatic load model that focuses on environmental and lifestyle factors, together with biological vulnerabilities, to explain the deterioration of human physiological systems and chronic degenerative disease. Although this perspective has informed medicine and public health, it is agnostic toward the functional significance of pathophysiology and health deterioration. Drawing on Life History (LH) theory, the current paper reviews the literature on disadvantaged families to serve as a conceptual model of stress-health relationships in which the allocation of reproductive effort is instantiated in the LH strategies of individuals and reflects the bioenergetic and material resource tradeoffs . We propose that researchers interested in health disparities reframe chronic degenerative diseases as outcomes resulting from strategic calibration of physiological systems to best adapt, survive, and reproduce in response to demands of specific developmental contexts. These effects of adversity on later-age degenerative disease are mediated, in part, by socioemotional and cognitive mechanisms expressed in different life history strategies.

Adversity, Adaptive Calibration, and Health: The Case of Disadvantaged Families

PubMed Central

de Baca, Tomás Cabeza; Wahl, Richard A.; Barnett, Melissa A.; Figueredo, Aurelio José; Ellis, Bruce J.

2016-01-01

Epidemiologists and medical researchers often employ an allostatic load model that focuses on environmental and lifestyle factors, together with biological vulnerabilities, to explain the deterioration of human physiological systems and chronic degenerative disease. Although this perspective has informed medicine and public health, it is agnostic toward the functional significance of pathophysiology and health deterioration. Drawing on Life History (LH) theory, the current paper reviews the literature on disadvantaged families to serve as a conceptual model of stress-health relationships in which the allocation of reproductive effort is instantiated in the LH strategies of individuals and reflects the bioenergetic and material resource tradeoffs. We propose that researchers interested in health disparities reframe chronic degenerative diseases as outcomes resulting from strategic calibration of physiological systems to best adapt, survive, and reproduce in response to demands of specific developmental contexts. These effects of adversity on later-age degenerative disease are mediated, in part, by socioemotional and cognitive mechanisms expressed in different life history strategies. PMID:27175327

Climate change in fish: effects of respiratory constraints on optimal life history and behaviour.

PubMed

Holt, Rebecca E; Jørgensen, Christian

2015-02-01

The difference between maximum metabolic rate and standard metabolic rate is referred to as aerobic scope, and because it constrains performance it is suggested to constitute a key limiting process prescribing how fish may cope with or adapt to climate warming. We use an evolutionary bioenergetics model for Atlantic cod (Gadus morhua) to predict optimal life histories and behaviours at different temperatures. The model assumes common trade-offs and predicts that optimal temperatures for growth and fitness lie below that for aerobic scope; aerobic scope is thus a poor predictor of fitness at high temperatures. Initially, warming expands aerobic scope, allowing for faster growth and increased reproduction. Beyond the optimal temperature for fitness, increased metabolic requirements intensify foraging and reduce survival; oxygen budgeting conflicts thus constrain successful completion of the life cycle. The model illustrates how physiological adaptations are part of a suite of traits that have coevolved. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Apoptosis-Inducing Factor (AIF) in Physiology and Disease: The Tale of a Repented Natural Born Killer.

PubMed

Bano, Daniele; Prehn, Jochen H M

2018-04-01

Apoptosis-inducing factor (AIF) is a mitochondrial oxidoreductase that contributes to cell death programmes and participates in the assembly of the respiratory chain. Importantly, AIF deficiency leads to severe mitochondrial dysfunction, causing muscle atrophy and neurodegeneration in model organisms as well as in humans. The purpose of this review is to describe functions of AIF and AIF-interacting proteins as regulators of cell death and mitochondrial bioenergetics. We describe how AIF deficiency induces pathogenic processes that alter metabolism and ultimately compromise cellular homeostasis. We report the currently known AIFM1 mutations identified in humans and discuss the variability of AIFM1-related disorders in terms of onset, organ involvement and symptoms. Finally, we summarize how the study of AIFM1-linked pathologies may help to further expand our understanding of rare inherited forms of mitochondrial diseases. Copyright © 2018 German Center for Neurodegenerative Diseases (DZNE). Published by Elsevier B.V. All rights reserved.

Creatine protects against mitochondrial dysfunction associated with HIV-1 Tat-induced neuronal injury.

PubMed

Stevens, Patrick R; Gawryluk, Jeremy W; Hui, Liang; Chen, Xuesong; Geiger, Jonathan D

2014-01-01

HIV-1 infected individuals live longer but experience a prevalence rate of over 50% for HIV-1 associated neurocognitive disorders (HAND) for which no effective treatment is available. Viral and cellular factors secreted by HIV-1 infected cells lead to neuronal injury and HIV-1 Tat continues to be implicated in the pathogenesis of HAND. Here we tested the hypothesis that creatine protected against HIV-1 Tat-induced neuronal injury by preventing mitochondrial bioenergetic crisis and/or redox catastrophe. Creatine blocked HIV-1 Tat(1-72)-induced increases in neuron cell death and synaptic area loss. Creatine protected against HIV-1 Tat-induced decreases in ATP. Creatine and creatine plus HIV-1 Tat increased cellular levels of creatine, and creatine plus HIV-1 Tat further decreased ratios of phosphocreatine to creatine observed with creatine or HIV-1 Tat treatments alone. Additionally, creatine protected against HIV-1 Tat-induced mitochondrial hypopolarization and HIV-1 Tat-induced mitochondrial permeability transition pore opening. Thus, creatine may be a useful adjunctive therapy against HAND.

Microglial brain region-dependent diversity and selective regional sensitivities to ageing

PubMed Central

Grabert, Kathleen; Michoel, Tom; Karavolos, Michail H; Clohisey, Sara; Baillie, J Kenneth; Stevens, Mark P; Freeman, Tom C; Summers, Kim M; McColl, Barry W

2015-01-01

Microglia play critical roles in neural development, homeostasis and neuroinflammation and are increasingly implicated in age-related neurological dysfunction. Neurodegeneration often occurs in disease-specific spatially-restricted patterns, the origins of which are unknown. We performed the first genome-wide analysis of microglia from discrete brain regions across the adult lifespan of the mouse and reveal that microglia have distinct region-dependent transcriptional identities and age in a regionally variable manner. In the young adult brain, differences in bioenergetic and immunoregulatory pathways were the major sources of heterogeneity and suggested that cerebellar and hippocampal microglia exist in a more immune vigilant state. Immune function correlated with regional transcriptional patterns. Augmentation of the distinct cerebellar immunophenotype and a contrasting loss in distinction of the hippocampal phenotype among forebrain regions were key features during ageing. Microglial diversity may enable regionally localised homeostatic functions but could also underlie region-specific sensitivities to microglial dysregulation and involvement in age-related neurodegeneration. PMID:26780511

A Systems Biology Approach Identifies Molecular Networks Defining Skeletal Muscle Abnormalities in Chronic Obstructive Pulmonary Disease

PubMed Central

Turan, Nil; Kalko, Susana; Stincone, Anna; Clarke, Kim; Sabah, Ayesha; Howlett, Katherine; Curnow, S. John; Rodriguez, Diego A.; Cascante, Marta; O'Neill, Laura; Egginton, Stuart; Roca, Josep; Falciani, Francesco

2011-01-01

Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory process of the lung inducing persistent airflow limitation. Extensive systemic effects, such as skeletal muscle dysfunction, often characterize these patients and severely limit life expectancy. Despite considerable research efforts, the molecular basis of muscle degeneration in COPD is still a matter of intense debate. In this study, we have applied a network biology approach to model the relationship between muscle molecular and physiological response to training and systemic inflammatory mediators. Our model shows that failure to co-ordinately activate expression of several tissue remodelling and bioenergetics pathways is a specific landmark of COPD diseased muscles. Our findings also suggest that this phenomenon may be linked to an abnormal expression of a number of histone modifiers, which we discovered correlate with oxygen utilization. These observations raised the interesting possibility that cell hypoxia may be a key factor driving skeletal muscle degeneration in COPD patients. PMID:21909251

Protective Effect of a Mitochondria-Targeted Peptide against the Development of Chemotherapy-Induced Peripheral Neuropathy in Mice.

PubMed

Toyama, Satoshi; Shimoyama, Naohito; Szeto, Hazel H; Schiller, Peter W; Shimoyama, Megumi

2018-04-18

Several chemotherapeutic agents used for cancer treatment induce dose-limiting peripheral neuropathy that compromises patients' quality of life and limits cancer treatment. Recently, mitochondrial dysfunction has been shown to be involved in the mechanism of chemotherapy-induced peripheral neuropathy. SS-20 is a mitochondria-targeted peptide that promotes mitochondrial respiration and restores mitochondrial bioenergetics. In the present study, we examined the protective effect of SS-20 against the development of chemotherapy-induced peripheral neuropathy utilizing a murine model of peripheral neuropathy induced by oxaliplatin, a first-line chemotherapy agent for colon cancer. Weekly administrations of oxaliplatin induced peripheral neuropathy as demonstrated by the development of neuropathic pain and loss of intraepidermal nerve fibers in the hind paw. Continuous administration of SS-20 protected against the development of oxaliplatin-induced neuropathic pain and mitigated the loss of intraepidermal nerve fibers to normal levels. Our findings suggest that SS-20 may be a drug candidate for the prevention of chemotherapy-induced peripheral neuropathy.

Cross Talk of Proteostasis and Mitostasis in Cellular Homeodynamics, Ageing, and Disease

PubMed Central

Gumeni, Sentiljana; Trougakos, Ioannis P.

2016-01-01

Mitochondria are highly dynamic organelles that provide essential metabolic functions and represent the major bioenergetic hub of eukaryotic cell. Therefore, maintenance of mitochondria activity is necessary for the proper cellular function and survival. To this end, several mechanisms that act at different levels and time points have been developed to ensure mitochondria quality control. An interconnected highly integrated system of mitochondrial and cytosolic chaperones and proteases along with the fission/fusion machinery represents the surveillance scaffold of mitostasis. Moreover, nonreversible mitochondrial damage targets the organelle to a specific autophagic removal, namely, mitophagy. Beyond the organelle dynamics, the constant interaction with the ubiquitin-proteasome-system (UPS) has become an emerging aspect of healthy mitochondria. Dysfunction of mitochondria and UPS increases with age and correlates with many age-related diseases including cancer and neurodegeneration. In this review, we discuss the functional cross talk of proteostasis and mitostasis in cellular homeodynamics and the impairment of mitochondrial quality control during ageing, cancer, and neurodegeneration. PMID:26977249

Bioenergetic properties of human sarcoma cells help define sensitivity to metabolic inhibitors

PubMed Central

Issaq, Sameer H; Teicher, Beverly A; Monks, Anne

2014-01-01

Sarcomas represent a diverse group of malignancies with distinct molecular and pathological features. A better understanding of the alterations associated with specific sarcoma subtypes is critically important to improve sarcoma treatment. Renewed interest in the metabolic properties of cancer cells has led to an exploration of targeting metabolic dependencies as a therapeutic strategy. In this study, we have characterized key bioenergetic properties of human sarcoma cells in order to identify metabolic vulnerabilities between sarcoma subtypes. We have also investigated the effects of compounds that inhibit glycolysis or mitochondrial respiration, either alone or in combination, and examined relationships between bioenergetic parameters and sensitivity to metabolic inhibitors. Using 2-deoxy-D-glucose (2-DG), a competitive inhibitor of glycolysis, oligomycin, an inhibitor of mitochondrial ATP synthase, and metformin, a widely used anti-diabetes drug and inhibitor of complex I of the mitochondrial respiratory chain, we evaluated the effects of metabolic inhibition on sarcoma cell growth and bioenergetic function. Inhibition of glycolysis by 2-DG effectively reduced the viability of alveolar rhabdomyosarcoma cells vs. embryonal rhabdomyosarcoma, osteosarcoma, and normal cells. Interestingly, inhibitors of mitochondrial respiration did not significantly affect viability, but were able to increase sensitivity of sarcomas to inhibition of glycolysis. Additionally, inhibition of glycolysis significantly reduced intracellular ATP levels, and sensitivity to 2-DG-induced growth inhibition was related to respiratory rates and glycolytic dependency. Our findings demonstrate novel relationships between sarcoma bioenergetics and sensitivity to metabolic inhibitors, and suggest that inhibition of metabolic pathways in sarcomas should be further investigated as a potential therapeutic strategy. PMID:24553119

Measurement of Instantaneous Velocity Vectors of Organelle Transport: Mitochondrial Transport and Bioenergetics in Hippocampal Neurons

PubMed Central

Gerencser, Akos A.; Nicholls, David G.

2008-01-01

Impaired transport of mitochondria, in dendrites and axons of neurons, and bioenergetic deficit are increasingly recognized to be of pathological importance in neurodegenerative diseases. To study the relationship between transport and bioenergetics, we have developed what to our knowledge is a novel technique to quantify organelle velocity in cultured cells. The aim was to combine measurement of motion and bioenergetic parameters while minimizing photodynamic oxidative artifacts evoked by fluorescence excitation. Velocity determination from sequential fluorescence images is not trivial, and here we describe an application of “optical flow”, the flow of gray values in grayscale images, to this problem. Based on the principles of photon shot noise occurring in low light level fluorescence microscopy, we describe and validate here an optical flow-based, robust method to measure velocity vectors for organelles expressing fluorescent proteins. This method features instantaneous velocity determination from a pair of images by detecting motion of edges, with no assumptions about the separation or shapes of the objects in the image. Optical flow was used in combination with single mitochondrion assay of mitochondrial thiol redox status by mitochondrially targeted redox-sensitive green fluorescent protein and measurement of mitochondrial membrane potential by tetramethylrhodamine methyl ester. Mitochondrial populations of resting cultured hippocampal neurons were analyzed. It was found that mitochondria with more oxidized thiol redox status have lower membrane potentials and are smaller in size. These mitochondria are more motile than the average; however, mitochondrial motility is only slightly dependent on the observed bioenergetic parameters and is correlated the best to the size of the mitochondria. PMID:18757564

Development of a bioenergetics model for the threespine stickleback Gasterosteus aculeatus

USGS Publications Warehouse

Hovel, Rachel A.; Beauchamp, David A.; Hansen, Adam G.; Sorel, Mark H.

2016-01-01

The Threespine Stickleback Gasterosteus aculeatus is widely distributed across northern hemisphere ecosystems, has ecological influence as an abundant planktivore, and is commonly used as a model organism, but the species lacks a comprehensive model to describe bioenergetic performance in response to varying environmental or ecological conditions. This study parameterized a bioenergetics model for the Threespine Stickleback using laboratory measurements to determine mass- and temperature-dependent functions for maximum consumption and routine respiration costs. Maximum consumption experiments were conducted across a range of temperatures from 7.5°C to 23.0°C and a range of fish weights from 0.5 to 4.5 g. Respiration experiments were conducted across a range of temperatures from 8°C to 28°C. Model sensitivity was consistent with other comparable models in that the mass-dependent parameters for maximum consumption were the most sensitive. Growth estimates based on the Threespine Stickleback bioenergetics model suggested that 22°C is the optimal temperature for growth when food is not limiting. The bioenergetics model performed well when used to predict independent, paired measures of consumption and growth observed from a separate wild population of Threespine Sticklebacks. Predicted values for consumption and growth (expressed as percent body weight per day) only deviated from observed values by 2.0%. Our model should provide insight into the physiological performance of this species across a range of environmental conditions and be useful for quantifying the trophic impact of this species in food webs containing other ecologically or economically important species.

Bioenergetic components of reproductive effort in viviparous snakes: costs of vitellogenesis exceed costs of pregnancy.

PubMed

Van Dyke, James U; Beaupre, Steven J

2011-12-01

Reproductive effort has been defined as the proportion of an organism's energy budget that is allocated to reproduction over a biologically meaningful time period. Historically, studies of reproductive bioenergetics considered energy content of gametes, but not costs of gamete production. Although metabolic costs of vitellogenesis (MCV) fundamentally reflect the primary bioenergetic cost of reproductive allocation in female reptiles, the few investigations that have considered costs of reproductive allocation have focused on metabolic costs of pregnancy (MCP) in viviparous species. We define MCP as energetic costs incurred by pregnant females, including all costs of maintaining gestation conditions necessary for embryogenesis. MCP by our definition do not include fetal costs of embryogenesis. We measured metabolic rates in five species of viviparous snakes (Agkistrodon contortrix, Boa constrictor, Eryx colubrinus, Nerodia sipedon, and Thamnophis sirtalis) during vitellogenesis and pregnancy in order to estimate MCV and MCP. Across all species, MCV were responsible for 30% increases in maternal metabolism. Phylogenetically-independent contrasts showed that MCV were significantly greater in B. constrictor than in other species, likely because B. constrictor yolk energy content was greater than that of other species. Estimates of MCP were not significantly different from zero in any species. In viviparous snakes, MCV appear to represent significant bioenergetic expenditures, while MCP do not. We suggest that MCV, together with yolk energy content, represent the most significant component of reptilian reproductive effort, and therefore deserve greater attention than MCP in studies of reptilian reproductive bioenergetics. Copyright © 2011 Elsevier Inc. All rights reserved.

Bioenergetic evaluation of diel vertical migration by bull trout ( Salvelinus confluentus ) in a thermally stratified reservoir

Treesearch

Madeleine Eckmann; Jason Dunham; Edward J. Connor; Carmen A. Welch

2016-01-01

Many species living in deeper lentic ecosystems exhibit daily movements that cycle through the water column, generally referred to as diel vertical migration (DVM). In this study, we applied bioenergetics modelling to evaluate growth as a hypothesis to explain DVM by bull trout (Salvelinus confluentus) in a thermally stratified reservoir (Ross Lake...

A bioenergetic model for zebrafish Danio rerio (Hamilton)

USGS Publications Warehouse

Chizinski, C.J.; Sharma, Bibek; Pope, K.L.; Patino, R.

2008-01-01

A bioenergetics model was developed from observed consumption, respiration and growth rates for zebrafish Danio rerio across a range (18-32?? C) of water temperatures, and evaluated with a 50 day laboratory trial at 28?? C. No significant bias in variable estimates was found during the validation trial; namely, predicted zebrafish mass generally agreed with observed mass. ?? 2008 The Authors.

Glucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release

PubMed Central

Huber, Heinrich J; Dussmann, Heiko; Kilbride, Seán M; Rehm, Markus; Prehn, Jochen H M

2011-01-01

Many anticancer drugs activate caspases via the mitochondrial apoptosis pathway. Activation of this pathway triggers a concomitant bioenergetic crisis caused by the release of cytochrome-c (cyt-c). Cancer cells are able to evade these processes by altering metabolic and caspase activation pathways. In this study, we provide the first integrated system study of mitochondrial bioenergetics and apoptosis signalling and examine the role of mitochondrial cyt-c release in these events. In accordance with single-cell experiments, our model showed that loss of cyt-c decreased mitochondrial respiration by 95% and depolarised mitochondrial membrane potential ΔΨm from −142 to −88 mV, with active caspase-3 potentiating this decrease. ATP synthase was reversed under such conditions, consuming ATP and stabilising ΔΨm. However, the direction and level of ATP synthase activity showed significant heterogeneity in individual cancer cells, which the model explained by variations in (i) accessible cyt-c after release and (ii) the cell's glycolytic capacity. Our results provide a quantitative and mechanistic explanation for the protective role of enhanced glucose utilisation for cancer cells to avert the otherwise lethal bioenergetic crisis associated with apoptosis initiation. PMID:21364572

Evaluation of a Mysis bioenergetics model

USGS Publications Warehouse

Chipps, S.R.; Bennett, D.H.

2002-01-01

Direct approaches for estimating the feeding rate of the opossum shrimp Mysis relicta can be hampered by variable gut residence time (evacuation rate models) and non-linear functional responses (clearance rate models). Bioenergetics modeling provides an alternative method, but the reliability of this approach needs to be evaluated using independent measures of growth and food consumption. In this study, we measured growth and food consumption for M. relicta and compared experimental results with those predicted from a Mysis bioenergetics model. For Mysis reared at 10??C, model predictions were not significantly different from observed values. Moreover, decomposition of mean square error indicated that 70% of the variation between model predictions and observed values was attributable to random error. On average, model predictions were within 12% of observed values. A sensitivity analysis revealed that Mysis respiration and prey energy density were the most sensitive parameters affecting model output. By accounting for uncertainty (95% CLs) in Mysis respiration, we observed a significant improvement in the accuracy of model output (within 5% of observed values), illustrating the importance of sensitive input parameters for model performance. These findings help corroborate the Mysis bioenergetics model and demonstrate the usefulness of this approach for estimating Mysis feeding rate.

Redox mechanism of levobupivacaine cytostatic effect on human prostate cancer cells.

PubMed

Jose, Caroline; Hebert-Chatelain, Etienne; Dias Amoedo, Nivea; Roche, Emmanuel; Obre, Emilie; Lacombe, Didier; Rezvani, Hamid Reza; Pourquier, Philippe; Nouette-Gaulain, Karine; Rossignol, Rodrigue

2018-05-31

Anti-cancer effects of local anesthetics have been reported but the mode of action remains elusive. Here, we examined the bioenergetic and REDOX impact of levobupivacaine on human prostate cancer cells (DU145) and corresponding non-cancer primary human prostate cells (BHP). Levobupivacaine induced a combined inhibition of glycolysis and oxidative phosphorylation in cancer cells, resulting in a reduced cellular ATP production and consecutive bioenergetic crisis, along with reactive oxygen species generation. The dose-dependent inhibition of respiratory chain complex I activity by levobupivacaine explained the alteration of mitochondrial energy fluxes. Furthermore, the potency of levobupivacaine varied with glucose and oxygen availability as well as the cellular energy demand, in accordance with a bioenergetic anti-cancer mechanism. The levobupivacaine-induced bioenergetic crisis triggered cytostasis in prostate cancer cells as evidenced by a S-phase cell cycle arrest, without apoptosis induction. In DU145 cells, levobupivacaine also triggered the induction of autophagy and blockade of this process potentialized the anti-cancer effect of the local anesthetic. Therefore, our findings provide a better characterization of the REDOX mechanisms underpinning the anti-effect of levobupivacaine against human prostate cancer cells. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Translation, validation and cultural adaptation of "The Eustachian Tube Dysfunction Questionnaire-7" (ETDQ-7) to Brazilian Portuguese (BR).

PubMed

Gallardo, Fernanda Pires; Onishi, Ektor Tsuneo; Lira, Francisco Iure; Suzuki, Flávia Barros; Testa, José Ricardo Gurgel

2018-04-19

Chronic Eustachian tube dysfunction can cause several symptoms and middle ear conditions that can impact patient quality of life. It is estimated to be relatively frequent, affecting approximately 5% of adults. The diagnostic tools for this condition are still inadequate. In 2012, McCoul et al. published a questionnaire for the evaluation of Eustachian tube dysfunction named ETDQ-7. They established its replicability and validity. The cutoff point for the diagnosis of chronic Eustachian tube dysfunction was equal to or greater than 14.5, with 100% sensitivity and 100% specificity. To translate, adapt and validate the ETDQ-7 questionnaire to Brazilian Portuguese. We translated the questionnaire into Brazilian Portuguese and applied it to 50 patients, 20 of whom had chronic Eustachian tube dysfunction, and 30 controls. The results obtained with the North-American questionnaire were confirmed in its Brazilian version. The cut-off point for the diagnosis of chronic Eustachian tube dysfunction was ≥14, also exhibiting high sensitivity and specificity, very similar to that of ETDQ-7. It is recommended that ETDQ-7 be used to complement the clinical history of patients with chronic Eustachian tube dysfunction; it can also be used as an important tool for diagnosis, patient follow-up and treatment management. Copyright © 2018 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

[Thermoresistance in Saccharomyces cerevisiae yeasts].

PubMed

Kaliuzhin, V A

2011-01-01

Under natural conditions, yeast Saccharomyces cerevisiae reproduce, as a rule, on the surface of solid or liquid medium. Thus, life cycle of yeast populations is substantially influenced by diurnal changes in ambient temperature. The pattern in the response of unrestricted yeast S. cerevisiae culture to changes in the temperature of cultivation is revealed experimentally. Yeast population, in the absence of environmental constraints on the functioning of cell chemosmotic bioenergetic system, demonstrates the ability of thermoresistance when the temperature of cultivation switches from the range of 12-36 degrees C to 37.5-40 degrees C. During the transient period that is associated with the temperature switching and lasts from 1 to 4 turnover cycles, yeast reproduction rate remains 1.5-2 times higher than under stationary conditions. This is due to evolutionary acquired adaptive activity of cell chemosmotic system. After the adaptive resources exhausting, yeast thermoresistance fully recovers at the temperature range of 12-36 degrees C within one generation time under conditions of both restricted and unrestricted nourishment. Adaptive significance of such thermoresistance seems obvious enough--it allows maintaining high reproduction rate in yeast when ambient temperature is reaching a brief maximum shortly after noon.

Bioenergetics estimate of the effects of stocking density on hatchery production of smallmouth bass fingerlings

USGS Publications Warehouse

Robel, G.L.; Fisher, W.L.

1999-01-01

Production of and consumption by hatchery-reared tingerling (age-0) smallmouth bass Micropterus dolomieu at various simulated stocking densities were estimated with a bioenergetics model. Fish growth rates and pond water temperatures during the 1996 growing season at two hatcheries in Oklahoma were used in the model. Fish growth and simulated consumption and production differed greatly between the two hatcheries, probably because of differences in pond fertilization and mortality rates. Our results suggest that appropriate stocking density depends largely on prey availability as affected by pond fertilization and on fingerling mortality rates. The bioenergetics model provided a useful tool for estimating production at various stocking density rates. However, verification of physiological parameters for age-0 fish of hatchery-reared species is needed.

NAD+ in Aging: Molecular Mechanisms and Translational Implications.

PubMed

Fang, Evandro F; Lautrup, Sofie; Hou, Yujun; Demarest, Tyler G; Croteau, Deborah L; Mattson, Mark P; Bohr, Vilhelm A

2017-10-01

The coenzyme NAD + is critical in cellular bioenergetics and adaptive stress responses. Its depletion has emerged as a fundamental feature of aging that may predispose to a wide range of chronic diseases. Maintenance of NAD + levels is important for cells with high energy demands and for proficient neuronal function. NAD + depletion is detected in major neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, cardiovascular disease and muscle atrophy. Emerging evidence suggests that NAD + decrements occur in various tissues during aging, and that physiological and pharmacological interventions bolstering cellular NAD + levels might retard aspects of aging and forestall some age-related diseases. Here, we discuss aspects of NAD + biosynthesis, together with putative mechanisms of NAD + action against aging, including recent preclinical and clinical trials. Published by Elsevier Ltd.

Testosterone Plus Low-Intensity Physical Training in Late Life Improves Functional Performance, Skeletal Muscle Mitochondrial Biogenesis, and Mitochondrial Quality Control in Male Mice

PubMed Central

Guo, Wen; Wong, Siu; Li, Michelle; Liang, Wentao; Liesa, Marc; Serra, Carlo; Jasuja, Ravi; Bartke, Andrzej; Kirkland, James L.; Shirihai, Orian; Bhasin, Shalender

2012-01-01

Testosterone supplementation increases muscle mass in older men but has not been shown to consistently improve physical function and activity. It has been hypothesized that physical exercise is required to induce the adaptations necessary for translation of testosterone-induced muscle mass gain into functional improvements. However, the effects of testosterone plus low intensity physical exercise training (T/PT) on functional performance and bioenergetics are unknown. In this pilot study, we tested the hypothesis that combined administration of T/PT would improve functional performance and bioenergetics in male mice late in life more than low-intensity physical training alone. 28-month old male mice were randomized to receive T/PT or vehicle plus physical training (V/PT) for 2 months. Compare to V/PT control, administration of T/PT was associated with improvements in muscle mass, grip strength, spontaneous physical movements, and respiratory activity. These changes were correlated with increased mitochondrial DNA copy number and expression of markers for mitochondrial biogenesis. Mice receiving T/PT also displayed increased expression of key elements for mitochondrial quality control, including markers for mitochondrial fission-and-fusion and mitophagy. Concurrently, mice receiving T/PT also displayed increased expression of markers for reduced tissue oxidative damage and improved muscle quality. Conclusion: Testosterone administered with low-intensity physical training improves grip strength, spontaneous movements, and respiratory activity. These functional improvements were associated with increased muscle mitochondrial biogenesis and improved mitochondrial quality control. PMID:23240002

Global Metabolic Stress of Isoeffort Continuous and High Intensity Interval Aerobic Exercise: A Comparative 1H NMR Metabonomic Study.

PubMed

Zafeiridis, Andreas; Chatziioannou, Anastasia Chrysovalantou; Sarivasiliou, Haralambos; Kyparos, Antonios; Nikolaidis, Michalis G; Vrabas, Ioannis S; Pechlivanis, Alexandros; Zoumpoulakis, Panagiotis; Baskakis, Constantinos; Dipla, Konstantina; Theodoridis, Georgios A

2016-12-02

The overall metabolic/energetic stress that occurs during an acute bout of exercise is proposed to be the main driving force for long-term training adaptations. Continuous and high-intensity interval exercise protocols (HIIE) are currently prescribed to acquire the muscular and metabolic benefits of aerobic training. We applied 1 H NMR-based metabonomics to compare the overall metabolic perturbation and activation of individual bioenergetic pathways of three popular aerobic exercises matched for effort/strain. Nine men performed continuous, long-interval (3 min), and short-interval (30 s) bouts of exercise under isoeffort conditions. Blood was collected before and after exercise. The multivariate PCA and OPLS-DA models showed a distinct separation of pre- and postexercise samples in three protocols. The two models did not discriminate the postexercise overall metabolic profiles of the three exercise types. Analysis focused on muscle bioenergetic pathways revealed an extensive upregulation of carbohydrate-lipid metabolism and the TCA cycle in all three protocols; there were only a few differences among protocols in the postexercise abundance of molecules when long-interval bouts were performed. In conclusion, continuous and HIIE exercise protocols, when performed with similar effort/strain, induce comparable global metabolic response/stress despite their marked differences in work-bout intensities. This study highlights the importance of NMR metabonomics in comprehensive monitoring of metabolic consequences of exercise training in the blood of athletes and exercising individuals.

AMP-activated Protein Kinase Mediates Apoptosis in Response to Bioenergetic Stress through Activation of the Pro-apoptotic Bcl-2 Homology Domain-3-only Protein BMF*

PubMed Central

Kilbride, Seán M.; Farrelly, Angela M.; Bonner, Caroline; Ward, Manus W.; Nyhan, Kristine C.; Concannon, Caoimhín G.; Wollheim, Claes B.; Byrne, Maria M.; Prehn, Jochen H. M.

2010-01-01

Heterozygous loss-of-function mutations in the hepatocyte nuclear factor 1A (HNF1A) gene result in the pathogenesis of maturity-onset diabetes-of-the-young type 3, (HNF1A-MODY). This disorder is characterized by a primary defect in metabolism-secretion coupling and decreased beta cell mass, attributed to excessive beta cell apoptosis. Here, we investigated the link between energy stress and apoptosis activation following HNF1A inactivation. This study employed single cell fluorescent microscopy, flow cytometry, gene expression analysis, and gene silencing to study the effects of overexpression of dominant-negative (DN)-HNF1A expression on cellular bioenergetics and apoptosis in INS-1 cells. Induction of DN-HNF1A expression led to reduced ATP levels and diminished the bioenergetic response to glucose. This was coupled with activation of the bioenergetic stress sensor AMP-activated protein kinase (AMPK), which preceded the onset of apoptosis. Pharmacological activation of AMPK using aminoimidazole carboxamide ribonucleotide (AICAR) was sufficient to induce apoptosis in naive cells. Conversely, inhibition of AMPK with compound C or AMPKα gene silencing protected against DN-HNF1A-induced apoptosis. Interestingly, AMPK mediated the induction of the pro-apoptotic Bcl-2 homology domain-3-only protein Bmf (Bcl-2-modifying factor). Bmf expression was also elevated in islets of DN-HNF1A transgenic mice. Furthermore, knockdown of Bmf expression in INS-1 cells using siRNA was sufficient to protect against DN-HNF1A-induced apoptosis. Our study suggests that overexpression of DN-HNF1A induces bioenergetic stress and activation of AMPK. This in turn mediates the transcriptional activation of the pro-apoptotic Bcl-2-homology protein BMF, coupling prolonged energy stress to apoptosis activation. PMID:20841353

Bioenergetic Effects of Mitochondrial-Targeted Coenzyme Q Analogs in Endothelial Cells

PubMed Central

Fink, Brian D.; Herlein, Judith A.; Yorek, Mark A.; Fenner, Amanda M.; Kerns, Robert J.

2012-01-01

Mitochondrial-targeted analogs of coenzyme Q (CoQ) are under development to reduce oxidative damage induced by a variety of disease states. However, there is a need to understand the bioenergetic effects of these agents and whether or not these effects are related to redox properties, including their known pro-oxidant effects. We examined the bioenergetic effects of two mitochondrial-targeted CoQ analogs in their quinol forms, mitoquinol (MitoQ) and plastoquinonyl-decyl-triphenylphosphonium (SkQ1), in bovine aortic endothelial cells. We used an extracellular oxygen and proton flux analyzer to assess mitochondrial action at the intact-cell level. Both agents, in dose-dependent fashion, reduced the oxygen consumption rate (OCR) directed at ATP turnover (OCRATP) (IC50 values of 189 ± 13 nM for MitoQ and 181 ± 7 for SKQ1; difference not significant) while not affecting or mildly increasing basal oxygen consumption. Both compounds increased extracellular acidification in the basal state consistent with enhanced glycolysis. Both compounds enhanced mitochondrial superoxide production assessed by using mitochondrial-targeted dihydroethidium, and both increased H2O2 production from mitochondria of cells treated before isolation of the organelles. The manganese superoxide dismutase mimetic manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin did not alter or actually enhanced the actions of the targeted CoQ analogs to reduce OCRATP. In contrast, N-acetylcysteine mitigated this effect of MitoQ and SkQ1. In summary, our data demonstrate the important bioenergetic effects of targeted CoQ analogs. Moreover, these effects are mediated, at least in part, through superoxide production but depend on conversion to H2O2. These bioenergetic and redox actions need to be considered as these compounds are developed for therapeutic purposes. PMID:22661629

Bioenergetic effects of mitochondrial-targeted coenzyme Q analogs in endothelial cells.

PubMed

Fink, Brian D; Herlein, Judith A; Yorek, Mark A; Fenner, Amanda M; Kerns, Robert J; Sivitz, William I

2012-09-01

Mitochondrial-targeted analogs of coenzyme Q (CoQ) are under development to reduce oxidative damage induced by a variety of disease states. However, there is a need to understand the bioenergetic effects of these agents and whether or not these effects are related to redox properties, including their known pro-oxidant effects. We examined the bioenergetic effects of two mitochondrial-targeted CoQ analogs in their quinol forms, mitoquinol (MitoQ) and plastoquinonyl-decyl-triphenylphosphonium (SkQ1), in bovine aortic endothelial cells. We used an extracellular oxygen and proton flux analyzer to assess mitochondrial action at the intact-cell level. Both agents, in dose-dependent fashion, reduced the oxygen consumption rate (OCR) directed at ATP turnover (OCR(ATP)) (IC₅₀ values of 189 ± 13 nM for MitoQ and 181 ± 7 for SKQ1; difference not significant) while not affecting or mildly increasing basal oxygen consumption. Both compounds increased extracellular acidification in the basal state consistent with enhanced glycolysis. Both compounds enhanced mitochondrial superoxide production assessed by using mitochondrial-targeted dihydroethidium, and both increased H₂O₂ production from mitochondria of cells treated before isolation of the organelles. The manganese superoxide dismutase mimetic manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin did not alter or actually enhanced the actions of the targeted CoQ analogs to reduce OCR(ATP). In contrast, N-acetylcysteine mitigated this effect of MitoQ and SkQ1. In summary, our data demonstrate the important bioenergetic effects of targeted CoQ analogs. Moreover, these effects are mediated, at least in part, through superoxide production but depend on conversion to H₂O₂. These bioenergetic and redox actions need to be considered as these compounds are developed for therapeutic purposes.

Differences in the bioenergetic potential of athletes participating in team sports.

PubMed

Malacko, Julijan; Doder, Dragan; Djurdjević, Slavisa; Savić, Biljana; Doder, Radoslava

2013-07-01

In modern training technology, assessment of aerobic bioenergetic potential in athletes is commonly performed by standard laboratory procedures to determine basic or specific functional abilities for specific sport activity or discipline. The aim of study was to assess the aerobic bioenergetic potential of athletes participating in basketball, football and handball. The study included 87 athletes (29 basketball players, 29 football players, and 29 handball players) aged 21-24. Evaluation of the aerobic bioenergetic potential of athletes participating in basketball, football and handball was performed followed by both univariate (ANOVA) and multivariate (MANOVA) statistical methods to determine differences among the athletes in relative (VO2 mL/kg/min) and absolute oxygen consumption (VO2 L/min). Statistically significant differences between absolute and relative oxygen consumption were found in basketball players (Mb), football players (Mf), and handball players (Mh) (MANOVA, p = 0.00). ANOVA also revealed significant differences in relative oxygen consumption (VO2 mL/kg/min) (p = 0.00). The football players (55.32 mL/kg/min) had the highest relative oxygen consumption, followed by the handball players (51.84 mL/kg/min) and basketball players (47.00 mL/kg/min). The highest absolute oxygen consumption was recorded in the basketball players (4.47 L/min), followed by the handball players (4.40 L/min) and footballers (4.16 L/min). Statistically significant differences in the aerobic bioenergetic potential, expressed by the relative oxygen consumption were found among atletes participating in different team sports. It can be assumed that the player from the sports in which it is necessary to cross greater distance in total during the match have a greater need for aerobic capacity.

Development and corroboration of a bioenergetics model for northern pikeminnow (Ptychocheilus oregonensis) feeding on juvenile salmonids in the Columbia River

USGS Publications Warehouse

Petersen, J.H.; Ward, D.L.

1999-01-01

A bioenergetics model was developed and corroborated for northern pikeminnow Ptychocheilus oregonensis, an important predator on juvenile salmonids in the Pacific Northwest. Predictions of modeled predation rate on salmonids were compared with field data from three areas of John Day Reservoir (Columbia River). To make bioenergetics model estimates of predation rate, three methods were used to approximate the change in mass of average predators during 30-d growth periods: observed change in mass between the first and the second month, predicted change in mass calculated with seasonal growth rates, and predicted change in mass based on an annual growth model. For all reservoir areas combined, bioenergetics model predictions of predation on salmon were 19% lower than field estimates based on observed masses, 45% lower than estimates based on seasonal growth rates, and 15% lower than estimates based on the annual growth model. For each growth approach, the largest differences in field-versus-model predation occurred at the midreservoir area (-84% to -67% difference). Model predictions of the rate of predation on salmonids were examined for sensitivity to parameter variation, swimming speed, sampling bias caused by gear selectivity, and asymmetric size distributions of predators. The specific daily growth rate of northern pikeminnow predicted by the model was highest in July and October and decreased during August. The bioenergetics model for northern pikeminnow performed well compared with models for other fish species that have been tested with field data. This model should be a useful tool for evaluating management actions such as predator removal, examining the influence of temperature on predation rates, and exploring interactions between predators in the Columbia River basin.

Constraints of bioenergetics on the ecology and distribution of vertebrate ectotherms: Progress report, 1 January 1988-31 August 1988

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spotila, J.R.

1988-07-01

We quantified the constraints of bioenergetics on the ecology and distribution of vertebrate ectotherms. During the first eight months of 1988 we conducted studies to determine the role of incubation temperature on the post hatching growth rate of the snapping turtle, Chelydra serpentina, to establish the rate of energy expenditure of the slider turtle, Trachemys scripta, in the field, to determine the field metabolic rates, body temperatures, and water flux rates of the box turtle, Terrapene carolina, and to measure the effect of diet type on the consumption rate, digestion rate and digestive efficiency of adult T. scripta. We alsomore » organized and chaired a national symposium on Constraints of Bioenergetics on Animal Population Dynamics at the 1987 meeting of the American Society of Zoologists. 18 refs.« less

Alkalizing Reactions Streamline Cellular Metabolism in Acidogenic Microorganisms

PubMed Central

Arioli, Stefania; Ragg, Enzio; Scaglioni, Leonardo; Fessas, Dimitrios; Signorelli, Marco; Karp, Matti; Daffonchio, Daniele; De Noni, Ivano; Mulas, Laura; Oggioni, Marco; Guglielmetti, Simone; Mora, Diego

2010-01-01

An understanding of the integrated relationships among the principal cellular functions that govern the bioenergetic reactions of an organism is necessary to determine how cells remain viable and optimise their fitness in the environment. Urease is a complex enzyme that catalyzes the hydrolysis of urea to ammonia and carbonic acid. While the induction of urease activity by several microorganisms has been predominantly considered a stress-response that is initiated to generate a nitrogen source in response to a low environmental pH, here we demonstrate a new role of urease in the optimisation of cellular bioenergetics. We show that urea hydrolysis increases the catabolic efficiency of Streptococcus thermophilus, a lactic acid bacterium that is widely used in the industrial manufacture of dairy products. By modulating the intracellular pH and thereby increasing the activity of β-galactosidase, glycolytic enzymes and lactate dehydrogenase, urease increases the overall change in enthalpy generated by the bioenergetic reactions. A cooperative altruistic behaviour of urease-positive microorganisms on the urease-negative microorganisms within the same environment was also observed. The physiological role of a single enzymatic activity demonstrates a novel and unexpected view of the non-transcriptional regulatory mechanisms that govern the bioenergetics of a bacterial cell, highlighting a new role for cytosol-alkalizing biochemical pathways in acidogenic microorganisms. PMID:21152088

A mild traumatic brain injury in mice produces lasting deficits in brain metabolism.

PubMed

Lyons, Danielle N; Vekaria, Hemendra; Macheda, Teresa; Bakshi, Vikas; Powell, David K; Gold, Brian T; Lin, Ai-Ling; Sulllivan, Pat; Bachstetter, Adam D

2018-05-29

Metabolic uncoupling has been well-characterized during the first minutes-to-days after a traumatic brain injury (TBI), yet mitochondrial bioenergetics during the weeks-to-months after a brain injury is poorly defined, particularly after a mild TBI. We hypothesized that a closed head injury (CHI) would be associated with deficits in mitochondrial bioenergetics at one month after the injury. A significant decrease in state-III (ATP production) and state-V (complex-I) driven mitochondrial respiration was found at 1-month post-injury in adult C57Bl/6J mice. Isolation of synaptic mitochondria demonstrated that the deficit in state-III and state-V was primarily neuronal. Injured mice had a temporally consistent deficit in memory recall at 1-month post injury. Using proton magnetic resonance spectroscopy (1H MRS) at 7-Tesla, we found significant decreases in phosphocreatine, N-Acetylaspartic acid (NAA), and total choline. We also found regional variations in cerebral blood flow, including both hypo- and hyper- perfusion, as measured by a pseudo-continuous arterial spin labeling MR sequence. Our results highlight a chronic deficit in mitochondrial bioenergetics associated with a CHI that may lead toward a novel approach for neurorestoration following a mild TBI. Magnetic resonance spectroscopy provides a potential biomarker for assessing the efficacy of candidate treatments targeted at improving mitochondrial bioenergetics.

Testing a bioenergetics-based habitat choice model: bluegill (Lepomis macrochirus) responses to food availability and temperature

USGS Publications Warehouse

2011-01-01

Using an automated shuttlebox system, we conducted patch choice experiments with 32, 8–12 g bluegill sunfish (Lepomis macrochirus) to test a behavioral energetics hypothesis of habitat choice. When patch temperature and food levels were held constant within patches but different between patches, we expected bluegill to choose patches that maximized growth based on the bioenergetic integration of food and temperature as predicted by a bioenergetics model. Alternative hypotheses were that bluegill may choose patches based only on food (optimal foraging) or temperature (behavioral thermoregulation). The behavioral energetics hypothesis was not a good predictor of short-term (from minutes to weeks) patch choice by bluegill; the behavioral thermoregulation hypothesis was the best predictor. In the short-term, food and temperature appeared to affect patch choice hierarchically; temperature was more important, although food can alter temperature preference during feeding periods. Over a 19-d experiment, mean temperatures occupied by fish offered low rations did decline as predicted by the behavioral energetics hypothesis, but the decline was less than 1.0 °C as opposed to a possible 5 °C decline. A short-term, bioenergetic response to food and temperature may be precluded by physiological costs of acclimation not considered explicitly in the behavioral energetics hypothesis.

Curcumin prevents cisplatin-induced renal alterations in mitochondrial bioenergetics and dynamic.

PubMed

Ortega-Domínguez, Bibiana; Aparicio-Trejo, Omar Emiliano; García-Arroyo, Fernando E; León-Contreras, Juan Carlos; Tapia, Edilia; Molina-Jijón, Eduardo; Hernández-Pando, Rogelio; Sánchez-Lozada, Laura Gabriela; Barrera-Oviedo, Diana; Pedraza-Chaverri, José

2017-09-01

Cisplatin is widely used as chemotherapeutic agent for treatment of diverse types of cancer, however, acute kidney injury (AKI) is an important side effect of this treatment. Diverse mechanisms have been involved in cisplatin-induced AKI, such as oxidative stress, apoptosis and mitochondrial damage. On the other hand, curcumin is a polyphenol extracted from the rhizome of Curcuma longa L. Previous studies have shown that curcumin protects against the cisplatin-induced AKI; however, it is unknown whether curcumin can reduce alterations in mitochondrial bioenergetics and dynamic in this model. It was found that curcumin prevents cisplatin-induced: (a) AKI and (b) alterations in the following mitochondrial parameters: bioenergetics, ultrastructure, hydrogen peroxide production and dynamic. In fact, curcumin prevented the increase of mitochondrial fission 1 protein (FIS1), the decrease of optic atrophy 1 protein (OPA1) and the decrease of NAD + -dependent deacetylase sirtuin-3 (SIRT3), a mitochondrial dynamic regulator as well as the increase in the mitophagy associated proteins parkin and phosphatase and tensin homologue (PTEN)-induced putative kinase protein 1 (PINK1). In conclusion, the protective effect of curcumin in cisplatin-induced AKI was associated with the prevention of the alterations in mitochondrial bioenergetics, ultrastructure, redox balance, dynamic, and SIRT3 levels. Copyright © 2017 Elsevier Ltd. All rights reserved.

Students with Sensory Integration Dysfunctions: Issues for School Counselors

ERIC Educational Resources Information Center

Katz, Idit

2006-01-01

A substantial number of school age children suffer from difficulties in integrating sensory input in an adaptive manner (termed sensory integration dysfunction--SID). These students are at high risk for emotional, social, and educational problems. This article defines SID, describes typical behaviors of children with SID, and presents guidelines…

Youth Violence as Adaptation? Introduction to the Special Issue

ERIC Educational Resources Information Center

Swisher, Raymond R.; Latzman, Robert D.

2008-01-01

This article introduces the special issue of the journal on the topic of youth violence as adaptation to community violence. Contrary to the predominant perspective that youth violence is a sign of dysfunction or maladaptation, the articles collected here consider whether some youth violence may have positively adaptive consequences in the face of…

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

PubMed Central

Friedrich, O.; Reid, M. B.; Van den Berghe, G.; Vanhorebeek, I.; Hermans, G.; Rich, M. M.; Larsson, L.

2015-01-01

Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca2+ dysregulation is present through altered Ca2+ homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models. PMID:26133937

Mitochondrial functions of THP-1 monocytes following the exposure to selected natural compounds.

PubMed

Schultze, Nadin; Wanka, Heike; Zwicker, Paula; Lindequist, Ulrike; Haertel, Beate

2017-02-15

The immune system is an important target of various xenobiotics, which may lead to severe adverse effects including immunosuppression or inappropriate immunostimulation. Mitochondrial toxicity is one possibility by which xenobiotics exert their toxic effects in cells or organs. In this study, we investigated the impact of three natural compounds, cyclosporine A (CsA), deoxynivalenol (DON) and cannabidiol (CBD) on mitochondrial functions in the THP-1 monocytic cell line. The cells were exposed for 24h to two different concentrations (IC 10 and IC 50 determined by MTT) of each compound. The cells showed concentration-dependent elevated intracellular reactive oxygen species (iROS) and induction of apoptosis (except DON) in response to the three test compounds. Mitochondrial functions were characterized by using bioenergetics profiling experiments. In THP-1 monocytes, the IC 50 of CsA decreased basal and maximal respiration as well as ATP production with an impact on spare capacity indicating a mitochondrial dysfunction. Similar reaction patterns were observed following CBD exposure. The basal respiration level and ATP-production decreased in the THP-1 cells exposed to the IC 50 of DON with no major impact on mitochondrial function. In conclusion, impaired mitochondrial function was accompanied by elevated iROS and apoptosis level in a monocytic cell line exposed to CsA and CBD. Mitochondrial dysfunction may be one explanation for the cytotoxicity of CBD and CsA also in other in immune cells. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A Predictive Model of Domestic Violence in Multicultural Families Focusing on Perpetrator.

PubMed

Choi, Eun Young; Hyun, Hye Jin

2016-09-01

This study was conducted to assess predictor variables of husbands in multicultural families and examine the relationship among variables after setting up a hypothetical model including influencing factors, so as to provide a framework necessary for developing nursing interventions of domestic violence. The participants were 260 husbands in multicultural families in four cities in Korea. Data were analyzed using SPSS 22.0 and AMOS 20.0. Self-control, social support, family of origin violence experience and stress on cultural adaptation directly affected to dysfunctional communication, and the explanatory power of the variables was 64.7%. Family of origin violence experience in domestic stress on cultural adaptation, and dysfunctional communication were directly related to domestic violence in multicultural families, and the explanatory power of the variables was 64.6%. We found out that all variables in the model had mediation effects to domestic violence through dysfunctional communication. In other words, self-control and social support had complete mediation effects, and family of origin violence experience in domestic violence and stress on cultural adaptation had partial mediation effects. The variables explained in this study should be considered as predictive factors of domestic violence in multicultural families, and used to provide preventive nursing intervention. Our resutls can be taken into account for developing and implementing programs on alleviating dysfunctional communication in multicultural families in Korea. Copyright © 2016. Published by Elsevier B.V.

Creatine target engagement with brain bioenergetics: a dose-ranging phosphorus-31 magnetic resonance spectroscopy study of adolescent females with SSRI-resistant depression.

PubMed

Kondo, Douglas G; Forrest, Lauren N; Shi, Xianfeng; Sung, Young-Hoon; Hellem, Tracy L; Huber, Rebekah S; Renshaw, Perry F

2016-08-01

Major depressive disorder (MDD) often begins during adolescence and is projected to become the leading cause of global disease burden by the year 2030. Yet, approximately 40 % of depressed adolescents fail to respond to standard antidepressant treatment with a selective serotonin reuptake inhibitor (SSRI). Converging evidence suggests that depression is related to brain mitochondrial dysfunction. Our previous studies of MDD in adult and adolescent females suggest that augmentation of SSRI pharmacotherapy with creatine monohydrate (CM) may improve MDD outcomes. Neuroimaging with phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS) can measure the high-energy phosphorus metabolites in vivo that reflect mitochondrial function. These include phosphocreatine (PCr), a substrate for the creatine kinase reaction that produces adenosine triphosphate. As part of the National Institute of Mental Health's experimental medicine initiative, we conducted a placebo-controlled dose-ranging study of adjunctive CM for adolescent females with SSRI-resistant MDD. Participants were randomized to receive placebo or CM 2, 4 or 10 g daily for 8 weeks. Pre- and post-treatment (31)P-MRS scans were used to measure frontal lobe PCr, to assess CM's target engagement with cerebral energy metabolism. Mean frontal lobe PCr increased by 4.6, 4.1 and 9.1 % in the 2, 4 and 10 g groups, respectively; in the placebo group, PCr fell by 0.7 %. There was no group difference in adverse events, weight gain or serum creatinine. Regression analysis of PCr and depression scores across the entire sample showed that frontal lobe PCr was inversely correlated with depression scores (p = 0.02). These results suggest that CM achieves target engagement with brain bioenergetics and that the target is correlated with a clinical signal. Further study of CM as a treatment for adolescent females with SSRI-resistant MDD is warranted.

Oxidative Stress Correlates with Headache Symptoms in Fibromyalgia: Coenzyme Q10 Effect on Clinical Improvement

PubMed Central

Cordero, Mario D.; Cano-García, Francisco Javier; Alcocer-Gómez, Elísabet; De Miguel, Manuel; Sánchez-Alcázar, José Antonio

2012-01-01

Background Fibromyalgia (FM) is a chronic pain syndrome with unknown etiology and a wide spectrum of symptoms such as allodynia, debilitating fatigue, joint stiffness and migraine. Recent studies have shown some evidences demonstrating that oxidative stress is associated to clinical symptoms in FM of fibromyalgia. We examined oxidative stress and bioenergetic status in blood mononuclear cells (BMCs) and its association to headache symptoms in FM patients. The effects of oral coenzyme Q10 (CoQ10) supplementation on biochemical markers and clinical improvement were also evaluated. Methods We studied 20 FM patients and 15 healthy controls. Clinical parameters were evaluated using the Fibromyalgia Impact Questionnaire (FIQ), visual analogues scales (VAS), and the Headache Impact Test (HIT-6). Oxidative stress was determined by measuring CoQ10, catalase and lipid peroxidation (LPO) levels in BMCs. Bioenergetic status was assessed by measuring ATP levels in BMCs. Results We found decreased CoQ10, catalase and ATP levels in BMCs from FM patients as compared to normal control (P<0.05 and P<0.001, respectively) We also found increased level of LPO in BMCs from FM patients as compared to normal control (P<0.001). Significant negative correlations between CoQ10 or catalase levels in BMCs and headache parameters were observed (r = −0.59, P<0.05; r = −0.68, P<0.05, respectively). Furthermore, LPO levels showed a significant positive correlation with HIT-6 (r = 0.33, P<0.05). Oral CoQ10 supplementation restored biochemical parameters and induced a significant improvement in clinical and headache symptoms (P<0.001). Discussion The results of this study suggest a role for mitochondrial dysfunction and oxidative stress in the headache symptoms associated with FM. CoQ10 supplementation should be examined in a larger placebo controlled trial as a possible treatment in FM. PMID:22532869

Oxidative stress correlates with headache symptoms in fibromyalgia: coenzyme Q₁₀ effect on clinical improvement.

PubMed

Cordero, Mario D; Cano-García, Francisco Javier; Alcocer-Gómez, Elísabet; De Miguel, Manuel; Sánchez-Alcázar, José Antonio

2012-01-01

Fibromyalgia (FM) is a chronic pain syndrome with unknown etiology and a wide spectrum of symptoms such as allodynia, debilitating fatigue, joint stiffness and migraine. Recent studies have shown some evidences demonstrating that oxidative stress is associated to clinical symptoms in FM of fibromyalgia. We examined oxidative stress and bioenergetic status in blood mononuclear cells (BMCs) and its association to headache symptoms in FM patients. The effects of oral coenzyme Q(10) (CoQ(10)) supplementation on biochemical markers and clinical improvement were also evaluated. We studied 20 FM patients and 15 healthy controls. Clinical parameters were evaluated using the Fibromyalgia Impact Questionnaire (FIQ), visual analogues scales (VAS), and the Headache Impact Test (HIT-6). Oxidative stress was determined by measuring CoQ(10), catalase and lipid peroxidation (LPO) levels in BMCs. Bioenergetic status was assessed by measuring ATP levels in BMCs. We found decreased CoQ(10), catalase and ATP levels in BMCs from FM patients as compared to normal control (P < 0.05 and P < 0.001, respectively) We also found increased level of LPO in BMCs from FM patients as compared to normal control (P < 0.001). Significant negative correlations between CoQ(10) or catalase levels in BMCs and headache parameters were observed (r  = -0.59, P < 0.05; r  =  -0.68, P < 0.05, respectively). Furthermore, LPO levels showed a significant positive correlation with HIT-6 (r = 0.33, P<0.05). Oral CoQ(10) supplementation restored biochemical parameters and induced a significant improvement in clinical and headache symptoms (P < 0.001). The results of this study suggest a role for mitochondrial dysfunction and oxidative stress in the headache symptoms associated with FM. CoQ10 supplementation should be examined in a larger placebo controlled trial as a possible treatment in FM.

A high-fat jelly diet restores bioenergetic balance and extends lifespan in the presence of motor dysfunction and lumbar spinal cord motor neuron loss in TDP-43A315T mutant C57BL6/J mice

PubMed Central

Coughlan, Karen S.; Halang, Luise; Woods, Ina

2016-01-01

ABSTRACT Transgenic transactivation response DNA-binding protein 43 (TDP-43) mice expressing the A315T mutation under control of the murine prion promoter progressively develop motor function deficits and are considered a new model for the study of amyotrophic lateral sclerosis (ALS); however, premature sudden death resulting from intestinal obstruction halts disease phenotype progression in 100% of C57BL6/J congenic TDP-43A315T mice. Similar to our recent results in SOD1G93A mice, TDP-43A315T mice fed a standard pellet diet showed increased 5′ adenosine monophosphate-activated protein kinase (AMPK) activation at postnatal day (P)80, indicating elevated energetic stress during disease progression. We therefore investigated the effects of a high-fat jelly diet on bioenergetic status and lifespan in TDP-43A315T mice. In contrast to standard pellet-fed mice, mice fed high-fat jelly showed no difference in AMPK activation up to P120 and decreased phosphorylation of acetly-CoA carboxylase (ACC) at early-stage time points. Exposure to a high-fat jelly diet prevented sudden death and extended survival, allowing development of a motor neuron disease phenotype with significantly decreased body weight from P80 onward that was characterised by deficits in Rotarod abilities and stride length measurements. Development of this phenotype was associated with a significant motor neuron loss as assessed by Nissl staining in the lumbar spinal cord. Our work suggests that a high-fat jelly diet improves the pre-clinical utility of the TDP-43A315T model by extending lifespan and allowing the motor neuron disease phenotype to progress, and indicates the potential benefit of this diet in TDP-43-associated ALS. PMID:27491077

A high-fat jelly diet restores bioenergetic balance and extends lifespan in the presence of motor dysfunction and lumbar spinal cord motor neuron loss in TDP-43A315T mutant C57BL6/J mice.

PubMed

Coughlan, Karen S; Halang, Luise; Woods, Ina; Prehn, Jochen H M

2016-09-01

Transgenic transactivation response DNA-binding protein 43 (TDP-43) mice expressing the A315T mutation under control of the murine prion promoter progressively develop motor function deficits and are considered a new model for the study of amyotrophic lateral sclerosis (ALS); however, premature sudden death resulting from intestinal obstruction halts disease phenotype progression in 100% of C57BL6/J congenic TDP-43(A315T) mice. Similar to our recent results in SOD1(G93A) mice, TDP-43(A315T) mice fed a standard pellet diet showed increased 5' adenosine monophosphate-activated protein kinase (AMPK) activation at postnatal day (P)80, indicating elevated energetic stress during disease progression. We therefore investigated the effects of a high-fat jelly diet on bioenergetic status and lifespan in TDP-43(A315T) mice. In contrast to standard pellet-fed mice, mice fed high-fat jelly showed no difference in AMPK activation up to P120 and decreased phosphorylation of acetly-CoA carboxylase (ACC) at early-stage time points. Exposure to a high-fat jelly diet prevented sudden death and extended survival, allowing development of a motor neuron disease phenotype with significantly decreased body weight from P80 onward that was characterised by deficits in Rotarod abilities and stride length measurements. Development of this phenotype was associated with a significant motor neuron loss as assessed by Nissl staining in the lumbar spinal cord. Our work suggests that a high-fat jelly diet improves the pre-clinical utility of the TDP-43(A315T) model by extending lifespan and allowing the motor neuron disease phenotype to progress, and indicates the potential benefit of this diet in TDP-43-associated ALS. © 2016. Published by The Company of Biologists Ltd.

Differential expression of the nuclear-encoded mitochondrial transcriptome in pediatric septic shock.

PubMed

Weiss, Scott L; Cvijanovich, Natalie Z; Allen, Geoffrey L; Thomas, Neal J; Freishtat, Robert J; Anas, Nick; Meyer, Keith; Checchia, Paul A; Shanley, Thomas P; Bigham, Michael T; Fitzgerald, Julie; Banschbach, Sharon; Beckman, Eileen; Howard, Kelli; Frank, Erin; Harmon, Kelli; Wong, Hector R

2014-11-19

Increasing evidence supports a role for mitochondrial dysfunction in organ injury and immune dysregulation in sepsis. Although differential expression of mitochondrial genes in blood cells has been reported for several diseases in which bioenergetic failure is a postulated mechanism, there are no data about the blood cell mitochondrial transcriptome in pediatric sepsis. We conducted a focused analysis using a multicenter genome-wide expression database of 180 children ≤ 10 years of age with septic shock and 53 healthy controls. Using total RNA isolated from whole blood within 24 hours of PICU admission for septic shock, we evaluated 296 nuclear-encoded mitochondrial genes using a false discovery rate of 1%. A series of bioinformatic approaches were applied to compare differentially expressed genes across previously validated gene expression-based subclasses (groups A, B, and C) of pediatric septic shock. In total, 118 genes were differentially regulated in subjects with septic shock compared to healthy controls, including 48 genes that were upregulated and 70 that were downregulated. The top scoring canonical pathway was oxidative phosphorylation, with general downregulation of the 51 genes corresponding to the electron transport system (ETS). The top two gene networks were composed primarily of mitochondrial ribosomal proteins highly connected to ETS complex I, and genes encoding for ETS complexes I, II, and IV that were highly connected to the peroxisome proliferator activated receptor (PPAR) family. There were 162 mitochondrial genes differentially regulated between groups A, B, and C. Group A, which had the highest maximum number of organ failures and mortality, exhibited a greater downregulation of mitochondrial genes compared to groups B and C. Based on a focused analysis of a pediatric septic shock transcriptomic database, nuclear-encoded mitochondrial genes were differentially regulated early in pediatric septic shock compared to healthy controls, as well as across genotypic and phenotypic distinct pediatric septic shock subclasses. The nuclear genome may be an important mechanism contributing to alterations in mitochondrial bioenergetic function and outcomes in pediatric sepsis.

Alterations in mitochondrial dynamics induced by tebufenpyrad and pyridaben in a dopaminergic neuronal cell culture model

PubMed Central

Charli, Adhithiya; Jin, Huajun; Anantharam, Vellareddy; Kanthasamy, Arthi; Kanthasamy, Anumantha G.

2015-01-01

Tebufenpyrad and pyridaben are two agro-chemically important acaricides that function like the known mitochondrial toxicant rotenone. Although these two compounds have been commonly used to kill populations of mites and ticks in commercial greenhouses, their neurotoxic profiles remain largely unknown. Therefore, we investigated the effects of these two pesticides on mitochondrial structure and function in an in vitro cell culture model using the Seahorse bioanalyzer and confocal fluorescence imaging. The effects were compared with rotenone. Exposing rat dopaminergic neuronal cells (N27 cells) to tebufenpyrad and pyridaben for 3 h induced dose-dependent cell death with an EC50 of 3.98 μM and 3.77 μM, respectively. Also, tebufenpyrad and pyridaben (3 μM) exposure induced reactive oxygen species (ROS) generation and m-aconitase damage, suggesting that the pesticide toxicity is associated with oxidative damage. Morphometric image analysis with the MitoTracker red fluorescent probe indicated that tebufenpyrad and pyridaben, as well as rotenone, caused abnormalities in mitochondrial morphology, including reduced mitochondrial length and circularity. Functional bioenergetic experiments using the Seahorse XF96 analyzer revealed that tebufenpyrad and pyridaben very rapidly suppressed the basal mitochondrial oxygen consumption rate similar to that of rotenone. Further analysis of bioenergetic curves also revealed dose-dependent decreases in ATP-linked respiration and respiratory capacity. The luminescence-based ATP measurement further confirmed that pesticide-induced mitochondrial inhibition of respiration is accompanied by the loss of cellular ATP. Collectively, our results suggest that exposure to the pesticides tebufenpyrad and pyridaben induces neurotoxicity by rapidly initiating mitochondrial dysfunction and oxidative damage in dopaminergic neuronal cells. Our findings also reveal that monitoring the kinetics of mitochondrial respiration with Seahorse could be used as an early neurotoxicological high-throughput index for assessing the risk that pesticides pose to the dopaminergic neuronal system. PMID:26141520

Low-level light therapy of the eye and brain.

PubMed

Rojas, Julio C; Gonzalez-Lima, F

2011-01-01

Low-level light therapy (LLLT) using red to near-infrared light energy has gained attention in recent years as a new scientific approach with therapeutic applications in ophthalmology, neurology, and psychiatry. The ongoing therapeutic revolution spearheaded by LLLT is largely propelled by progress in the basic science fields of photobiology and bioenergetics. This paper describes the mechanisms of action of LLLT at the molecular, cellular, and nervous tissue levels. Photoneuromodulation of cytochrome oxidase activity is the most important primary mechanism of action of LLLT. Cytochrome oxidase is the primary photoacceptor of light in the red to near-infrared region of the electromagnetic spectrum. It is also a key mitochondrial enzyme for cellular bioenergetics, especially for nerve cells in the retina and the brain. Evidence shows that LLLT can secondarily enhance neural metabolism by regulating mitochondrial function, intraneuronal signaling systems, and redox states. Current knowledge about LLLT dosimetry relevant for its hormetic effects on nervous tissue, including noninvasive in vivo retinal and transcranial effects, is also presented. Recent research is reviewed that supports LLLT potential benefits in retinal disease, stroke, neurotrauma, neurodegeneration, and memory and mood disorders. Since mitochondrial dysfunction plays a key role in neurodegeneration, LLLT has potential significant applications against retinal and brain damage by counteracting the consequences of mitochondrial failure. Upon transcranial delivery in vivo, LLLT induces brain metabolic and antioxidant beneficial effects, as measured by increases in cytochrome oxidase and superoxide dismutase activities. Increases in cerebral blood flow and cognitive functions induced by LLLT have also been observed in humans. Importantly, LLLT given at energy densities that exert beneficial effects does not induce adverse effects. This highlights the value of LLLT as a novel paradigm to treat visual, neurological, and psychological conditions, and supports that neuronal energy metabolism could constitute a major target for neurotherapeutics of the eye and brain.

Differential acute and chronic effects of burn trauma on murine skeletal muscle bioenergetics

PubMed Central

Porter, Craig; Herndon, David N.; Bhattarai, Nisha; Ogunbileje, John O.; Szczesny, Bartosz; Szabo, Csaba; Toliver-Kinsky, Tracy; Sidossis, Labros S.

2015-01-01

Altered skeletal muscle mitochondrial function contributes to the pathophysiological stress response to burns. However, the acute and chronic impact of burn trauma on skeletal muscle bioenergetics remains poorly understood. Here, we determined the temporal relationship between burn trauma and mitochondrial function in murine skeletal muscle local to and distal from burn wounds. Male BALB/c mice (8–10 weeks old) were burned by submersion of the dorsum in water (~95°C) to create a full thickness burn on ~30% of the body. Skeletal muscle was harvested from spinotrapezius underneath burn wounds (local) and the quadriceps (distal) of sham and burn treated mice at 3h, 24h, 4d and 10d post-injury. Mitochondrial respiration was determined in permeabilized myofiber bundles by high-resolution respirometry. Caspase 9 and caspase 3 protein concentration were determined by western blot. In muscle local to burn wounds, respiration coupled to ATP production was significantly diminished at 3h and 24h post-injury (P<0.001), as was mitochondrial coupling control (P<0.001). There was a 5- (P<0.05) and 8-fold (P<0.001) increase in respiration in response to cytochrome at 3h and 24h post burn, indicating damage to the outer mitochondrial membranes. Moreover, we also observed greater active caspase 9 and caspase 3 in muscle local to burn wounds, indicating the induction of apoptosis. Distal muscle mitochondrial function was unaltered by burn trauma until 10d post burn, where both respiratory capacity (P<0.05) and coupling control (P<0.05) was significantly lower than sham. These data highlight a differential response in muscle mitochondrial function to burn trauma, where the timing, degree and mode of dysfunction are dependent on whether the muscle is local or distal to the burn wound. PMID:26615714

Low-level light therapy of the eye and brain

PubMed Central

Rojas, Julio C; Gonzalez-Lima, F

2011-01-01

Low-level light therapy (LLLT) using red to near-infrared light energy has gained attention in recent years as a new scientific approach with therapeutic applications in ophthalmology, neurology, and psychiatry. The ongoing therapeutic revolution spearheaded by LLLT is largely propelled by progress in the basic science fields of photobiology and bioenergetics. This paper describes the mechanisms of action of LLLT at the molecular, cellular, and nervous tissue levels. Photoneuromodulation of cytochrome oxidase activity is the most important primary mechanism of action of LLLT. Cytochrome oxidase is the primary photoacceptor of light in the red to near-infrared region of the electromagnetic spectrum. It is also a key mitochondrial enzyme for cellular bioenergetics, especially for nerve cells in the retina and the brain. Evidence shows that LLLT can secondarily enhance neural metabolism by regulating mitochondrial function, intraneuronal signaling systems, and redox states. Current knowledge about LLLT dosimetry relevant for its hormetic effects on nervous tissue, including noninvasive in vivo retinal and transcranial effects, is also presented. Recent research is reviewed that supports LLLT potential benefits in retinal disease, stroke, neurotrauma, neurodegeneration, and memory and mood disorders. Since mitochondrial dysfunction plays a key role in neurodegeneration, LLLT has potential significant applications against retinal and brain damage by counteracting the consequences of mitochondrial failure. Upon transcranial delivery in vivo, LLLT induces brain metabolic and antioxidant beneficial effects, as measured by increases in cytochrome oxidase and superoxide dismutase activities. Increases in cerebral blood flow and cognitive functions induced by LLLT have also been observed in humans. Importantly, LLLT given at energy densities that exert beneficial effects does not induce adverse effects. This highlights the value of LLLT as a novel paradigm to treat visual, neurological, and psychological conditions, and supports that neuronal energy metabolism could constitute a major target for neurotherapeutics of the eye and brain. PMID:28539775

Real-Time Measurement of Host Bioenergetics During Mycobacterium Tuberculosis Infection

DTIC Science & Technology

2015-05-01

antimycobacterial drugs on Mtb bioenergetics. We focused on Clofazimine (CFZ, targets Complex I), Bedaquiline (BDQ/TMC207, targets Complex V) and Q203 (targets... Complex III). Firstly we investigated the effect of CFZ and BDQ on the OCR profiles of Mtb mc2 6230 (Figure 3). These experiments were done in...addition with of CFZ. The decrease in OCR is consistent with ETC complex inhibition. BDQ caused a very surprising concentration-depended increase

Field Verification Program (Aquatic Disposal). Bioenergetic Effects of Black Rock Harbor Dredged Material on the Polychaete Nephtys incisa: A Field Verification.

DTIC Science & Technology

1988-03-01

observed in the laboratory, and to determine the degree of correlation between the bioaccumulation of contaminants and bioenergetic responses...toxicity of liquid, suspended particulate, and solid phases; (c) estimating the potential contami- nant bioaccumulation ; and (d) describing the initial... bioaccumulation of dredged material contami- nants with biological responses from laboratory and field exposure to dredged material. However, this study

Alteration of the bioenergetic phenotype of mitochondria is a hallmark of breast, gastric, lung and oesophageal cancer.

PubMed Central

Isidoro, Antonio; Martínez, Marta; Fernández, Pedro L; Ortega, Alvaro D; Santamaría, Gema; Chamorro, Margarita; Reed, John C; Cuezva, José M

2004-01-01

Recent findings indicate that the expression of the beta-catalytic subunit of the mitochondrial H+-ATP synthase (beta-F1-ATPase) is depressed in liver, kidney and colon carcinomas, providing further a bioenergetic signature of cancer that is associated with patient survival. In the present study, we performed an analysis of mitochondrial and glycolytic protein markers in breast, gastric and prostate adenocarcinomas, and in squamous oesophageal and lung carcinomas. The expression of mitochondrial and glycolytic markers varied significantly in these carcinomas, when compared with paired normal tissues, with the exception of prostate cancer. Overall, the relative expression of beta-F1-ATPase was significantly reduced in breast and gastric adenocarcinomas, as well as in squamous oesophageal and lung carcinomas, strongly suggesting that alteration of the bioenergetic function of mitochondria is a hallmark of these types of cancer. PMID:14683524

AMP kinase promotes glioblastoma bioenergetics and tumour growth.

PubMed

Chhipa, Rishi Raj; Fan, Qiang; Anderson, Jane; Muraleedharan, Ranjithmenon; Huang, Yan; Ciraolo, Georgianne; Chen, Xiaoting; Waclaw, Ronald; Chow, Lionel M; Khuchua, Zaza; Kofron, Matthew; Weirauch, Matthew T; Kendler, Ady; McPherson, Christopher; Ratner, Nancy; Nakano, Ichiro; Dasgupta, Nupur; Komurov, Kakajan; Dasgupta, Biplab

2018-06-18

Stress is integral to tumour evolution, and cancer cell survival depends on stress management. We found that cancer-associated stress chronically activates the bioenergetic sensor AMP kinase (AMPK) and, to survive, tumour cells hijack an AMPK-regulated stress response pathway conserved in normal cells. Analysis of The Cancer Genome Atlas data revealed that AMPK isoforms are highly expressed in the lethal human cancer glioblastoma (GBM). We show that AMPK inhibition reduces viability of patient-derived GBM stem cells (GSCs) and tumours. In stressed (exercised) skeletal muscle, AMPK is activated to cooperate with CREB1 (cAMP response element binding protein-1) and promote glucose metabolism. We demonstrate that oncogenic stress chronically activates AMPK in GSCs that coopt the AMPK-CREB1 pathway to coordinate tumour bioenergetics through the transcription factors HIF1α and GABPA. Finally, we show that adult mice tolerate systemic deletion of AMPK, supporting the use of AMPK pharmacological inhibitors in the treatment of GBM.

Distribution and dynamics of electron transport complexes in cyanobacterial thylakoid membranes☆

PubMed Central

Liu, Lu-Ning

2016-01-01

The cyanobacterial thylakoid membrane represents a system that can carry out both oxygenic photosynthesis and respiration simultaneously. The organization, interactions and mobility of components of these two electron transport pathways are indispensable to the biosynthesis of thylakoid membrane modules and the optimization of bioenergetic electron flow in response to environmental changes. These are of fundamental importance to the metabolic robustness and plasticity of cyanobacteria. This review summarizes our current knowledge about the distribution and dynamics of electron transport components in cyanobacterial thylakoid membranes. Global understanding of the principles that govern the dynamic regulation of electron transport pathways in nature will provide a framework for the design and synthetic engineering of new bioenergetic machinery to improve photosynthesis and biofuel production. This article is part of a Special Issue entitled: Organization and dynamics of bioenergetic systems in bacteria, edited by Conrad Mullineaux. PMID:26619924

Distribution and dynamics of electron transport complexes in cyanobacterial thylakoid membranes.

PubMed

Liu, Lu-Ning

2016-03-01

The cyanobacterial thylakoid membrane represents a system that can carry out both oxygenic photosynthesis and respiration simultaneously. The organization, interactions and mobility of components of these two electron transport pathways are indispensable to the biosynthesis of thylakoid membrane modules and the optimization of bioenergetic electron flow in response to environmental changes. These are of fundamental importance to the metabolic robustness and plasticity of cyanobacteria. This review summarizes our current knowledge about the distribution and dynamics of electron transport components in cyanobacterial thylakoid membranes. Global understanding of the principles that govern the dynamic regulation of electron transport pathways in nature will provide a framework for the design and synthetic engineering of new bioenergetic machinery to improve photosynthesis and biofuel production. This article is part of a Special Issue entitled: Organization and dynamics of bioenergetic systems in bacteria, edited by Conrad Mullineaux. Copyright © 2015 The Author. Published by Elsevier B.V. All rights reserved.

Sensory Processing Dysfunctions as Expressed among Children with Different Severities of Intellectual Developmental Disabilities

ERIC Educational Resources Information Center

Engel-Yeger, Batya; Hardal-Nasser, Reem; Gal, Eynat

2011-01-01

High frequency of sensory processing dysfunctions (SPD) is prevalent among children with intellectual developmental disabilities and contributes to their maladaptive behaviors. However, the knowledge about the expressions of SPD in different levels of IDD severity is limited. As SPD may reduce adaptive responses and limit participation, this…

The Effects of Diabetic Retinopathy and Pan-Retinal Photocoagulation on Photoreceptor Cell Function as Assessed by Dark Adaptometry

PubMed Central

Bavinger, J. Clay; Dunbar, Grace E.; Stem, Maxwell S.; Blachley, Taylor S.; Kwark, Leon; Farsiu, Sina; Jackson, Gregory R.; Gardner, Thomas W.

2016-01-01

Purpose The pathophysiology of vision loss in persons with diabetic retinopathy (DR) is complex and incompletely defined. We hypothesized that retinal pigment epithelium (RPE) and rod and cone photoreceptor dysfunction, as measured by dark adaptometry, would increase with severity of DR, and that pan-retinal photocoagulation (PRP) would exacerbate this dysfunction. Methods Dark adaptation (DA) was measured in subjects with diabetes mellitus and healthy controls. Dark adaptation was measured at 5° superior to the fovea following a flash bleach, and the data were analyzed to yield cone and rod sensitivity curves. Retinal layer thicknesses were quantified using spectral-domain optical coherence tomography (OCT). Results The sample consisted of 23 controls and 73 diabetic subjects. Subjects with moderate nonproliferative diabetic retinopathy (NPDR) exhibited significant impairment of rod recovery rate compared with control subjects (P = 0.04). Cone sensitivity was impaired in subjects with proliferative diabetic retinopathy (PDR) (type 1 diabetes mellitus [T1DM]: P = 0.0047; type 2 diabetes mellitus [T2DM]: P < 0.001). Subjects with untreated PDR compared with subjects treated with PRP exhibited similar rod recovery rates and cone sensitivities. Thinner RPE as assessed by OCT was associated with slower rod recovery and lower cone sensitivity, and thinner photoreceptor inner segment/outer segment layer was associated with lower cone sensitivity. Conclusions The results suggest that RPE and photoreceptor cell dysfunction, as assessed by cone sensitivity level and rod- and RPE-mediated dark adaptation, progresses with worsening DR, and rod recovery dysfunction occurs earlier than cone dysfunction. Function was preserved following PRP. The findings suggest multiple defects in retinoid function and provide potential points to improve visual function in persons with PDR. PMID:26803796

Caffeine and acetaminophen association: Effects on mitochondrial bioenergetics.

PubMed

Gonçalves, Débora F; de Carvalho, Nelson R; Leite, Martim B; Courtes, Aline A; Hartmann, Diane D; Stefanello, Sílvio T; da Silva, Ingrid K; Franco, Jéferson L; Soares, Félix A A; Dalla Corte, Cristiane L

2018-01-15

Many studies have been demonstrating the role of mitochondrial function in acetaminophen (APAP) hepatotoxicity. Since APAP is commonly consumed with caffeine, this work evaluated the effects of the combination of APAP and caffeine on hepatic mitochondrial bioenergetic function in mice. Mice were treated with caffeine (20mg/kg, intraperitoneal (i.p.)) or its vehicle and, after 30minutes, APAP (250mg/kg, i.p.) or its vehicle. Four hours later, livers were removed, and the parameters associated with mitochondrial function and oxidative stress were evaluated. Hepatic cellular oxygen consumption was evaluated by high-resolution respirometry (HRR). APAP treatment decreased cellular oxygen consumption and mitochondrial complex activities in the livers of mice. Additionally, treatment with APAP increased swelling of isolated mitochondria from mice livers. On the other hand, caffeine administered with APAP was able to improve hepatic mitochondrial bioenergetic function. Treatment with APAP increased lipid peroxidation and reactive oxygen species (ROS) production and decreased glutathione levels in the livers of mice. Caffeine administered with APAP was able to prevent lipid peroxidation and the ROS production in mice livers, which may be associated with the improvement of mitochondrial function caused by caffeine treatment. We suggest that the antioxidant effects of caffeine and/or its interactions with mitochondrial bioenergetics may be involved in its beneficial effects against APAP hepatotoxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

The effects of increased stream temperatures on juvenile steelhead growth in the Yakima River Basin based on projected climate change scenarios

USGS Publications Warehouse

Hardiman, Jill M.; Mesa, Matthew G.

2013-01-01

Stakeholders within the Yakima River Basin expressed concern over impacts of climate change on mid-Columbia River steelhead (Oncorhynchus mykiss), listed under the Endangered Species Act. We used a bioenergetics model to assess the impacts of changing stream temperatures—resulting from different climate change scenarios—on growth of juvenile steelhead in the Yakima River Basin. We used diet and fish size data from fieldwork in a bioenergetics model and integrated baseline and projected stream temperatures from down-scaled air temperature climate modeling into our analysis. The stream temperature models predicted that daily mean temperatures of salmonid-rearing streams in the basin could increase by 1–2°C and our bioenergetics simulations indicated that such increases could enhance the growth of steelhead in the spring, but reduce it during the summer. However, differences in growth rates of fish living under different climate change scenarios were minor, ranging from about 1–5%. Because our analysis focused mostly on the growth responses of steelhead to changes in stream temperatures, further work is needed to fully understand the potential impacts of climate change. Studies should include evaluating changing stream flows on fish activity and energy budgets, responses of aquatic insects to climate change, and integration of bioenergetics, population dynamics, and habitat responses to climate change.

Adaptive and regulatory mechanisms in aged rats with postoperative cognitive dysfunction

PubMed Central

Bi, Yanlin; Liu, Shuyun; Yu, Xinjuan; Wang, Mingshan; Wang, Yuelan

2014-01-01

Inflammation may play a role in postoperative cognitive dysfunction. 5′ Adenosine monophosphate-activated protein kinase, nuclear factor-kappa B, interleukin-1β, and tumor necrosis factor-α are involved in inflammation. Therefore, these inflammatory mediators may be involved in postoperative cognitive dysfunction. Western immunoblot analysis revealed 5′ adenosine monophosphate-activated protein kinase and nuclear factor-kappa B in the hippocampus of aged rats were increased 1–7 days after splenectomy. Moreover, interleukin-1β and tumor necrosis factor-α were upregulated and gradually decreased. Therefore, these inflammatory mediators may participate in the splenectomy model of postoperative cognitive dysfunction in aged rats. PMID:25206851

Temperature effects induced by climate change on the growth and consumption by salmonines in Lakes Michigan and Huron

USGS Publications Warehouse

Kao, Yu-Chun; Madenjian, Charles P.; Bunnell, David B.; Lofgren, Brent M.; Perroud, Marjorie

2015-01-01

We used bioenergetics models to investigate temperature effects induced by climate change on the growth and consumption by Chinook salmon Oncorhynchus tshawytscha, lake trout Salvelinus namaycush, and steelhead O. mykiss in Lakes Michigan and Huron. We updated biological inputs to account for recent changes in the food webs and used temperature inputs in response to regional climate observed in the baseline period (1964–1993) and projected in the future period (2043–2070).Bioenergetics simulations were run across multiple age-classes and across all four seasons in different scenarios of prey availability. Due to the increased capacity of prey consumption, future growth and consumption by these salmonines were projected to increase substantially when prey availability was not limited. When prey consumption remained constant, future growth of these salmonines was projected to decrease in most cases but increase in some cases where the increase in metabolic cost can be compensated by the decrease in waste (egestion and excretion) loss. Consumption by these salmonines was projected to increase the most during spring and fall when prey energy densities are relatively high. Such seasonality benefits their future growth through increasing annual gross energy intake. Our results indicated that lake trout and steelhead would be better adapted to the warming climate than Chinook salmon. To maintain baseline growth into the future, an increase of 10 % in baseline prey consumption was required for Chinook salmon but considerably smaller increases, or no increases, in prey consumption were needed by lake trout and steelhead.

Children's Story Stem Responses: A Measure of Program Impact on Developmental Risks Associated with Dysfunctional Parenting.

ERIC Educational Resources Information Center

Robinson, JoAnn; Herot, Christine; Mantz-Simmons, Linda; Haynes, Phillip

2000-01-01

This article explores using the MacArthur Story Stem Battery to investigate the interior life of children, its potential usefulness in evaluating interventions geared to prevent dysfunctional parenting, and how the method has been adapted for use with low-income African American children. Case examples support the method's application. (Author/CR)

Melatonin successfully rescues hippocampal bioenergetics and improves cognitive function following drug intoxication by promoting Nrf2-ARE signaling activity.

PubMed

Chen, Li-You; Renn, Ting-Yi; Liao, Wen-Chieh; Mai, Fu-Der; Ho, Ying-Jui; Hsiao, George; Lee, Ai-Wei; Chang, Hung-Ming

2017-09-01

Prolonged exposure to gamma-hydroxybutyric acid (GHB) would cause drug intoxication in which impaired cognitive function results from enhanced hippocampal oxidative stress may serve as a major symptom in this deficiency. Considering melatonin possesses significant anti-oxidative efficacy, this study aimed to determine whether melatonin would successfully promote the nuclear factor erythroid 2-related factor 2 and antioxidant responsive element (Nrf2-ARE) signaling, depress oxidative stress, and rescue hippocampal bioenergetics and cognitive function following drug intoxication injury. Adolescent rats subjected to 10 days of GHB were received melatonin at doses of either 10 or 100 mg/kg. Time-of-flight secondary ion mass spectrometry, biochemical assay, quantitative histochemistry, [ 14 C]-2-deoxyglucose analysis, together with Morris water maze were employed to detect the molecular signaling, oxidative status, bioenergetic level, as well as the cognitive performances, respectively. Results indicated that in GHB-intoxicated rats, enhanced oxidative stress, increased cholesterol level, and decreased anti-oxidative enzymes activities were detected in hippocampal regions. Intense oxidative stress paralleled well with reduced bioenergetics and poor performance in behavioral testing. However, in rats treated with melatonin following GHB intoxication, all above parameters and cognitive function were gradually returned to nearly normal levels. Melatonin also remarkably promoted the translocation of Nrf2 from cytoplasm to nucleus in a dose-dependent manner, thereby increased the Nrf2-ARE signaling-related downstream anti-oxidative enzymes activities. As melatonin effectively rescues hippocampal bioenergetics through depressing the oxidative stress by promoting Nrf2-ARE molecular machinery, this study thus highlights for the first time that clinical use of melatonin may serve as a therapeutic strategy to improve the cognitive function in unsuspecting victims suffered from GHB intoxication injury. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Bioenergetic reprogramming plasticity under nitrogen depletion by the unicellular green alga Scenedesmus obliquus.

PubMed

Papazi, Aikaterini; Korelidou, Anna; Andronis, Efthimios; Parasyri, Athina; Stamatis, Nikolaos; Kotzabasis, Kiriakos

2018-03-01

Simultaneous nitrogen depletion and 3,4-dichlorophenol addition induce a bioenergetic microalgal reprogramming, through strong Cyt b 6 f synthesis, that quench excess electrons from dichlorophenol's biodegradation to an overactivated photosynthetic electron flow and H 2 -productivity. Cellular energy management includes "rational" planning and operation of energy production and energy consumption units. Microalgae seem to have the ability to calculate their energy reserves and select the most profitable bioenergetic pathways. Under oxygenic mixotrophic conditions, microalgae invest the exogenously supplied carbon source (glucose) to biomass increase. If 3,4-dichlorophenol is added in the culture medium, then glucose is invested more to biodegradation rather than to growth. The biodegradation yield is enhanced in nitrogen-depleted conditions, because of an increase in the starch accumulation and a delay in the establishment of oxygen-depleted conditions in a closed system. In nitrogen-depleted conditions, starch cannot be invested in PSII-dependent and PSII-independent pathways for H 2 -production, mainly because of a strong decrease of the cytochrome b 6 f complex of the photosynthetic electron flow. For this reason, it seems more profitable for the microalga under these conditions to direct the metabolism to the synthesis of lipids as cellular energy reserves. Nitrogen-depleted conditions with exogenously supplied 3,4-dichlorophenol induce reprogramming of the microalgal bioenergetic strategy. Cytochrome b 6 f is strongly synthesized (mainly through catabolism of polyamines) to manage the electron bypass from the dichlorophenol biodegradation procedure to the photosynthetic electron flow (at the level of PQ pool) and consequently through cytochrome b 6 f and PSI to hydrogenase and H 2 -production. All the above showed that the selection of the appropriate cultivation conditions is the key for the manipulation of microalgal bioenergetic strategy that leads to different metabolic products and paves the way for a future microalgal "smart" biotechnology.

Impaired Bioenergetics in Mutant Mitochondrial DNA Determines Cell Fate During Seizure-Like Activity.

PubMed

Kovac, Stjepana; Preza, Elisavet; Houlden, Henry; Walker, Matthew C; Abramov, Andrey Y

2018-04-27

Mutations in genes affecting mitochondrial proteins are increasingly recognised in patients with epilepsy, but the factors determining cell fate during seizure activity in these mutations remain unknown. Fluorescent dye imaging techniques were applied to fibroblast cell lines from patients suffering from common mitochondrial mutations and to age-matched controls. Using live cell imaging techniques in fibroblasts, we show that fibroblasts with mutations in the mitochondrial genome had reduced mitochondrial membrane potential and NADH pools and higher redox indices, indicative of respiratory chain dysfunction. Increasing concentrations of ferutinin, a Ca 2+ ionophore, led to oscillatory Ca 2+ signals in fibroblasts resembling dynamic Ca 2+ changes that occur during seizure-like activity. Co-monitoring of mitochondrial membrane potential (ΔΨ m ) changes induced by ferutinin showed accelerated membrane depolarisation and cell collapse in fibroblasts with mutations in the mitochondrial genome when compared to controls. Ca 2+ flash photolysis using caged Ca 2+ confirmed impaired Ca 2+ handling in fibroblasts with mitochondrial mutations. Findings indicate that intracellular Ca 2+ levels cannot be compensated during periods of hyperexcitability, leading to Ca 2+ overload and subsequent cell death in mitochondrial diseases.

Creatine protects against mitochondrial dysfunction associated with HIV-1 Tat-induced neuronal injury

PubMed Central

Stevens, Patrick R.; Gawryluk, Jeremy W.; Hui, Liang; Chen, Xuesong; Geiger, Jonathan D.

2015-01-01

HIV-1 infected individuals are living longer but experiencing a prevalence rate of over 50% for HIV-1 associated neurocognitive disorders (HAND) for which no effective treatment is available. Viral and cellular factors secreted by HIV-1 infected cells leads to neuronal injury and HIV-1 Tat continues to be implicated in the pathogenesis of HAND. Here we tested the hypothesis that creatine protected against HIV-1 Tat-induced neuronal injury by preventing mitochondrial bioenergetic crisis and/or redox catastrophe. Creatine blocked HIV-1 Tat1-72-induced increases in neuron cell death and synaptic area loss. Creatine protected against HIV-1 Tat-induced decreases in ATP. Creatine and creatine plus HIV-1 Tat increased cellular levels of creatine, and creatine plus HIV-1 Tat further decreased ratios of phosphocreatine to creatine observed with creatine or HIV-1 Tat treatments alone. Additionally, creatine protected against HIV-1 Tat-induced mitochondrial hypopolarization and HIV-1 Tat-induced mitochondrial permeability transition pore opening. Thus, creatine may be a useful adjunctive therapy against HAND. PMID:25613139

Metabolic Stress and Disorders Related to Alterations in Mitochondrial Fission or Fusion

PubMed Central

Babbar, Mansi; Sheikh, M. Saeed

2014-01-01

Mitochondrial morphology and metabolism play an important role in cellular homeostasis. Recent studies have shown that the fidelity of mitochondrial morphology is important in maintaining mitochondrial shape, number, size, membrane potential, ATP synthesis, mtDNA, motility, signaling, quality control, response to cellular stress, mitophagy and apoptosis. This article provides an overview of the current state of knowledge of the fission and fusion machinery with a focus on the mechanisms underlying the regulation of the mitochondrial morphology and cellular energy state. Several lines of evidence indicate that dysregulation of mitochondrial fission or fusion is associated with mitochondrial dysfunction, which in turn impacts mitophagy and apoptosis. Metabolic disorders are also associated with dysregulation of fission or fusion and the available lines of evidence point to a bidirectional interplay between the mitochondrial fission or fusion reactions and bioenergetics. Clearly, more in-depth studies are needed to fully elucidate the mechanisms that control mitochondrial fission and fusion. It is envisioned that the outcome of such studies will improve the understanding of the molecular basis of related metabolic disorders and also facilitate the development of better therapeutics. PMID:24533171

Brain aging and neurodegeneration: from a mitochondrial point of view.

PubMed

Grimm, Amandine; Eckert, Anne

2017-11-01

Aging is defined as a progressive time-related accumulation of changes responsible for or at least involved in the increased susceptibility to disease and death. The brain seems to be particularly sensitive to the aging process since the appearance of neurodegenerative diseases, including Alzheimer's disease, is exponential with the increasing age. Mitochondria were placed at the center of the 'free-radical theory of aging', because these paramount organelles are not only the main producers of energy in the cells, but also to main source of reactive oxygen species. Thus, in this review, we aim to look at brain aging processes from a mitochondrial point of view by asking: (i) What happens to brain mitochondrial bioenergetics and dynamics during aging? (ii) Why is the brain so sensitive to the age-related mitochondrial impairments? (iii) Is there a sex difference in the age-induced mitochondrial dysfunction? Understanding mitochondrial physiology in the context of brain aging may help identify therapeutic targets against neurodegeneration. This article is part of a series "Beyond Amyloid". © 2017 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.

S-Nitrosation of monocarboxylate transporter 1: Inhibition of pyruvate-fueled respiration and proliferation of breast cancer cells

PubMed Central

Diers, Anne R.; Broniowska, Katarzyna A.; Chang, Ching-Fang; Hill, R. Blake; Hogg, Neil

2014-01-01

Summary Energy substrates metabolized through mitochondria (e.g., pyruvate, glutamine) are required for biosynthesis of macromolecules in proliferating cells. Since several mitochondrial proteins are known to be targets of S-nitrosation, we determined whether bioenergetics are modulated by S-nitrosation and defined the subsequent effects on proliferation. The nitrosating agent S-nitroso-L-cysteine (L-CysNO) was used to initiate intracellular S-nitrosation, and treatment decreased mitochondrial function and inhibited proliferation of MCF7 mammary adenocarcinoma cells. Surprisingly, the D isomer of CysNO (D-CysNO) which is not transported into cells also caused mitochondrial dysfunction and limited proliferation. Both L- and D-CysNO also inhibited cellular pyruvate uptake and caused S-nitrosation of thiol groups on monocarboxylate transporter 1, a proton-linked pyruvate transporter. These data demonstrate the importance of mitochondrial metabolism in proliferative responses in breast cancer and highlight a novel role for inhibition of metabolic substrate uptake through S-nitrosation of exofacial protein thiols in cellular responses to nitrosative stress. PMID:24486553

The Rise of Mitochondria in Medicine

PubMed Central

Picard, Martin; Wallace, Douglas C; Burelle, Yan

2016-01-01

Once considered exclusively the cell's powerhouse, mitochondria are now recognized to perform multiple essential cellular functions beyond energy production, impacting most areas of cell biology and medicine. Since the emergence of molecular biology and the discovery of pathogenic mitochondrial DNA defects in the 1980's, research advances have revealed a number of common human diseases which share an underlying pathogenesis involving mitochondrial dysfunction. Mitochondria undergo function-defining dynamic shape changes, communicate with each other, regulate gene expression within the nucleus, modulate synaptic transmission within the brain, release molecules that contribute to oncogenic transformation and trigger inflammatory responses systemically, and influence the regulation of complex physiological systems. Novel “mitopathogenic” mechanisms are thus being uncovered across a number of medical disciplines including genetics, oncology, neurology, immunology, and critical care medicine. Increasing knowledge of the bioenergetic aspects of human disease has provided new opportunities for diagnosis, therapy, prevention, and in connecting various domains of medicine. In this article, we overview specific aspects of mitochondrial biology that have contributed to – and likely will continue to enhance the progress of modern medicine. PMID:27423788

Mitochondrial dysfunction in autism spectrum disorders: a population-based study.

PubMed

Oliveira, G; Diogo, L; Grazina, M; Garcia, P; Ataíde, A; Marques, C; Miguel, T; Borges, L; Vicente, A M; Oliveira, C R

2005-03-01

A minority of cases of autism has been associated with several different organic conditions, including bioenergetic metabolism deficiency. In a population-based study, we screened associated medical conditions in a group of 120 children with autism (current age range 11y 5mo to 14y 4mo, mean age 12y 11mo [SD 9.6mo], male:female ratio 2.9:1). Children were diagnosed using Diagnostic and Statistical Manual of Mental Disorders criteria, the Autism Diagnostic Interview--Revised, and the Childhood Autism Rating Scale; 76% were diagnosed with typical autism and 24% with atypical autism. Cognitive functional level was assessed with the Griffiths scale and the Wechsler Intelligence Scale for Children and was in the normal range in 17%. Epilepsy was present in 19 patients. Plasma lactate levels were measured in 69 patients, and in 14 we found hyperlactacidemia. Five of 11 patients studied were classified with definite mitochondrial respiratory chain disorder, suggesting that this might be one of the most common disorders associated with autism (5 of 69; 7.2%) and warranting further investigation.

Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes.

PubMed

Roy Chowdhury, Subir K; Smith, Darrell R; Saleh, Ali; Schapansky, Jason; Marquez, Alexandra; Gomes, Suzanne; Akude, Eli; Morrow, Dwane; Calcutt, Nigel A; Fernyhough, Paul

2012-06-01

Mitochondrial dysfunction occurs in sensory neurons and may contribute to distal axonopathy in animal models of diabetic neuropathy. The adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling axis senses the metabolic demands of cells and regulates mitochondrial function. Studies in muscle, liver and cardiac tissues have shown that the activity of adenosine monophosphate-activated protein kinase and PGC-1α is decreased under hyperglycaemia. In this study, we tested the hypothesis that deficits in adenosine monophosphate-activated protein kinase/PGC-1α signalling in sensory neurons underlie impaired axonal plasticity, suboptimal mitochondrial function and development of neuropathy in rodent models of type 1 and type 2 diabetes. Phosphorylation and expression of adenosine monophosphate-activated protein kinase/PGC-1α and mitochondrial respiratory chain complex proteins were downregulated in dorsal root ganglia of both streptozotocin-diabetic rats and db/db mice. Adenoviral-mediated manipulation of endogenous adenosine monophosphate-activated protein kinase activity using mutant proteins modulated neurotrophin-directed neurite outgrowth in cultures of sensory neurons derived from adult rats. Addition of resveratrol to cultures of sensory neurons derived from rats after 3-5 months of streptozotocin-induced diabetes, significantly elevated adenosine monophosphate-activated protein kinase levels, enhanced neurite outgrowth and normalized mitochondrial inner membrane polarization in axons. The bioenergetics profile (maximal oxygen consumption rate, coupling efficiency, respiratory control ratio and spare respiratory capacity) was aberrant in cultured sensory neurons from streptozotocin-diabetic rats and was corrected by resveratrol treatment. Finally, resveratrol treatment for the last 2 months of a 5-month period of diabetes reversed thermal hypoalgesia and attenuated foot skin intraepidermal nerve fibre loss and reduced myelinated fibre mean axonal calibre in streptozotocin-diabetic rats. These data suggest that the development of distal axonopathy in diabetic neuropathy is linked to nutrient excess and mitochondrial dysfunction via defective signalling of the adenosine monophosphate-activated protein kinase/PGC-1α pathway.

Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress

PubMed Central

2013-01-01

Background A variety of oncogenic and environmental factors alter tumor metabolism to serve the distinct cellular biosynthetic and bioenergetic needs present during oncogenesis. Extracellular acidosis is a common microenvironmental stress in solid tumors, but little is known about its metabolic influence, particularly when present in the absence of hypoxia. In order to characterize the extent of tumor cell metabolic adaptations to acidosis, we employed stable isotope tracers to examine how acidosis impacts glucose, glutamine, and palmitate metabolism in breast cancer cells exposed to extracellular acidosis. Results Acidosis increased both glutaminolysis and fatty acid β-oxidation, which contribute metabolic intermediates to drive the tricarboxylic acid cycle (TCA cycle) and ATP generation. Acidosis also led to a decoupling of glutaminolysis and novel glutathione (GSH) synthesis by repressing GCLC/GCLM expression. We further found that acidosis redirects glucose away from lactate production and towards the oxidative branch of the pentose phosphate pathway (PPP). These changes all serve to increase nicotinamide adenine dinucleotide phosphate (NADPH) production and counter the increase in reactive oxygen species (ROS) present under acidosis. The reduced novel GSH synthesis under acidosis may explain the increased demand for NADPH to recycle existing pools of GSH. Interestingly, acidosis also disconnected novel ribose synthesis from the oxidative PPP, seemingly to reroute PPP metabolites to the TCA cycle. Finally, we found that acidosis activates p53, which contributes to both the enhanced PPP and increased glutaminolysis, at least in part, through the induction of G6PD and GLS2 genes. Conclusions Acidosis alters the cellular metabolism of several major metabolites, which induces a significant degree of metabolic inflexibility. Cells exposed to acidosis largely rely upon mitochondrial metabolism for energy generation to the extent that metabolic intermediates are redirected away from several other critical metabolic processes, including ribose and glutathione synthesis. These alterations lead to both a decrease in cellular proliferation and increased sensitivity to ROS. Collectively, these data reveal a role for p53 in cellular metabolic reprogramming under acidosis, in order to permit increased bioenergetic capacity and ROS neutralization. Understanding the metabolic adaptations that cancer cells make under acidosis may present opportunities to generate anti-tumor therapeutic agents that are more tumor-specific. PMID:24359630

Hunt warm, rest cool: bioenergetic strategy underlying diel vertical migration of a benthic shark.

PubMed

Sims, David W; Wearmouth, Victoria J; Southall, Emily J; Hill, Jacqueline M; Moore, Pippa; Rawlinson, Kate; Hutchinson, Neil; Budd, Georgina C; Righton, David; Metcalfe, Julian D; Nash, Jon P; Morritt, David

2006-01-01

1. Diel vertical migration (DVM) is a widespread phenomenon among marine and freshwater organisms and many studies with various taxa have sought to understand its adaptive significance. Among crustacean zooplankton and juveniles of some fish species DVM is accepted widely as an antipredator behaviour, but little is known about its adaptive value for relatively large-bodied, adult predatory fish such as sharks. Moreover, the majority of studies have focused on pelagic forms, which raises the question of whether DVM occurs in bottom-living predators. 2. To investigate DVM in benthic predatory fish in the marine environment and to determine why it might occur we tracked movements of adult male dogfish (Scyliorhinus canicula) by short- and long-term acoustic and archival telemetry. Movement studies were complemented with measurements of prey abundance and availability and thermal habitat within home ranges. A thermal choice experiment and energy budget modelling was used to investigate trade-offs between foraging and thermal habitat selection. 3. Male dogfish undertook normal DVM (nocturnal ascent) within relatively small home ranges (-100 x 100 m) comprising along-bottom movements up submarine slopes from deeper, colder waters occupied during the day into warmer, shallow prey-rich areas above the thermocline at night. Few daytime vertical movements occurred. Levels of activity were higher during the night above the thermocline compared to below it during the day indicating they foraged in warm water and rested in colder depths. 4. A thermal choice experiment using environmentally realistic temperatures supported the field observation that dogfish positively avoided warmer water even when it was associated with greater food availability. Males in laboratory aquaria moved into warm water from a cooler refuge only to obtain food, and after food consumption they preferred to rest and digest in cooler water. 5. Modelling of energy budgets under different realistic thermal-choice scenarios indicated dogfish adopting a 'hunt warm - rest cool' strategy could lower daily energy costs by just over 4%. Our results provide the first clear evidence that are consistent with the hypothesis that a benthic marine-fish predator utilizes DVM as an energy conservation strategy that increases bioenergetic efficiency.

Co-administration of creatine and guanidinoacetic acid for augmented tissue bioenergetics: A novel approach?

PubMed

Ostojic, Sergej M

2017-07-01

A confined absorption of exogenous creatine through creatine transporter (CRT1) seems to hamper its optimal uptake in bioenergetical deficits. Co-administration of guanidinoacetic acid (GAA) along with creatine could target other transport channels besides CRT1, and supremely improve cellular levels of creatine. This innovative approach might tackle tissues difficult to reach with conventional creatine interventions, providing a potentially more effective and safe mixture in clinical pharmacology and therapeutics. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Short-term sleep deprivation with exposure to nocturnal light alters mitochondrial bioenergetics in Drosophila.

PubMed

Rodrigues, Nathane Rosa; Macedo, Giulianna Echeverria; Martins, Illana Kemmerich; Gomes, Karen Kich; de Carvalho, Nélson Rodrigues; Posser, Thaís; Franco, Jeferson Luis

2018-05-20

Many studies have shown the effects of sleep deprivation in several aspects of health and disease. However, little is known about how mitochondrial bioenergetics function is affected under this condition. To clarify this, we developed a simple model of short-term sleep deprivation, in which fruit-flies were submitted to a nocturnal light condition and then mitochondrial parameters were assessed by high resolution respirometry (HRR). Exposure of flies to constant light was able to alter sleep patterns, causing locomotor deficits, increasing ROS production and lipid peroxidation, affecting mitochondrial activity, antioxidant defense enzymes and caspase activity. HRR analysis showed that sleep deprivation affected mitochondrial bioenergetics capacity, decreasing respiration at oxidative phosphorylation (OXPHOS) and electron transport system (ETS). In addition, the expression of genes involved in the response to oxidative stress and apoptosis were increased. Thus, our results suggest a connection between sleep deprivation and oxidative stress, pointing to mitochondria as a possible target of this relationship. Copyright © 2018 Elsevier Inc. All rights reserved.

Estrogen receptor-β in mitochondria: implications for mitochondrial bioenergetics and tumorigenesis.

PubMed

Liao, Tien-Ling; Tzeng, Chii-Ruey; Yu, Chao-Lan; Wang, Yi-Pei; Kao, Shu-Huei

2015-09-01

Estrogen enhances mitochondrial function by enhancing mitochondrial biogenesis and sustaining mitochondrial energy-transducing capacity. Shifts in mitochondrial bioenergetic pathways from oxidative phosphorylation to glycolysis have been hypothesized to be involved in estrogen-induced tumorigenesis. Studies have shown that mitochondria are an important target of estrogen. Estrogen receptor-β (ERβ) has been shown to localize to mitochondria in a ligand-dependent or -independent manner and can affect mitochondrial bioenergetics and anti-apoptotic signaling. However, the functional role of mitochondrial ERβ in tumorigenesis remains unclear. Clinical studies of ERβ-related tumorigenesis have shown that ERβ stimulates mitochondrial metabolism to meet the high energy demands of processes such as cell proliferation, cell survival, and transformation. Thus, in elucidating the precise role of mitochondrial ERβ in cell transformation and tumorigenesis, it will be particularly valuable to explore new approaches for the development of medical treatments targeting mitochondrial ERβ-mediated mitochondrial function and preventing apoptosis. © 2015 New York Academy of Sciences.

ERBB2 Deficiency Alters an E2F-1-Dependent Adaptive Stress Response and Leads to Cardiac Dysfunction

PubMed Central

Perry, Marie-Claude; Dufour, Catherine R.; Eichner, Lillian J.; Tsang, David W. K.; Deblois, Geneviève; Muller, William J.

2014-01-01

The tyrosine kinase receptor ERBB2 is required for normal development of the heart and is a potent oncogene in breast epithelium. Trastuzumab, a monoclonal antibody targeting ERBB2, improves the survival of breast cancer patients, but cardiac dysfunction is a major side effect of the drug. The molecular mechanisms underlying how ERBB2 regulates cardiac function and why trastuzumab is cardiotoxic remain poorly understood. We show here that ERBB2 hypomorphic mice develop cardiac dysfunction that mimics the side effects observed in patients treated with trastuzumab. We demonstrate that this phenotype is related to the critical role played by ERBB2 in cardiac homeostasis and physiological hypertrophy. Importantly, genetic and therapeutic reduction of ERBB2 activity in mice, as well as ablation of ERBB2 signaling by trastuzumab or siRNAs in human cardiomyocytes, led to the identification of an impaired E2F-1-dependent genetic program critical for the cardiac adaptive stress response. These findings demonstrate the existence of a previously unknown mechanistic link between ERBB2 and E2F-1 transcriptional activity in heart physiology and trastuzumab-induced cardiac dysfunction. PMID:25246633

BP180 dysfunction triggers spontaneous skin inflammation in mice.

PubMed

Zhang, Yang; Hwang, Bin-Jin; Liu, Zhen; Li, Ning; Lough, Kendall; Williams, Scott E; Chen, Jinbo; Burette, Susan W; Diaz, Luis A; Su, Maureen A; Xiao, Shengxiang; Liu, Zhi

2018-06-04

BP180, also known as collagen XVII, is a hemidesmosomal component and plays a key role in maintaining skin dermal/epidermal adhesion. Dysfunction of BP180, either through genetic mutations in junctional epidermolysis bullosa (JEB) or autoantibody insult in bullous pemphigoid (BP), leads to subepidermal blistering accompanied by skin inflammation. However, whether BP180 is involved in skin inflammation remains unknown. To address this question, we generated a BP180-dysfunctional mouse strain and found that mice lacking functional BP180 (termed Δ NC16A ) developed spontaneous skin inflammatory disease, characterized by severe itch, defective skin barrier, infiltrating immune cells, elevated serum IgE levels, and increased expression of thymic stromal lymphopoietin (TSLP). Severe itch is independent of adaptive immunity and histamine, but dependent on increased expression of TSLP by keratinocytes. In addition, a high TSLP expression is detected in BP patients. Our data provide direct evidence showing that BP180 regulates skin inflammation independently of adaptive immunity, and BP180 dysfunction leads to a TSLP-mediated itch. The newly developed mouse strain could be a model for elucidation of disease mechanisms and development of novel therapeutic strategies for skin inflammation and BP180-related skin conditions.

Modeling cardiac action potential shortening driven by oxidative stress-induced mitochondrial oscillations in guinea pig cardiomyocytes.

PubMed

Zhou, Lufang; Cortassa, Sonia; Wei, An-Chi; Aon, Miguel A; Winslow, Raimond L; O'Rourke, Brian

2009-10-07

Ischemia-induced shortening of the cardiac action potential and its heterogeneous recovery upon reperfusion are thought to set the stage for reentrant arrhythmias and sudden cardiac death. We have recently reported that the collapse of mitochondrial membrane potential (DeltaPsi(m)) through a mechanism triggered by reactive oxygen species (ROS), coupled to the opening of sarcolemmal ATP-sensitive potassium (K(ATP)) channels, contributes to electrical dysfunction during ischemia-reperfusion. Here we present a computational model of excitation-contraction coupling linked to mitochondrial bioenergetics that incorporates mitochondrial ROS-induced ROS release with coupling between the mitochondrial energy state and electrical excitability mediated by the sarcolemmal K(ATP) current (I(K,ATP)). Whole-cell model simulations demonstrate that increasing the fraction of oxygen diverted from the respiratory chain to ROS production triggers limit-cycle oscillations of DeltaPsi(m), redox potential, and mitochondrial respiration through the activation of a ROS-sensitive inner membrane anion channel. The periods of transient mitochondrial uncoupling decrease the cytosolic ATP/ADP ratio and activate I(K,ATP), consequently shortening the cellular action potential duration and ultimately suppressing electrical excitability. The model simulates emergent behavior observed in cardiomyocytes subjected to metabolic stress and provides a new tool for examining how alterations in mitochondrial oxidative phosphorylation will impact the electrophysiological, contractile, and Ca(2+) handling properties of the cardiac cell. Moreover, the model is an important step toward building multiscale models that will permit investigation of the role of spatiotemporal heterogeneity of mitochondrial metabolism in the mechanisms of arrhythmogenesis and contractile dysfunction in cardiac muscle.

Sorafenib and FH535 in combination act synergistically on hepatocellular carcinoma by targeting cell bioenergetics and mitochondrial function.

PubMed

Turcios, Lilia; Vilchez, Valery; Acosta, Luis F; Poyil, Pratheeshkumar; Butterfield, David Allan; Mitov, Mihail; Marti, Francesc; Gedaly, Roberto

2017-06-01

Treatment of advanced hepatocellular carcinoma (HCC) remains a challenge due to the high tumor heterogeneity. In the present study, we aim to evaluate the impact of the β-catenin inhibitor, FH535, alone or in combination with the Ras/Raf/MAPK inhibitor Sorafenib, on the bioenergetics profiles of the HCC cell lines Huh7 and PLC/PRF/5. Single low-dose treatments with FH535 or Sorafenib promoted different effects on mitochondrial respiration and glycolysis in a cell type specific manner. However, the combination of these drugs significantly reduced both mitochondrial respiration and glycolytic rates regardless of the HCC cells. The significant changes in mitochondrial respiration observed in cells treated with the Sorafenib-FH535 combination may correspond to differential targeting of ETC complexes and changes in substrate utilization mediated by each drug. Moreover, the bioenergetics changes and the loss of mitochondrial membrane potential that were evidenced by treatment of HCC cells with the combination of FH535 and Sorafenib, preceded the induction of cell apoptosis. Overall, our results demonstrated that Sorafenib-FH535 drug combination induce the disruption of the bioenergetics of HCC by the simultaneous targeting of mitochondrial respiration and glycolytic flux that leads the synergistic effect on inhibition of cell proliferation. These findings support the therapeutic potential of combinatory FH535-Sorafenib treatment of the HCC heterogeneity by the simultaneous targeting of different molecular pathways. Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Juvenile coho salmon growth and health in streams across an urbanization gradient

USGS Publications Warehouse

Spanjer, Andrew R.; Moran, Patrick W.; Larsen, Kimberly; Wetzel, Lisa; Hansen, Adam G.; Beauchamp, David A.

2018-01-01

Expanding human population and urbanization alters freshwater systems through structural changes to habitat, temperature effects from increased runoff and reduced canopy cover, altered flows, and increased toxicants. Current stream assessments stop short of measuring health or condition of species utilizing these freshwater habitats and fail to link specific stressors mechanistically to the health of organisms in the stream. Juvenile fish growth integrates both external and internal conditions providing a useful indicator of habitat quality and ecosystem health. Thus, there is a need to account for ecological and environmental influences on fish growth accurately. Bioenergetics models can simulate changes in growth and consumption in response to environmental conditions and food availability to account for interactions between an organism's environmental experience and utilization of available resources. The bioenergetics approach accounts for how thermal regime, food supply, and food quality affect fish growth. This study used a bioenergetics modeling approach to evaluate the environmental factors influencing juvenile coho salmon growth among ten Pacific Northwest streams spanning an urban gradient. Urban streams tended to be warmer, have earlier emergence dates and stronger early season growth. However, fish in urban streams experienced increased stress through lower growth efficiencies, especially later in the summer as temperatures warmed, with as much as a 16.6% reduction when compared to fish from other streams. Bioenergetics modeling successfully characterized salmonid growth in small perennial streams as part of a more extensive monitoring program and provides a powerful assessment tool for characterizing mixed life-stage specific responses in urban streams.

Polar bears exhibit genome-wide signatures of bioenergetic adaptation to life in the arctic environment.

PubMed

Welch, Andreanna J; Bedoya-Reina, Oscar C; Carretero-Paulet, Lorenzo; Miller, Webb; Rode, Karyn D; Lindqvist, Charlotte

2014-02-01

Polar bears (Ursus maritimus) face extremely cold temperatures and periods of fasting, which might result in more severe energetic challenges than those experienced by their sister species, the brown bear (U. arctos). We have examined the mitochondrial and nuclear genomes of polar and brown bears to investigate whether polar bears demonstrate lineage-specific signals of molecular adaptation in genes associated with cellular respiration/energy production. We observed increased evolutionary rates in the mitochondrial cytochrome c oxidase I gene in polar but not brown bears. An amino acid substitution occurred near the interaction site with a nuclear-encoded subunit of the cytochrome c oxidase complex and was predicted to lead to a functional change, although the significance of this remains unclear. The nuclear genomes of brown and polar bears demonstrate different adaptations related to cellular respiration. Analyses of the genomes of brown bears exhibited substitutions that may alter the function of proteins that regulate glucose uptake, which could be beneficial when feeding on carbohydrate-dominated diets during hyperphagia, followed by fasting during hibernation. In polar bears, genes demonstrating signatures of functional divergence and those potentially under positive selection were enriched in functions related to production of nitric oxide (NO), which can regulate energy production in several different ways. This suggests that polar bears may be able to fine-tune intracellular levels of NO as an adaptive response to control trade-offs between energy production in the form of adenosine triphosphate versus generation of heat (thermogenesis).

Polar Bears Exhibit Genome-Wide Signatures of Bioenergetic Adaptation to Life in the Arctic Environment

PubMed Central

Welch, Andreanna J.; Carretero-Paulet, Lorenzo; Miller, Webb; Rode, Karyn D.; Lindqvist, Charlotte

2014-01-01

Polar bears (Ursus maritimus) face extremely cold temperatures and periods of fasting, which might result in more severe energetic challenges than those experienced by their sister species, the brown bear (U. arctos). We have examined the mitochondrial and nuclear genomes of polar and brown bears to investigate whether polar bears demonstrate lineage-specific signals of molecular adaptation in genes associated with cellular respiration/energy production. We observed increased evolutionary rates in the mitochondrial cytochrome c oxidase I gene in polar but not brown bears. An amino acid substitution occurred near the interaction site with a nuclear-encoded subunit of the cytochrome c oxidase complex and was predicted to lead to a functional change, although the significance of this remains unclear. The nuclear genomes of brown and polar bears demonstrate different adaptations related to cellular respiration. Analyses of the genomes of brown bears exhibited substitutions that may alter the function of proteins that regulate glucose uptake, which could be beneficial when feeding on carbohydrate-dominated diets during hyperphagia, followed by fasting during hibernation. In polar bears, genes demonstrating signatures of functional divergence and those potentially under positive selection were enriched in functions related to production of nitric oxide (NO), which can regulate energy production in several different ways. This suggests that polar bears may be able to fine-tune intracellular levels of NO as an adaptive response to control trade-offs between energy production in the form of adenosine triphosphate versus generation of heat (thermogenesis). PMID:24504087

Polar bears exhibit genome-wide signatures of bioenergetic adaptation to life in the Arctic environment

USGS Publications Warehouse

Welch, Andreanna J.; Bedoya-Reina, Oscar C.; Carretero-Paulet, Lorenzo; Miller, Webb; Rode, Karyn D.; Lindqvist, Charlotte

2014-01-01

Polar bears (Ursus maritimus) face extremely cold temperatures and periods of fasting, which might result in more severe energetic challenges than those experienced by their sister species, the brown bear (U. arctos). We have examined the mitochondrial and nuclear genomes of polar and brown bears to investigate if polar bears demonstrate lineage-specific signals of molecular adaptation in genes associated with cellular respiration/energy production. We observed increased evolutionary rates in the mitochondrial cytochrome c oxidase I gene in polar but not brown bears. An amino acid substitution occurred near the interaction site with a nuclear-encoded subunit of the cytochrome c oxidase complex, and was predicted to lead to a functional change, although the significance of this remains unclear. The nuclear genomes of brown and polar bears demonstrate different adaptations related to cellular respiration. Analyses of the genomes of brown bears exhibited substitutions that may alter the function of proteins that regulate glucose uptake, which could be beneficial when feeding on carbohydrate-dominated diets during hyperphagia, followed by fasting during hibernation. In polar bears, genes demonstrating signatures of functional divergence and those potentially under positive selection were enriched in functions related to production of nitric oxide, which can regulate energy production in several different ways. This suggests that polar bears may be able to fine-tune intracellular levels of nitric oxide as an adaptive response to control trade-offs between energy production in the form of ATP versus generation of heat (thermogenesis).

Reduced oxygen utilization in septic shock: disorder or adaptation?

PubMed

Steiner, Alexandre A

2015-01-01

A fall in oxygen utilization during septic or endotoxic shock is thought to reflect circulatory hypoxia or mitochondrial dysfunction, but these pathology-oriented hypotheses do not explain all clinical observations. Here we discuss an alternative hypothesis of how oxygen utilization could fall as the result of a physiological thermometabolic adaptation.

Disciplinary style and child abuse potential: association with indicators of positive functioning in children with behavior problems.

PubMed

Rodriguez, Christina M; Eden, Ann M

2008-06-01

Reduction of ineffective parenting is promoted in parent training components of mental health treatment for children with externalizing behavior disorders, but minimal research has considered whether disciplinary style and lower abuse risk could also be associated with positive functioning in such children. The present study examined whether lower dysfunctional disciplinary style and child abuse risk was associated with children's positive self-concept, adaptive attributional style, and hopefulness. Recruited from children undergoing treatment for disruptive behavior disorders, 69 mother-child dyads participated, with maternal caregivers reporting on their disciplinary style and abuse potential and children reporting independently on their positive functioning (adaptive attributional style, overall self-concept, and hopelessness). Findings supported the hypothesized association, with lower scores on mothers' dysfunctional discipline style and abuse potential significantly predicting children's reported positive functioning. Future research directions pertaining to more adaptive functioning in children with behavior problems are discussed.

Personal and Environmental Resources Mediate the Positivity-Emotional Dysfunction Relationship.

PubMed

Lehrer, H Matthew; Janus, Katherine C; Gloria, Christian T; Steinhardt, Mary A

2017-03-01

We investigated the relationships among positivity, perceived personal and environmental resources, and emotional dysfunction in adolescent girls. We hypothesized that perceived resources would mediate the relationship between positivity and emotional dysfunction. Participants (N = 510) attending an all-girls public school completed a survey assessing emotional dysfunction (depressive symptoms and perceived stress), positivity (positive/negative emotions), and personal/ environmental resources (resilience, hope, percent adaptive coping, community connectedness, social support, and school connectedness). Perceived resources were combined into one latent variable, and structural equation modeling tested the mediating effect of perceived resources on the relationship between positivity and emotional dysfunction. The model accounted for 63% of the variance in emotional dysfunction. Positivity exerted a significant direct effect on emotional dysfunction (β = -.14, p < .01), but its influence was primarily mediated through perceived resources (indirect effect: β = -.43, p < .001). The impact of positivity on emotional dysfunction is primarily but not entirely mediated by perceived personal and environmental resources. Schools should consider strategies to enhance experiences of positive emotions and/or decrease experiences of negative emotions, in conjunction with encouraging student awareness and development of personal and environmental resources.

Protein tyrosine phosphatase non-receptor type 2 and inflammatory bowel disease.

PubMed

Spalinger, Marianne R; McCole, Declan F; Rogler, Gerhard; Scharl, Michael

2016-01-21

Genome wide association studies have associated single nucleotide polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) with the onset of inflammatory bowel disease (IBD) and other inflammatory disorders. Expression of PTPN2 is enhanced in actively inflamed intestinal tissue featuring a marked up-regulation in intestinal epithelial cells. PTPN2 deficient mice suffer from severe intestinal and systemic inflammation and display aberrant innate and adaptive immune responses. In particular, PTPN2 is involved in the regulation of inflammatory signalling cascades, and critical for protecting intestinal epithelial barrier function, regulating innate and adaptive immune responses, and finally for maintaining intestinal homeostasis. On one hand, dysfunction of PTPN2 has drastic effects on innate host defence mechanisms, including increased secretion of pro-inflammatory cytokines, limited autophagosome formation in response to invading pathogens, and disruption of the intestinal epithelial barrier. On the other hand, PTPN2 function is crucial for controlling adaptive immune functions, by regulating T cell proliferation and differentiation as well as maintaining T cell tolerance. In this way, dysfunction of PTPN2 contributes to the manifestation of IBD. The aim of this review is to present an overview of recent findings on the role of PTPN2 in intestinal homeostasis and the impact of dysfunctional PTPN2 on intestinal inflammation.

Mindfulness in schizophrenia: Associations with self-reported motivation, emotion regulation, dysfunctional attitudes, and negative symptoms.

PubMed

Tabak, Naomi T; Horan, William P; Green, Michael F

2015-10-01

Mindfulness-based interventions are gaining empirical support as alternative or adjunctive treatments for a variety of mental health conditions, including anxiety, depression, and substance use disorders. Emerging evidence now suggests that mindfulness-based treatments may also improve clinical features of schizophrenia, including negative symptoms. However, no research has examined the construct of mindfulness and its correlates in schizophrenia. In this study, we examined self-reported mindfulness in patients (n=35) and controls (n=25) using the Five-Facet Mindfulness Questionnaire. We examined correlations among mindfulness, negative symptoms, and psychological constructs associated with negative symptoms and adaptive functioning, including motivation, emotion regulation, and dysfunctional attitudes. As hypothesized, patients endorsed lower levels of mindfulness than controls. In patients, mindfulness was unrelated to negative symptoms, but it was associated with more adaptive emotion regulation (greater reappraisal) and beliefs (lower dysfunctional attitudes). Some facets of mindfulness were also associated with self-reported motivation (behavioral activation and inhibition). These patterns of correlations were similar in patients and controls. Findings from this initial study suggest that schizophrenia patients may benefit from mindfulness-based interventions because they (a) have lower self-reported mindfulness than controls and (b) demonstrate strong relationships between mindfulness and psychological constructs related to adaptive functioning. Copyright © 2015 Elsevier B.V. All rights reserved.

Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells.

PubMed

Smolková, Katarína; Plecitá-Hlavatá, Lydie; Bellance, Nadége; Benard, Giovanni; Rossignol, Rodrigue; Ježek, Petr

2011-07-01

We posit the following hypothesis: Independently of whether malignant tumors are initiated by a fundamental reprogramming of gene expression or seeded by stem cells, "waves" of gene expression that promote metabolic changes occur during carcinogenesis, beginning with oncogene-mediated changes, followed by hypoxia-induced factor (HIF)-mediated gene expression, both resulting in the highly glycolytic "Warburg" phenotype and suppression of mitochondrial biogenesis. Because high proliferation rates in malignancies cause aglycemia and nutrient shortage, the third (second oncogene) "wave" of adaptation stimulates glutaminolysis, which in certain cases partially re-establishes oxidative phosphorylation; this involves the LKB1-AMPK-p53, PI3K-Akt-mTOR axes and MYC dysregulation. Oxidative glutaminolysis serves as an alternative pathway compensating for cellular ATP. Together with anoxic glutaminolysis it provides pyruvate, lactate, and the NADPH pool (alternatively to pentose phosphate pathway). Retrograde signaling from revitalized mitochondria might constitute the fourth "wave" of gene reprogramming. In turn, upon reversal of the two Krebs cycle enzymes, glutaminolysis may partially (transiently) function even during anoxia, thereby further promoting malignancy. The history of the carcinogenic process within each malignant tumor determines the final metabolic phenotype of the selected surviving cells, resulting in distinct cancer bioenergetic phenotypes ranging from the highly glycolytic "classic Warburg" to partial or enhanced oxidative phosphorylation. We discuss the bioenergetically relevant functions of oncogenes, the involvement of mitochondrial biogenesis/degradation in carcinogenesis, the yet unexplained Crabtree effect of instant glucose blockade of respiration, and metabolic signaling stemming from the accumulation of succinate, fumarate, pyruvate, lactate, and oxoglutarate by interfering with prolyl hydroxylase domain enzyme-mediated hydroxylation of HIFα prolines. Copyright © 2010 Elsevier Ltd. All rights reserved.

An overview of methods for developing bioenergetic and life history models for rare and endangered species

USGS Publications Warehouse

Petersen, J.H.; DeAngelis, D.L.; Paukert, C.P.

2008-01-01

Many fish species are at risk to some degree, and conservation efforts are planned or underway to preserve sensitive populations. For many imperiled species, models could serve as useful tools for researchers and managers as they seek to understand individual growth, quantify predator-prey dynamics, and identify critical sources of mortality. Development and application of models for rare species however, has been constrained by small population sizes, difficulty in obtaining sampling permits, limited opportunities for funding, and regulations on how endangered species can be used in laboratory studies. Bioenergetic and life history models should help with endangered species-recovery planning since these types of models have been used successfully in the last 25 years to address management problems for many commercially and recreationally important fish species. In this paper we discuss five approaches to developing models and parameters for rare species. Borrowing model functions and parameters from related species is simple, but uncorroborated results can be misleading. Directly estimating parameters with laboratory studies may be possible for rare species that have locally abundant populations. Monte Carlo filtering can be used to estimate several parameters by means of performing simple laboratory growth experiments to first determine test criteria. Pattern-oriented modeling (POM) is a new and developing field of research that uses field-observed patterns to build, test, and parameterize models. Models developed using the POM approach are closely linked to field data, produce testable hypotheses, and require a close working relationship between modelers and empiricists. Artificial evolution in individual-based models can be used to gain insight into adaptive behaviors for poorly understood species and thus can fill in knowledge gaps. ?? Copyright by the American Fisheries Society 2008.

Copper deficiency alters cell bioenergetics and induces mitochondrial fusion through up-regulation of MFN2 and OPA1 in erythropoietic cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bustos, Rodrigo I.; Jensen, Erik L.; Ruiz, Lina M.

2013-08-02

Highlights: •In copper deficiency, cell proliferation is not affected. In turn, cell differentiation is impaired. •Enlarged mitochondria are due to up-regulation of MNF2 and OPA1. •Mitochondria turn off respiratory chain and ROS production. •Energy metabolism switch from mitochondria to glycolysis. -- Abstract: Copper is essential in cell physiology, participating in numerous enzyme reactions. In mitochondria, copper is a cofactor for respiratory complex IV, the cytochrome c oxidase. Low copper content is associated with anemia and the appearance of enlarged mitochondria in erythropoietic cells. These findings suggest a connection between copper metabolism and bioenergetics, mitochondrial dynamics and erythropoiesis, which has notmore » been explored so far. Here, we describe that bathocuproine disulfonate-induced copper deficiency does not alter erythropoietic cell proliferation nor induce apoptosis. However it does impair erythroid differentiation, which is associated with a metabolic switch between the two main energy-generating pathways. That is, from mitochondrial function to glycolysis. Switching off mitochondria implies a reduction in oxygen consumption and ROS generation along with an increase in mitochondrial membrane potential. Mitochondrial fusion proteins MFN2 and OPA1 were up-regulated along with the ability of mitochondria to fuse. Morphometric analysis of mitochondria did not show changes in total mitochondrial biomass but rather bigger mitochondria because of increased fusion. Similar results were also obtained with human CD34+, which were induced to differentiate into red blood cells. In all, we have shown that adequate copper levels are important for maintaining proper mitochondrial function and for erythroid differentiation where the energy metabolic switch plus the up-regulation of fusion proteins define an adaptive response to copper deprivation to keep cells alive.« less

Positive Feedback Amplifies the Response of Mitochondrial Membrane Potential to Glucose Concentration in Clonal Pancreatic Beta Cells

PubMed Central

GERENCSER, Akos A.; MOOKERJEE, Shona A.; JASTROCH, Martin; BRAND, Martin D.

2016-01-01

Analysis of the cellular mechanisms of metabolic disorders, including type 2 diabetes mellitus, is complicated by the large number of reactions and interactions in metabolic networks. Metabolic control analysis with appropriate modularization is a powerful method for simplifying and analyzing these networks. To analyze control of cellular energy metabolism in adherent cell cultures of the INS-1 832/13 pancreatic β-cell model we adapted our microscopy assay of absolute mitochondrial membrane potential (ΔψM) to a fluorescence microplate reader format, and applied it in conjunction with cell respirometry. In these cells the sensitive response of ΔψM to extracellular glucose concentration drives glucose-stimulated insulin secretion. Using metabolic control analysis we identified the control properties that generate this sensitive response. Force-flux relationships between ΔψM and respiration were used to calculate kinetic responses to ΔψM of processes both upstream (glucose oxidation) and downstream (proton leak and ATP turnover) of ΔψM. The analysis revealed that glucose-evoked ΔψM hyperpolarization is amplified by increased glucose oxidation activity caused by factors downstream of ΔψM. At high glucose, the hyperpolarized ΔψM is stabilized almost completely by the action of glucose oxidation, whereas proton leak also contribute to the homeostatic control of ΔψM at low glucose. These findings suggest a strong positive feedback loop in the regulation of β-cell energetics, and a possible regulatory role of proton leak in the fasting state. Analysis of islet bioenergetics from published cases of type 2 diabetes suggests that disruption of this feedback can explain the damaged bioenergetic response of β-cells to glucose. PMID:27771512

Testing the Nanoparticle-Allostatic Cross Adaptation-Sensitization Model for Homeopathic Remedy Effects

PubMed Central

Bell, Iris R.; Koithan, Mary; Brooks, Audrey J.

2012-01-01

Key concepts of the Nanoparticle-Allostatic Cross-Adaptation-Sensitization (NPCAS) Model for the action of homeopathic remedies in living systems include source nanoparticles as low level environmental stressors, heterotypic hormesis, cross-adaptation, allostasis (stress response network), time-dependent sensitization with endogenous amplification and bidirectional change, and self-organizing complex adaptive systems. The model accommodates the requirement for measurable physical agents in the remedy (source nanoparticles and/or source adsorbed to silica nanoparticles). Hormetic adaptive responses in the organism, triggered by nanoparticles; bipolar, metaplastic change, dependent on the history of the organism. Clinical matching of the patient’s symptom picture, including modalities, to the symptom pattern that the source material can cause (cross-adaptation and cross-sensitization). Evidence for nanoparticle-related quantum macro-entanglement in homeopathic pathogenetic trials. This paper examines research implications of the model, discussing the following hypotheses: Variability in nanoparticle size, morphology, and aggregation affects remedy properties and reproducibility of findings. Homeopathic remedies modulate adaptive allostatic responses, with multiple dynamic short- and long-term effects. Simillimum remedy nanoparticles, as novel mild stressors corresponding to the organism’s dysfunction initiate time-dependent cross-sensitization, reversing the direction of dysfunctional reactivity to environmental stressors. The NPCAS model suggests a way forward for systematic research on homeopathy. The central proposition is that homeopathic treatment is a form of nanomedicine acting by modulation of endogenous adaptation and metaplastic amplification processes in the organism to enhance long-term systemic resilience and health. PMID:23290882

Current versus future reproduction and longevity: a re-evaluation of predictions and mechanisms.

PubMed

Zhang, Yufeng; Hood, Wendy R

2016-10-15

Oxidative damage is predicted to be a mediator of trade-offs between current reproduction and future reproduction or survival, but most studies fail to support such predictions. We suggest that two factors underlie the equivocal nature of these findings: (1) investigators typically assume a negative linear relationship between current reproduction and future reproduction or survival, even though this is not consistently shown by empirical studies; and (2) studies often fail to target mechanisms that could link interactions between sequential life-history events. Here, we review common patterns of reproduction, focusing on the relationships between reproductive performance, survival and parity in females. Observations in a range of species show that performance between sequential reproductive events can decline, remain consistent or increase. We describe likely bioenergetic consequences of reproduction that could underlie these changes in fitness, including mechanisms that could be responsible for negative effects being ephemeral, persistent or delayed. Finally, we make recommendations for designing future studies. We encourage investigators to carefully consider additional or alternative measures of bioenergetic function in studies of life-history trade-offs. Such measures include reactive oxygen species production, oxidative repair, mitochondrial biogenesis, cell proliferation, mitochondrial DNA mutation and replication error and, importantly, a measure of the respiratory function to determine whether measured differences in bioenergetic state are associated with a change in the energetic capacity of tissues that could feasibly affect future reproduction or lifespan. More careful consideration of the life-history context and bioenergetic variables will improve our understanding of the mechanisms that underlie the life-history patterns of animals. © 2016. Published by The Company of Biologists Ltd.

A Novel Methodology for Bioenergetic Analysis of Plasmodium falciparum Reveals a Glucose-Regulated Metabolic Shift and Enables Mode of Action Analyses of Mitochondrial Inhibitors.

PubMed

Sakata-Kato, Tomoyo; Wirth, Dyann F

2016-12-09

Given that resistance to all drugs in clinical use has arisen, discovery of new antimalarial drug targets is eagerly anticipated. The Plasmodium mitochondrion has been considered a promising drug target largely based on its significant divergence from the host organelle as well as its involvement in ATP production and pyrimidine biosynthesis. However, the functions of Plasmodium mitochondrial protein complexes and associated metabolic pathways are not fully characterized. Here, we report the development of novel and robust bioenergetic assay protocols for Plasmodium falciparum asexual parasites utilizing a Seahorse Bioscience XFe24 Extracellular Flux Analyzer. These protocols allowed us to simultaneously assess the direct effects of metabolites and inhibitors on mitochondrial respiration and glycolytic activity in real-time with the readout of oxygen consumption rate and extracellular acidification rate. Using saponin-freed parasites at the schizont stage, we found that succinate, malate, glycerol-3-phosphate, and glutamate, but not pyruvate, were able to increase the oxygen consumption rate and that glycerol-3-phosphate dehydrogenase had the largest potential as an electron donor among tested mitochondrial dehydrogenases. Furthermore, we revealed the presence of a glucose-regulated metabolic shift between oxidative phosphorylation and glycolysis. We measured proton leak and reserve capacity and found bioenergetic evidence for oxidative phosphorylation in erythrocytic stage parasites but at a level much lower than that observed in mammalian cells. Lastly, we developed an assay platform for target identification and mode of action studies of mitochondria-targeting antimalarials. This study provides new insights into the bioenergetics and metabolomics of the Plasmodium mitochondria.

Current versus future reproduction and longevity: a re-evaluation of predictions and mechanisms

PubMed Central

Zhang, Yufeng

2016-01-01

ABSTRACT Oxidative damage is predicted to be a mediator of trade-offs between current reproduction and future reproduction or survival, but most studies fail to support such predictions. We suggest that two factors underlie the equivocal nature of these findings: (1) investigators typically assume a negative linear relationship between current reproduction and future reproduction or survival, even though this is not consistently shown by empirical studies; and (2) studies often fail to target mechanisms that could link interactions between sequential life-history events. Here, we review common patterns of reproduction, focusing on the relationships between reproductive performance, survival and parity in females. Observations in a range of species show that performance between sequential reproductive events can decline, remain consistent or increase. We describe likely bioenergetic consequences of reproduction that could underlie these changes in fitness, including mechanisms that could be responsible for negative effects being ephemeral, persistent or delayed. Finally, we make recommendations for designing future studies. We encourage investigators to carefully consider additional or alternative measures of bioenergetic function in studies of life-history trade-offs. Such measures include reactive oxygen species production, oxidative repair, mitochondrial biogenesis, cell proliferation, mitochondrial DNA mutation and replication error and, importantly, a measure of the respiratory function to determine whether measured differences in bioenergetic state are associated with a change in the energetic capacity of tissues that could feasibly affect future reproduction or lifespan. More careful consideration of the life-history context and bioenergetic variables will improve our understanding of the mechanisms that underlie the life-history patterns of animals. PMID:27802148

Metabolic Reprogramming Is Required for Myofibroblast Contractility and Differentiation*

PubMed Central

Bernard, Karen; Logsdon, Naomi J.; Ravi, Saranya; Xie, Na; Persons, Benjamin P.; Rangarajan, Sunad; Zmijewski, Jaroslaw W.; Mitra, Kasturi; Liu, Gang; Darley-Usmar, Victor M.; Thannickal, Victor J.

2015-01-01

Contraction is crucial in maintaining the differentiated phenotype of myofibroblasts. Contraction is an energy-dependent mechanism that relies on the production of ATP by mitochondria and/or glycolysis. Although the role of mitochondrial biogenesis in the adaptive responses of skeletal muscle to exercise is well appreciated, mechanisms governing energetic adaptation of myofibroblasts are not well understood. Our study demonstrates induction of mitochondrial biogenesis and aerobic glycolysis in response to the differentiation-inducing factor transforming growth factor β1 (TGF-β1). This metabolic reprogramming is linked to the activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Inhibition of p38 MAPK decreased accumulation of active peroxisome proliferator-activated receptor γ coactivator 1α in the nucleus and altered the translocation of mitochondrial transcription factor A to the mitochondria. Genetic or pharmacologic approaches that block mitochondrial biogenesis or glycolysis resulted in decreased contraction and reduced expression of TGF-β1-induced α-smooth muscle actin and collagen α-2(I) but not of fibronectin or collagen α-1(I). These data indicate a critical role for TGF-β1-induced metabolic reprogramming in regulating myofibroblast-specific contractile signaling and support the concept of integrating bioenergetics with cellular differentiation. PMID:26318453

Exercise and nutritional interventions for improving aging muscle health.

PubMed

Forbes, Scott C; Little, Jonathan P; Candow, Darren G

2012-08-01

Skeletal muscle mass declines with age (i.e., sarcopenia) resulting in muscle weakness and functional limitations. Sarcopenia has been associated with physiological changes in muscle morphology, protein and hormonal kinetics, insulin resistance, inflammation, and oxidative stress. The purpose of this review is to highlight how exercise and nutritional intervention strategies may benefit aging muscle. It is well known that resistance exercise training increases muscle strength and size and evidence also suggests that resistance training can increase mitochondrial content and decrease oxidative stress in older adults. Recent findings suggest that fast-velocity resistance exercise may be an effective intervention for older adults to enhance muscle power and functional capacity. Aerobic exercise training may also benefit aging skeletal muscle by enhancing mitochondrial bioenergetics, improving insulin sensitivity, and/or decreasing oxidative stress. In addition to exercise, creatine monohydrate, milk-based proteins, and essential fatty acids all have biological effects which could enhance some of the physiological adaptations from exercise training in older adults. Additional research is needed to determine whether skeletal muscle adaptations to increased activity in older adults are further enhanced with effective nutritional interventions and whether this is due to enhanced muscle protein synthesis, improved mitochondrial function, and/or a reduced inflammatory response.

Spaceflight Sensorimotor Analogs: Simulating Acute and Adaptive Effects

NASA Technical Reports Server (NTRS)

Taylor, Laura C.; Harm, Deborah L.; Kozlovskaya, Inessa; Reschke, Millard F.; Wood, Scott J.

2009-01-01

Adaptive changes in sensorimotor function during spaceflight are reflected by spatial disorientation, motion sickness, gaze destabilization and decrements in balance, locomotion and eye-hand coordination that occur during and following transitions between different gravitational states. The purpose of this study was to conduct a meta-synthesis of data from spaceflight analogs to evaluate their effectiveness in simulating adaptive changes in sensorimotor function. METHODS. The analogs under review were categorized as either acute analogs used to simulate performance decrements accompanied with transient changes, or adaptive analogs used to drive sensorimotor learning to altered sensory feedback. The effectiveness of each analog was evaluated in terms of mechanisms of action, magnitude and time course of observed deficits compared to spaceflight data, and the effects of amplitude and exposure duration. RESULTS. Parabolic flight has been used extensively to examine effects of acute variation in gravitational loads, ranging from hypergravity to microgravity. More recently, galvanic vestibular stimulation has been used to elicit acute postural, locomotor and gaze dysfunction by disrupting vestibular afferents. Patient populations, e.g., with bilateral vestibular loss or cerebellar dysfunction, have been proposed to model acute sensorimotor dysfunction. Early research sponsored by NASA involved living onboard rotating rooms, which appeared to approximate the time course of adaptation and post-exposure recovery observed in astronauts following spaceflight. Exposure to different bed-rest paradigms (6 deg head down, dry immersion) result in similar motor deficits to that observed following spaceflight. Shorter adaptive analogs have incorporated virtual reality environments, visual distortion paradigms, exposure to conflicting tilt-translation cues, and exposure to 3Gx centrifugation. As with spaceflight, there is considerable variability in responses to most of the analogs reviewed. DISCUSSION. A true ground-based flight analog for sensorimotor function is not feasible. A combination of flight analogs; however, can be used to selectively mimic different aspects of the spaceflight-induced sensorimotor performance decrements.

Trial-unique, delayed nonmatching-to-location (TUNL) touchscreen testing for mice: sensitivity to dorsal hippocampal dysfunction.

PubMed

Kim, Chi Hun; Romberg, Carola; Hvoslef-Eide, Martha; Oomen, Charlotte A; Mar, Adam C; Heath, Christopher J; Berthiaume, Andrée-Anne; Bussey, Timothy J; Saksida, Lisa M

2015-11-01

The hippocampus is implicated in many of the cognitive impairments observed in conditions such as Alzheimer's disease (AD) and schizophrenia (SCZ). Often, mice are the species of choice for models of these diseases and the study of the relationship between brain and behaviour more generally. Thus, automated and efficient hippocampal-sensitive cognitive tests for the mouse are important for developing therapeutic targets for these diseases, and understanding brain-behaviour relationships. One promising option is to adapt the touchscreen-based trial-unique nonmatching-to-location (TUNL) task that has been shown to be sensitive to hippocampal dysfunction in the rat. This study aims to adapt the TUNL task for use in mice and to test for hippocampus-dependency of the task. TUNL training protocols were altered such that C57BL/6 mice were able to acquire the task. Following acquisition, dysfunction of the dorsal hippocampus (dHp) was induced using a fibre-sparing excitotoxin, and the effects of manipulation of several task parameters were examined. Mice could acquire the TUNL task using training optimised for the mouse (experiments 1). TUNL was found to be sensitive to dHp dysfunction in the mouse (experiments 2, 3 and 4). In addition, we observed that performance of dHp dysfunction group was somewhat consistently lower when sample locations were presented in the centre of the screen. This study opens up the possibility of testing both mouse and rat models on this flexible and hippocampus-sensitive touchscreen task.

Intermittent fasting results in tissue-specific changes in bioenergetics and redox state.

PubMed

Chausse, Bruno; Vieira-Lara, Marcel A; Sanchez, Angélica B; Medeiros, Marisa H G; Kowaltowski, Alicia J

2015-01-01

Intermittent fasting (IF) is a dietary intervention often used as an alternative to caloric restriction (CR) and characterized by 24 hour cycles alternating ad libitum feeding and fasting. Although the consequences of CR are well studied, the effects of IF on redox status are not. Here, we address the effects of IF on redox state markers in different tissues in order to uncover how changes in feeding frequency alter redox balance in rats. IF rats displayed lower body mass due to decreased energy conversion efficiency. Livers in IF rats presented increased mitochondrial respiratory capacity and enhanced levels of protein carbonyls. Surprisingly, IF animals also presented an increase in oxidative damage in the brain that was not related to changes in mitochondrial bioenergetics. Conversely, IF promoted a substantial protection against oxidative damage in the heart. No difference in mitochondrial bioenergetics or redox homeostasis was observed in skeletal muscles of IF animals. Overall, IF affects redox balance in a tissue-specific manner, leading to redox imbalance in the liver and brain and protection against oxidative damage in the heart.

Intermittent Fasting Results in Tissue-Specific Changes in Bioenergetics and Redox State

PubMed Central

Chausse, Bruno; Vieira-Lara, Marcel A.; Sanchez, Angélica B.; Medeiros, Marisa H. G.; Kowaltowski, Alicia J.

2015-01-01

Intermittent fasting (IF) is a dietary intervention often used as an alternative to caloric restriction (CR) and characterized by 24 hour cycles alternating ad libitum feeding and fasting. Although the consequences of CR are well studied, the effects of IF on redox status are not. Here, we address the effects of IF on redox state markers in different tissues in order to uncover how changes in feeding frequency alter redox balance in rats. IF rats displayed lower body mass due to decreased energy conversion efficiency. Livers in IF rats presented increased mitochondrial respiratory capacity and enhanced levels of protein carbonyls. Surprisingly, IF animals also presented an increase in oxidative damage in the brain that was not related to changes in mitochondrial bioenergetics. Conversely, IF promoted a substantial protection against oxidative damage in the heart. No difference in mitochondrial bioenergetics or redox homeostasis was observed in skeletal muscles of IF animals. Overall, IF affects redox balance in a tissue-specific manner, leading to redox imbalance in the liver and brain and protection against oxidative damage in the heart. PMID:25749501

Specialized project in biophotonics

NASA Astrophysics Data System (ADS)

Garcia Martin, Agueda L.; Sastriques-Silva, Pedro O.; Martinez-Fundora, Julia N.; Augier Calderin, Angel G.; Lopez-Cepero, Xonia

2000-06-01

As science advances, it is more evident the necessity of a health interdisciplinary approach in Medicine. In the case of medical applications of light, the knowledge of the use of dispositives, equipment, diagnostic and treatment means, as well as the bases for the use of this update technologies is required. At the present moment, the outstanding work of specialized professionals of different profiles requires personnel with high professional formation in keeping with the latest trends in science and technology. The authors present here an Specialized Project in Biophotonics, with the aim of increasing the professional preparation of university graduates with an ample profile--physicists and engineers--who work in Biomedical Optics, thus contributing to the specialized formation of medic and paramedic personnel. The course is structured into six-subject-modules and into two phases. As to the basic professional formation, each one attending this course, will select between two variants of the Basic Formation Postgraduate Course: Anatomy and Physiology, Physical Bioenergetics, Clinic Bioenergetics; or Physics in Medicine, Optics and Applied Information Theory, depending on the student's professional profile. In the second phase, the General Formation Postgraduate Course: Biomedical Optics, Optical Bioenergetics and Laser in Medicine.

Real-Time Monitoring of Cellular Bioenergetics with a Multi-Analyte Screen-Printed Electrode

PubMed Central

McKenzie, Jennifer R.; Cognata, Andrew C.; Davis, Anna N.; Wikswo, John P.; Cliffel, David E.

2016-01-01

Real-time monitoring of changes to cellular bioenergetics can provide new insights into mechanisms of action for disease and toxicity. This work describes the development of a multi-analyte screen-printed electrode for the detection of analytes central to cellular bioenergetics: glucose, lactate, oxygen, and pH. Platinum screen-printed electrodes were designed in-house and printed by Pine Research Instrumentation. Electrochemical plating techniques were used to form quasi-reference and pH electrodes. A Dimatix materials inkjet printer was used to deposit enzyme and polymer films to form sensors for glucose, lactate, and oxygen. These sensors were evaluated in bulk solution and microfluidic environments, and found to behave reproducibly and possess a lifetime of up to six weeks. Linear ranges and limits of detection for enzyme-based sensors were found to have an inverse relationship with enzyme loading, and iridium oxide pH sensors were found to have super-Nernstian responses. Preliminary measurements where the sensor was enclosed within a microfluidic channel with RAW 264.7 macrophages were performed to demonstrate the sensors’ capabilities for performing real-time microphysiometry measurements. PMID:26125545

Test of a foraging-bioenergetics model to evaluate growth dynamics of endangered pallid sturgeon (Scaphirhynchus albus)

USGS Publications Warehouse

Deslauriers, David; Heironimus, Laura B.; Chipps, Steven R.

2016-01-01

Factors affecting feeding and growth of early life stages of the federally endangered pallid sturgeon (Scaphirhynchus albus) are not fully understood, owing to their scarcity in the wild. In this study was we evaluated the performance of a combined foraging-bioenergetics model as a tool for assessing growth of age-0 pallid sturgeon in the Missouri River. In the laboratory, three size classes of sturgeon larvae (18–44 mm; 0.027–0.329 g) were grown for 7 to 14 days under differing temperature (14–24 °C) and prey density (0–9 Chironomidae larvae/d) regimes. After accounting for effects of water temperature and prey density on fish activity, we compared observed final weight, final length, and number of prey consumed to values generated from the foraging-bioenergetics model. When confronted with an independent dataset, the combined model provided reliable estimates (within 13% of observations) of fish growth and prey consumption, underscoring the usefulness of the modeling approach for evaluating growth dynamics of larval fish when empirical data are lacking.

Differential effects of p,p'-DDE on testis and liver mitochondria: implications for reproductive toxicology.

PubMed

Mota, Paula C; Cordeiro, Marília; Pereira, Susana P; Oliveira, Paulo J; Moreno, António J; Ramalho-Santos, João

2011-01-01

The release of environmental contaminants can contribute to impaired male fertility. The bioenergetics of isolated liver mitochondria have been used as a toxicological indicator, an inexpensive first line model to screen possible effects of several substances. Here we report the effects of 2,2-bis(4-chlorophenyl)-1,1-dichloro-ethylene (DDE) on the bioenergetical parameters of testicular mitochondria. A significant decrease in repolarization potential (after a phosphorylative cycle), state 3 respiration and uncoupled respiration, with a concomitant increase in lag phase was found, demonstrating a decrease in mitochondrial function. Importantly, there was also a clear increase in maximum potential in DDE-treated testis mitochondria, which was not mirrored by more commonly used liver mitochondria. Indeed, comparative studies showed that testis and liver mitochondria have strikingly different sensitivities and patterns of response to DDE, indicating that testis mitochondria should be used as a primary toxicological model for a proper evaluation of putative effects of environmental toxicants on the bioenergetics of spermatogenesis and male fertility. Copyright © 2010 Elsevier Inc. All rights reserved.

[Stress and coping with stress by mothers of children with mild cerebral dysfunctions].

PubMed

Virtanen, T; Moilanen, I

1991-09-01

Adapting the paradigm developed by Richard Lazarus, parenting stress and coping were studied among mothers of children (n = 42) with Minimal Brain Dysfunction (MBD) and mothers with non-disabled children (n = 42), aged 6 to 9. The children of control mothers were matched by age, sex, social status, and maternal marital status with the MBD children. The mothers of MBD children were found to experience more parenting difficulties, more negatively toned cognitive appraisals of their stakes in parenting and less positive adaptational outcomes than their controls. The mothers of MBD children appraised their mastery lower than their controls. However, family well-being, or self-esteem did not differ between the mothers of MBD children and their controls.

Chronic Lung Allograft Dysfunction: A Systematic Review of Mechanisms.

PubMed

Royer, Pierre-Joseph; Olivera-Botello, Gustavo; Koutsokera, Angela; Aubert, John-David; Bernasconi, Eric; Tissot, Adrien; Pison, Christophe; Nicod, Laurent; Boissel, Jean-Pierre; Magnan, Antoine

2016-09-01

Chronic lung allograft dysfunction (CLAD) is the major limitation of long-term survival after lung transplantation. Chronic lung allograft dysfunction manifests as bronchiolitis obliterans syndrome or the recently described restrictive allograft syndrome. Although numerous risk factors have been identified so far, the physiopathological mechanisms of CLAD remain poorly understood. We investigate here the immune mechanisms involved in the development of CLAD after lung transplantation. We explore the innate or adaptive immune reactions induced by the allograft itself or by the environment and how they lead to allograft dysfunction. Because current literature suggests bronchiolitis obliterans syndrome and restrictive allograft syndrome as 2 distinct entities, we focus on the specific factors behind one or the other syndromes. Chronic lung allograft dysfunction is a multifactorial disease that remains irreversible and unpredictable so far. We thus finally discuss the potential of systems-biology approach to predict its occurrence and to better understand its underlying mechanisms.

Metabolic and Epigenetic Coordination of T Cell and Macrophage Immunity.

PubMed

Phan, Anthony T; Goldrath, Ananda W; Glass, Christopher K

2017-05-16

Recognition of pathogens by innate and adaptive immune cells instructs rapid alterations of cellular processes to promote effective resolution of infection. To accommodate increased bioenergetic and biosynthetic demands, metabolic pathways are harnessed to maximize proliferation and effector molecule production. In parallel, activation initiates context-specific gene-expression programs that drive effector functions and cell fates that correlate with changes in epigenetic landscapes. Many chromatin- and DNA-modifying enzymes make use of substrates and cofactors that are intermediates of metabolic pathways, providing potential cross talk between metabolism and epigenetic regulation of gene expression. In this review, we discuss recent studies of T cells and macrophages supporting a role for metabolic activity in integrating environmental signals with activation-induced gene-expression programs through modulation of the epigenome and speculate as to how this may influence context-specific macrophage and T cell responses to infection. Copyright © 2017 Elsevier Inc. All rights reserved.

Metabolic and epigenetic coordination of T cell and Macrophage immunity

PubMed Central

Phan, Anthony T.; Goldrath, Ananda W.; Glass, Christopher K.

2017-01-01

Recognition of pathogens by innate and adaptive immune cells instructs rapid alterations of cellular processes to promote effective resolution of infection. To accommodate increased bioenergetic and biosynthetic demands, metabolic pathways are harnessed to maximize proliferation and effector molecule production. In parallel, activation initiates context-specific gene-expression programs that drive effector functions and cell fates that correlate with changes in epigenetic landscapes. Many chromatin- and DNA-modifying enzymes make use of substrates and cofactors that are intermediates of metabolic pathways, providing potential cross talk between metabolism and epigenetic regulation of gene expression. In this review, we discuss recent studies of T cells and macrophages supporting a role for metabolic activity in integrating environmental signals with activation-induced gene-expression programs through modulation of the epigenome and speculate as to how this may influence context-specific macrophage and T cell responses to infection. PMID:28514673

Redox Aspects of Chaperones in Cardiac Function

PubMed Central

Penna, Claudia; Sorge, Matteo; Femminò, Saveria; Pagliaro, Pasquale; Brancaccio, Mara

2018-01-01

Molecular chaperones are stress proteins that allow the correct folding or unfolding as well as the assembly or disassembly of macromolecular cellular components. Changes in expression and post-translational modifications of chaperones have been linked to a number of age- and stress-related diseases including cancer, neurodegeneration, and cardiovascular diseases. Redox sensible post-translational modifications, such as S-nitrosylation, glutathionylation and phosphorylation of chaperone proteins have been reported. Redox-dependent regulation of chaperones is likely to be a phenomenon involved in metabolic processes and may represent an adaptive response to several stress conditions, especially within mitochondria, where it impacts cellular bioenergetics. These post-translational modifications might underlie the mechanisms leading to cardioprotection by conditioning maneuvers as well as to ischemia/reperfusion injury. In this review, we discuss this topic and focus on two important aspects of redox-regulated chaperones, namely redox regulation of mitochondrial chaperone function and cardiac protection against ischemia/reperfusion injury. PMID:29615920

Feast and famine: Adipose tissue adaptations for healthy aging.

PubMed

Lettieri Barbato, Daniele; Aquilano, Katia

2016-07-01

Proper adipose tissue function controls energy balance with favourable effects on metabolic health and longevity. The molecular and metabolic asset of adipose tissue quickly and dynamically readapts in response to nutrient fluctuations. Once delivered into cells, nutrients are managed by mitochondria that represent a key bioenergetics node. A persistent nutrient overload generates mitochondrial exhaustion and uncontrolled reactive oxygen species ((mt)ROS) production. In adipocytes, metabolic/molecular reorganization is triggered culminating in the acquirement of a hypertrophic and hypersecretory phenotype that accelerates aging. Conversely, dietary regimens such as caloric restriction or time-controlled fasting endorse mitochondrial functionality and (mt)ROS-mediated signalling, thus promoting geroprotection. In this perspective view, we argued some important molecular and metabolic aspects related to adipocyte response to nutrient stress. Finally we delineated hypothetical routes by which molecularly and metabolically readapted adipose tissue promotes healthy aging. Copyright © 2016 Elsevier B.V. All rights reserved.

Progesterone induces neuroprotection following reperfusion-promoted mitochondrial dysfunction after focal cerebral ischemia in rats.

PubMed

Andrabi, Syed Suhail; Parvez, Suhel; Tabassum, Heena

2017-06-01

Organelle damage and increases in mitochondrial permeabilization are key events in the development of cerebral ischemic tissue injury because they cause both modifications in ATP turnover and cellular apoptosis/necrosis. Early restoration of blood flow and improvement of mitochondrial function might reverse the situation and help in recovery following an onset of stroke. Mitochondria and related bioenergetic processes can be effectively used as pharmacological targets. Progesterone (P4), one of the promising neurosteroids, has been found to be neuroprotective in various models of neurological diseases, through a number of mechanisms. This influenced us to investigate the possible role of P4 in the mitochondria-mediated neuroprotective mechanism in an ischemic stroke model of rat. In this study, we have shown the positive effect of P4 administration on behavioral deficits and mitochondrial health in an ischemic stroke injury model of transient middle cerebral artery occlusion (tMCAO). After induction of tMCAO, the rats received an initial intraperitoneal injection of P4 (8 mg/kg body weight) or vehicle at 1 h post-occlusion followed by subcutaneous injections at 6, 12 and 18 h. Behavioral assessment for functional deficits included grip strength, motor coordination and gait analysis. Findings revealed a significant improvement with P4 treatment in tMCAO animals. Staining of isolated brain slices from P4-treated rats with 2,3,5-triphenyltetrazolium chloride (TTC) showed a reduction in the infarct area in comparison to the vehicle group, indicating the presence of an increased number of viable mitochondria. P4 treatment was also able to attenuate mitochondrial reactive oxygen species (ROS) production, as well as block the mitochondrial permeability transition pore (mPTP), in the tMCAO injury model. In addition, it was also able to ameliorate the altered mitochondrial membrane potential and respiration ratio in the ischemic animals, thereby suggesting that P4 has a positive effect on mitochondrial bioenergetics. In conclusion, these results demonstrate that P4 treatment is beneficial in preserving the mitochondrial functions that are altered in cerebral ischemic injury and thus can help in defining better therapies. © 2017. Published by The Company of Biologists Ltd.

MDMA in humans: factors which affect the neuropsychobiological profiles of recreational ecstasy users, the integrative role of bioenergetic stress.

PubMed

Parrott, Andy C

2006-03-01

Many recreational ecstasy/MDMA users display neuropsychobiological deficits, whereas others remain problem free. This review will investigate some of the drug and non-drug factors which influence the occurrence of these deficits. Acute and chronic MDMA usage are both important. Intensive use within a session is often associated with more problems. In term of lifetime usage, novice users generally remain unimpaired, whereas most heavy users report memory or other psychobiological problems which they attribute to ecstasy. These complaints are confirmed by objective deficits in working memory, attention, frontal-executive, and episodic memory tasks. Psychobiological deficits include disturbed sleep, sexual dysfunction, reduced immuno-competence, and increased oxidative stress. Further MDMA-related factors which may contribute to these changes, include acute and chronic tolerance, and drug dependence. Around 90ñ95% of ecstasy/MDMA users also take cannabis, and this can independently contribute to the adverse neuropsychobiological pro.les; although in some situations the acute co-use of these two drugs may be interactive rather than additive, since cannabis has relaxant and hypothermic properties. Alcohol, nicotine, amphetamine, and other drugs, can also affect the psychobiological pro.les of ecstasy polydrug users in complex ways. Pure MDMA users are rare but they have been shown to display significant neurocognitive deficits. Psychiatric aspects are debated in the context of the diathesis-stress model. Here the stressor of ecstasy polydrug drug use, interacts with various predisposition factors (genetic, neurochemical, personality), to determine the psychiatric outcome. Recreational MDMA is typically taken in hot and crowded dances/raves. Prolonged dancing, feeling hot, and raised body temperature, can also be associated with more psychobiological problems. This is consistent with the animal literature, where high ambient temperature and other metabolic stimulants boost the acute effects of MDMA, and cause greater serotonergic neurotoxicity. In conclusion, the neuropsychobiological effects of MDMA are modulated by a wide range of drug and non-drug factors. These multiple influences are integrated within a bioenergetic stress model, where factors which heighten acute metabolic distress lead to more neuropsychobiological problems.

Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease.

PubMed

Pera, Marta; Larrea, Delfina; Guardia-Laguarta, Cristina; Montesinos, Jorge; Velasco, Kevin R; Agrawal, Rishi R; Xu, Yimeng; Chan, Robin B; Di Paolo, Gilbert; Mehler, Mark F; Perumal, Geoffrey S; Macaluso, Frank P; Freyberg, Zachary Z; Acin-Perez, Rebeca; Enriquez, Jose Antonio; Schon, Eric A; Area-Gomez, Estela

2017-11-15

In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by β-secretase to generate a 99-aa C-terminal fragment (C99) that is then cleaved by γ-secretase to generate the β-amyloid (Aβ) found in senile plaques. In previous reports, we and others have shown that γ-secretase activity is enriched in mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) and that ER-mitochondrial connectivity and MAM function are upregulated in AD We now show that C99, in addition to its localization in endosomes, can also be found in MAM, where it is normally processed rapidly by γ-secretase. In cell models of AD, however, the concentration of unprocessed C99 increases in MAM regions, resulting in elevated sphingolipid turnover and an altered lipid composition of both MAM and mitochondrial membranes. In turn, this change in mitochondrial membrane composition interferes with the proper assembly and activity of mitochondrial respiratory supercomplexes, thereby likely contributing to the bioenergetic defects characteristic of AD. © 2017 The Authors. Published under the terms of the CC BY 4.0 license.

Dysfunctional Coq9 protein causes predominant encephalomyopathy associated with CoQ deficiency.

PubMed

García-Corzo, Laura; Luna-Sánchez, Marta; Doerrier, Carolina; García, José A; Guarás, Adela; Acín-Pérez, Rebeca; Bullejos-Peregrín, Javier; López, Ana; Escames, Germaine; Enríquez, José A; Acuña-Castroviejo, Darío; López, Luis C

2013-03-15

Coenzyme Q10 (CoQ(10)) or ubiquinone is a well-known component of the mitochondrial respiratory chain. In humans, CoQ(10) deficiency causes a mitochondrial syndrome with an unexplained variability in the clinical presentations. To try to understand this heterogeneity in the clinical phenotypes, we have generated a Coq9 Knockin (R239X) mouse model. The lack of a functional Coq9 protein in homozygous Coq9 mutant (Coq9(X/X)) mice causes a severe reduction in the Coq7 protein and, as consequence, a widespread CoQ deficiency and accumulation of demethoxyubiquinone. The deficit in CoQ induces a brain-specific impairment of mitochondrial bioenergetics performance, a reduction in respiratory control ratio, ATP levels and ATP/ADP ratio and specific loss of respiratory complex I. These effects lead to neuronal death and demyelinization with severe vacuolization and astrogliosis in the brain of Coq9(X/X) mice that consequently die between 3 and 6 months of age. These results suggest that the instability of mitochondrial complex I in the brain, as a primary event, triggers the development of mitochondrial encephalomyopathy associated with CoQ deficiency.

Mitochondrial poly(ADP-ribose) polymerase: The Wizard of Oz at work.

PubMed

Brunyanszki, Attila; Szczesny, Bartosz; Virág, László; Szabo, Csaba

2016-11-01

Among multiple members of the poly(ADP-ribose) polymerase (PARP) family, PARP1 accounts for the majority of PARP activity in mammalian cells. Although PARP1 is predominantly localized to the nucleus, and its nuclear regulatory roles are most commonly studied and are the best characterized, several lines of data demonstrate that PARP1 is also present in the mitochondria, and suggest that mitochondrial PARP (mtPARP) plays an important role in the regulation of various cellular functions in health and disease. The goal of the current article is to review the experimental evidence for the mitochondrial localization of PARP1 and its intra-mitochondrial functions, with focus on cellular bioenergetics, mitochondrial DNA repair and mitochondrial dysfunction. In addition, we also propose a working model for the interaction of mitochondrial and nuclear PARP during oxidant-induced cell death. MtPARP is similar to the Wizard of Oz in the sense that it is enigmatic, it has been elusive for a long time and it remains difficult to be interrogated. mtPARP - at least in some cell types - works incessantly "behind the curtains" as an orchestrator of many important cellular functions. Copyright © 2016 Elsevier Inc. All rights reserved.

Ascorbic acid ameliorates behavioural deficits and neuropathological alterations in rat model of Alzheimer's disease.

PubMed

Olajide, Olayemi Joseph; Yawson, Emmanuel Olusola; Gbadamosi, Ismail Temitayo; Arogundade, Tolulope Timothy; Lambe, Ezra; Obasi, Kosisochukwu; Lawal, Ismail Tayo; Ibrahim, Abdulmumin; Ogunrinola, Kehinde Yomi

2017-03-01

Exploring the links between neural pathobiology and behavioural deficits in Alzheimer's disease (AD), and investigating substances with known therapeutic advantages over subcellular mechanisms underlying these dysfunctions could advance the development of potent therapeutic molecules for AD treatment. Here we investigated the efficacy of ascorbic acid (AA) in reversing aluminium chloride (AlCl 3 )-induced behavioural deficits and neurotoxic cascades within prefrontal cortex (PFC) and hippocampus of rats. A group of rats administered oral AlCl 3 (100mg/kg) daily for 15days showed degenerative changes characterised by significant weight loss, reduced exploratory/working memory, frontal-dependent motor deficits, cognitive decline, memory dysfunction and anxiety during behavioural assessments compared to control. Subsequent analysis showed that oxidative impairment-indicated by depleted superoxide dismutase and lipid peroxidation (related to glutathione-S-transferase activity), cholinergic deficits seen by increased neural acetylcholinesterase (AChE) expression and elevated lactate dehydrogenase underlie behavioural alterations. Furthermore, evidences of proteolysis were seen by reduced Nissl profiles in neuronal axons and dendrites which correspond to apoptotic changes observed in H&E staining of PFC and hippocampal sections. Interestingly, AA (100mg/kg daily for 15days) significantly attenuated behavioural deficits in rats through inhibition of molecular and cellular stressor proteins activated by AlCl 3. Our results showed that the primary mechanisms underlying AA therapeutic advantages relates closely with its abilities to scavenge free radicals, prevent membrane lipid peroxidation, modulate neuronal bioenergetics, act as AChE inhibitor and through its anti-proteolytic properties. These findings suggest that supplementing endogenous AA capacity through its pharmacological intake may inhibit progression of AD-related neurodegenerative processes and behavioural alterations. Copyright © 2017 Elsevier B.V. All rights reserved.

Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria.

PubMed

Santos, N A G; Catão, C S; Martins, N M; Curti, C; Bianchi, M L P; Santos, A C

2007-07-01

The clinical use of cisplatin (cis-diamminedichloroplatinum II) is highly limited by its nephrotoxicity. The precise mechanisms involved in cisplatin-induced mitochondrial dysfunction in kidney have not been completely clarified. Therefore, we investigated in vivo the effects of cisplatin on mitochondrial bioenergetics, redox state, and oxidative stress as well as the occurrence of cell death by apoptosis in cisplatin-treated rat kidney. Adult male Wistar rats weighing 200-220 g were divided into two groups. The control group (n = 8) was treated only with an intraperitoneal (i.p.) injection of saline solution (1 ml per 100 g body weight), and the cisplatin group (n = 8) was given a single injection of cisplatin (10 mg/kg body weight, i.p.). Animals were sacrificed 72 h after the treatment. The cisplatin group presented acute renal failure characterized by increased plasmatic creatinine and urea levels. Mitochondrial dysfunction was evidenced by the decline in membrane electrochemical potential and the substantial decrease in mitochondrial calcium uptake. The mitochondrial antioxidant defense system was depleted, as shown by decreased GSH and NADPH levels, GSH/GSSG ratio, and increased GSSG level. Moreover, cisplatin induced oxidative damage to mitochondrial lipids, including cardiolipin, and oxidation of mitochondrial proteins, as demonstrated by the significant decrease of sulfhydryl protein concentrations and increased levels of carbonylated proteins. Additionally, aconitase activity, which is essential for mitochondrial function, was also found to be lower in the cisplatin group. Renal cell death via apoptosis was evidenced by the increased caspase-3 activity. Results show the central role of mitochondria and the intensification of apoptosis in cisplatin-induced acute renal failure, highlighting a number of steps that might be targeted to minimize cisplatin-induced nephrotoxicity.

Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons

PubMed Central

Magrané, Jordi; Sahawneh, Mary Anne; Przedborski, Serge; Estévez, Álvaro G.; Manfredi, Giovanni

2012-01-01

Mutations in Cu,Zn superoxide dismutase (SOD1) cause familial amyotrophic lateral sclerosis (FALS), a rapidly fatal motor neuron disease. Mutant SOD1 has pleiotropic toxic effects on motor neurons, among which mitochondrial dysfunction has been proposed as one of the contributing factors in motor neuron demise. Mitochondria are highly dynamic in neurons; they are constantly reshaped by fusion and move along neurites to localize at sites of high-energy utilization, such as synapses. The finding of abnormal mitochondria accumulation in neuromuscular junctions, where the SOD1-FALS degenerative process is though to initiate, suggests that impaired mitochondrial dynamics in motor neurons may be involved in pathogenesis. We addressed this hypothesis by live imaging microscopy of photo-switchable fluorescent mitoDendra in transgenic rat motor neurons expressing mutant or wild type human SOD1. We demonstrate that mutant SOD1 motor neurons have impaired mitochondrial fusion in axons and cell bodies. Mitochondria also display selective impairment of retrograde axonal transport, with reduced frequency and velocity of movements. Fusion and transport defects are associated with smaller mitochondrial size, decreased mitochondrial density, and defective mitochondrial membrane potential. Furthermore, mislocalization of mitochondria at synapses among motor neurons, in vitro, correlates with abnormal synaptic number, structure, and function. Dynamics abnormalities are specific to mutant SOD1 motor neuron mitochondria, since they are absent in wild type SOD1 motor neurons, they do not involve other organelles, and they are not found in cortical neurons. Taken together, these results suggest that impaired mitochondrial dynamics may contribute to the selective degeneration of motor neurons in SOD1-FALS. PMID:22219285

Epigallocatechin-3-gallate induces oxidative phosphorylation by activating cytochrome c oxidase in human cultured neurons and astrocytes

PubMed Central

Castellano-González, Gloria; Pichaud, Nicolas; Ballard, J. William O.; Bessede, Alban; Marcal, Helder; Guillemin, Gilles J.

2016-01-01

Mitochondrial dysfunction and resulting energy impairment have been identified as features of many neurodegenerative diseases. Whether this energy impairment is the cause of the disease or the consequence of preceding impairment(s) is still under discussion, however a recovery of cellular bioenergetics would plausibly prevent or improve the pathology. In this study, we screened different natural molecules for their ability to increase intracellular adenine triphosphate purine (ATP). Among them, epigallocatechin-3-gallate (EGCG), a polyphenol from green tea, presented the most striking results. We found that it increases ATP production in both human cultured astrocytes and neurons with different kinetic parameters and without toxicity. Specifically, we showed that oxidative phosphorylation in human cultured astrocytes and neurons increased at the level of the routine respiration on the cells pre-treated with the natural molecule. Furthermore, EGCG-induced ATP production was only blocked by sodium azide (NaN3) and oligomycin, inhibitors of cytochrome c oxidase (CcO; complex IV) and ATP synthase (complex V) respectively. These findings suggest that the EGCG modulates CcO activity, as confirmed by its enzymatic activity. CcO is known to be regulated differently in neurons and astrocytes. Accordingly, EGCG treatment is acting differently on the kinetic parameters of the two cell types. To our knowledge, this is the first study showing that EGCG promotes CcO activity in human cultured neurons and astrocytes. Considering that CcO dysfunction has been reported in patients having neurodegenerative diseases such as Alzheimer's disease (AD), we therefore suggest that EGCG could restore mitochondrial function and prevent subsequent loss of synaptic function. PMID:26760769

Profound bioenergetic abnormalities in peri-infarct myocardial regions.

PubMed

Hu, Qingsong; Wang, Xiaohong; Lee, Joseph; Mansoor, Abdul; Liu, Jingbo; Zeng, Lepeng; Swingen, Cory; Zhang, Ge; Feygin, Julia; Ochiai, Koichi; Bransford, Toni L; From, Arthur H L; Bache, Robert J; Zhang, Jianyi

2006-08-01

Regions of myocardial infarct (MI) are surrounded by a border zone (BZ) of normally perfused but dysfunctional myocardium. Although systolic dysfunction has been attributed to elevated wall stress in this region, there is evidence that intrinsic abnormalities of contractile performance exist in BZ myocardium. This study examined whether decreases of high-energy phosphates (HEP) and mitochondrial F(1)F(0)-ATPase (mtATPase) subunits typical of failing myocardium exist in BZ myocardium of compensated postinfarct remodeled hearts. Eight pigs were studied 6 wk after MI was produced by ligation of the left anterior descending coronary artery (LAD) distal to the second diagonal. Animals developed compensated LV remodeling with a decrease of ejection fraction from 54.6 +/- 5.4% to 31 +/- 2.1% (MRI) 5 wk after LAD occlusion. The remote zone (RZ) myocardium demonstrated modest decreases of ATP and mtATPase components. In contrast, BZ myocardium demonstrated profound abnormalities with ATP levels decreased to 42% of normal, and phosphocreatine-to-ATP ratio ((31)P-magnetic resonance spectroscopy) decreased from 2.06 +/- 0.19 in normal hearts to 1.07 +/- 0.10, with decreases in alpha-, beta-, OSCP, and IF(1) subunits of mtATPase, especially in the subendocardium. The reduction of myocardial creatine kinase isoform protein expression was also more severe in the BZ relative to the RZ myocardium. These abnormalities were independent of a change in mitochondrial content because the mitochondrial citrate synthase protein level was not different between the BZ and RZ. This regional heterogeneity of ATP content and expression of key enzymes in ATP production suggests that energetic insufficiency in the peri-infarct region may contribute to the transition from compensated LV remodeling to congestive heart failure.

Role of Choline Deficiency in the Fatty Liver Phenotype of Mice Fed a Low Protein, Very Low Carbohydrate Ketogenic Diet

PubMed Central

Schugar, Rebecca C.; Huang, Xiaojing; Moll, Ashley R.; Brunt, Elizabeth M.; Crawford, Peter A.

2013-01-01

Though widely employed for clinical intervention in obesity, metabolic syndrome, seizure disorders and other neurodegenerative diseases, the mechanisms through which low carbohydrate ketogenic diets exert their ameliorative effects still remain to be elucidated. Rodent models have been used to identify the metabolic and physiologic alterations provoked by ketogenic diets. A commonly used rodent ketogenic diet (Bio-Serv F3666) that is very high in fat (~94% kcal), very low in carbohydrate (~1% kcal), low in protein (~5% kcal), and choline restricted (~300 mg/kg) provokes robust ketosis and weight loss in mice, but through unknown mechanisms, also causes significant hepatic steatosis, inflammation, and cellular injury. To understand the independent and synergistic roles of protein restriction and choline deficiency on the pleiotropic effects of rodent ketogenic diets, we studied four custom diets that differ only in protein (5% kcal vs. 10% kcal) and choline contents (300 mg/kg vs. 5 g/kg). C57BL/6J mice maintained on the two 5% kcal protein diets induced the most significant ketoses, which was only partially diminished by choline replacement. Choline restriction in the setting of 10% kcal protein also caused moderate ketosis and hepatic fat accumulation, which were again attenuated when choline was replete. Key effects of the 5% kcal protein diet – weight loss, hepatic fat accumulation, and mitochondrial ultrastructural disarray and bioenergetic dysfunction – were mitigated by choline repletion. These studies indicate that synergistic effects of protein restriction and choline deficiency influence integrated metabolism and hepatic pathology in mice when nutritional fat content is very high, and support the consideration of dietary choline content in ketogenic diet studies in rodents to limit hepatic mitochondrial dysfunction and fat accumulation. PMID:24009777

Molecular mechanisms underlying protective effects of quercetin against mitochondrial dysfunction and progressive dopaminergic neurodegeneration in cell culture and MitoPark transgenic mouse models of Parkinson's Disease.

PubMed

Ay, Muhammet; Luo, Jie; Langley, Monica; Jin, Huajun; Anantharam, Vellareddy; Kanthasamy, Arthi; Kanthasamy, Anumantha G

2017-06-01

Quercetin, one of the major flavonoids in plants, has been recently reported to have neuroprotective effects against neurodegenerative processes. However, since the molecular signaling mechanisms governing these effects are not well clarified, we evaluated quercetin's effect on the neuroprotective signaling events in dopaminergic neuronal models and further tested its efficacy in the MitoPark transgenic mouse model of Parkinson's disease (PD). Western blot analysis revealed that quercetin significantly induced the activation of two major cell survival kinases, protein kinase D1 (PKD1) and Akt in MN9D dopaminergic neuronal cells. Furthermore, pharmacological inhibition or siRNA knockdown of PKD1 blocked the activation of Akt, suggesting that PKD1 acts as an upstream regulator of Akt in quercetin-mediated neuroprotective signaling. Quercetin also enhanced cAMP response-element binding protein phosphorylation and expression of the cAMP response-element binding protein target gene brain-derived neurotrophic factor. Results from qRT-PCR, Western blot analysis, mtDNA content analysis, and MitoTracker assay experiments revealed that quercetin augmented mitochondrial biogenesis. Quercetin also increased mitochondrial bioenergetics capacity and protected MN9D cells against 6-hydroxydopamine-induced neurotoxicity. To further evaluate the neuroprotective efficacy of quercetin against the mitochondrial dysfunction underlying PD, we used the progressive dopaminergic neurodegenerative MitoPark transgenic mouse model of PD. Oral administration of quercetin significantly reversed behavioral deficits, striatal dopamine depletion, and TH neuronal cell loss in MitoPark mice. Together, our findings demonstrate that quercetin activates the PKD1-Akt cell survival signaling axis and suggest that further exploration of quercetin as a promising neuroprotective agent for treating PD may offer clinical benefits. © 2017 International Society for Neurochemistry.

Role of choline deficiency in the Fatty liver phenotype of mice fed a low protein, very low carbohydrate ketogenic diet.

PubMed

Schugar, Rebecca C; Huang, Xiaojing; Moll, Ashley R; Brunt, Elizabeth M; Crawford, Peter A

2013-01-01

Though widely employed for clinical intervention in obesity, metabolic syndrome, seizure disorders and other neurodegenerative diseases, the mechanisms through which low carbohydrate ketogenic diets exert their ameliorative effects still remain to be elucidated. Rodent models have been used to identify the metabolic and physiologic alterations provoked by ketogenic diets. A commonly used rodent ketogenic diet (Bio-Serv F3666) that is very high in fat (~94% kcal), very low in carbohydrate (~1% kcal), low in protein (~5% kcal), and choline restricted (~300 mg/kg) provokes robust ketosis and weight loss in mice, but through unknown mechanisms, also causes significant hepatic steatosis, inflammation, and cellular injury. To understand the independent and synergistic roles of protein restriction and choline deficiency on the pleiotropic effects of rodent ketogenic diets, we studied four custom diets that differ only in protein (5% kcal vs. 10% kcal) and choline contents (300 mg/kg vs. 5 g/kg). C57BL/6J mice maintained on the two 5% kcal protein diets induced the most significant ketoses, which was only partially diminished by choline replacement. Choline restriction in the setting of 10% kcal protein also caused moderate ketosis and hepatic fat accumulation, which were again attenuated when choline was replete. Key effects of the 5% kcal protein diet - weight loss, hepatic fat accumulation, and mitochondrial ultrastructural disarray and bioenergetic dysfunction - were mitigated by choline repletion. These studies indicate that synergistic effects of protein restriction and choline deficiency influence integrated metabolism and hepatic pathology in mice when nutritional fat content is very high, and support the consideration of dietary choline content in ketogenic diet studies in rodents to limit hepatic mitochondrial dysfunction and fat accumulation.

Differential expression of glucose-metabolizing enzymes in multiple sclerosis lesions.

PubMed

Nijland, Philip G; Molenaar, Remco J; van der Pol, Susanne M A; van der Valk, Paul; van Noorden, Cornelis J F; de Vries, Helga E; van Horssen, Jack

2015-12-04

Demyelinated axons in multiple sclerosis (MS) lesions have an increased energy demand in order to maintain conduction. However, oxidative stress-induced mitochondrial dysfunction likely alters glucose metabolism and consequently impairs neuronal function in MS. Imaging and pathological studies indicate that glucose metabolism is altered in MS, although the underlying mechanisms and its role in neurodegeneration remain elusive. We investigated expression patterns of key enzymes involved in glycolysis, tricarboxylic acid (TCA) cycle and lactate metabolism in well-characterized MS tissue to establish which regulators of glucose metabolism are involved in MS and to identify underlying mechanisms. Expression levels of glycolytic enzymes were increased in active and inactive MS lesions, whereas expression levels of enzymes involved in the TCA cycle were upregulated in active MS lesions, but not in inactive MS lesions. We observed reduced expression and production capacity of mitochondrial α-ketoglutarate dehydrogenase (αKGDH) in demyelinated axons, which correlated with signs of axonal dysfunction. In inactive lesions, increased expression of lactate-producing enzymes was observed in astrocytes, whereas lactate-catabolising enzymes were mainly detected in axons. Our results demonstrate that the expression of various enzymes involved in glucose metabolism is increased in both astrocytes and axons in active MS lesions. In inactive MS lesions, we provide evidence that astrocytes undergo a glycolytic shift resulting in enhanced astrocyte-axon lactate shuttling, which may be pivotal for the survival of demyelinated axons. In conclusion, we show that key enzymes involved in energy metabolism are differentially expressed in active and inactive MS lesions. Our findings imply that, in addition to reduced oxidative phosphorylation activity, other bioenergetic pathways are affected as well, which may contribute to ongoing axonal degeneration in MS.

Targeted apoptosis in ovarian cancer cells through mitochondrial dysfunction in response to Sambucus nigra agglutinin.

PubMed

Chowdhury, Shreya Roy; Ray, Upasana; Chatterjee, Bishnu P; Roy, Sib S

2017-05-04

Ovarian carcinoma (OC) patients encounter the severe challenge of clinical management owing to lack of screening measures, chemoresistance and finally dearth of non-toxic therapeutics. Cancer cells deploy various defense strategies to sustain the tumor microenvironment, among which deregulated apoptosis remains a versatile promoter of cancer progression. Although recent research has focused on identifying agents capable of inducing apoptosis in cancer cells, yet molecules efficiently breaching their survival advantage are yet to be classified. Here we identify lectin, Sambucus nigra agglutinin (SNA) to exhibit selectivity towards identifying OC by virtue of its specific recognition of α-2, 6-linked sialic acids. Superficial binding of SNA to the OC cells confirm the hyper-sialylated status of the disease. Further, SNA activates the signaling pathways of AKT and ERK1/2, which eventually promotes de-phosphorylation of dynamin-related protein-1 (Drp-1). Upon its translocation to the mitochondrial fission loci Drp-1 mediates the central role of switch in the mitochondrial phenotype to attain fragmented morphology. We confirmed mitochondrial outer membrane permeabilization resulting in ROS generation and cytochrome-c release into the cytosol. SNA response resulted in an allied shift of the bioenergetics profile from Warburg phenotype to elevated mitochondrial oxidative phosphorylation, altogether highlighting the involvement of mitochondrial dysfunction in restraining cancer progression. Inability to replenish the SNA-induced energy crunch of the proliferating cancer cells on the event of perturbed respiratory outcome resulted in cell cycle arrest before G2/M phase. Our findings position SNA at a crucial juncture where it proves to be a promising candidate for impeding progression of OC. Altogether we unveil the novel aspect of identifying natural molecules harboring the inherent capability of targeting mitochondrial structural dynamics, to hold the future for developing non-toxic therapeutics for treating OC.

Influence of experimental rat model of multiple organ dysfunction on cefepime and amikacin pharmacokinetics.

PubMed Central

Mimoz, O; Jacolot, A; Padoin, C; Quillard, J; Tod, M; Louchahi, K; Samii, K; Petitjean, O

1996-01-01

We adapted an experimental model of multiple organ dysfunction to study the alterations it induces in the pharmacology of cefepime and amikacin. The half-lives of both antibiotics were significantly prolonged because of nonsignificant enhancement of the volume of distribution and reduced renal elimination. In the presence of multiple organ dysfunction, the concentration of each antibiotic in the lungs, compared with that in the lungs of healthy controls, was significantly decreased, despite similar concentrations in plasma, indicating that the application of a standard antibiotic concentration in plasma could lead to underdosage in tissues during the initial days of therapy. PMID:8851623

Hypothesis: the chaos and complexity theory may help our understanding of fibromyalgia and similar maladies.

PubMed

Martinez-Lavin, Manuel; Infante, Oscar; Lerma, Claudia

2008-02-01

Modern clinicians are often frustrated by their inability to understand fibromyalgia and similar maladies since these illnesses cannot be explained by the prevailing linear-reductionist medical paradigm. This article proposes that new concepts derived from the Complexity Theory may help understand the pathogenesis of fibromyalgia, chronic fatigue syndrome, and Gulf War syndrome. This hypothesis is based on the recent recognition of chaos fractals and complex systems in human physiology. These nonlinear dynamics concepts offer a different perspective to the notion of homeostasis and disease. They propose that the essence of disease is dysfunction and not structural damage. Studies using novel nonlinear instruments have shown that fibromyalgia and similar maladies may be caused by the degraded performance of our main complex adaptive system. This dysfunction explains the multifaceted manifestations of these entities. To understand and alleviate the suffering associated with these complex illnesses, a paradigm shift from reductionism to holism based on the Complexity Theory is suggested. This shift perceives health as resilient adaptation and some chronic illnesses as rigid dysfunction.

31P Magnetic Resonance Spectroscopy Assessment of Muscle Bioenergetics as a Predictor of Gait Speed in the Baltimore Longitudinal Study of Aging.

PubMed

Choi, Seongjin; Reiter, David A; Shardell, Michelle; Simonsick, Eleanor M; Studenski, Stephanie; Spencer, Richard G; Fishbein, Kenneth W; Ferrucci, Luigi

2016-12-01

Aerobic fitness and muscle bioenergetic capacity decline with age; whether such declines explain age-related slowing of walking speed is unclear. We hypothesized that muscle energetics and aerobic capacity are independent correlates of walking speed in simple and challenging performance tests and that they account for the observed age-related decline in walking speed in these same tests. Muscle bioenergetics was assessed as postexercise recovery rate of phosphocreatine (PCr), k PCr , using phosphorus magnetic resonance spectroscopy ( 31 P-MRS) in 126 participants (53 men) of the Baltimore Longitudinal Study of Aging aged 26-91 years (mean = 72 years). Four walking tasks were administered-usual pace over 6 m and 150 seconds and fast pace over 6 m and 400 m. Separately, aerobic fitness was assessed as peak oxygen consumption (peak VO 2 ) using a graded treadmill test. All gait speeds, k PCr , and peak VO 2 were lower with older age. Independent of age, sex, height, and weight, both k PCr and peak VO 2 were positively and significantly associated with fast pace and long distance walking but only peak VO 2 and not k PCr was significantly associated with usual gait speed over 6 m. Both k PCr and peak VO 2 substantially attenuated the association between age and gait speed for all but the least stressful walking task of 6 m at usual pace. Muscle bioenergetics assessed using 31 P-MRS is highly correlated with walking speed and partially explains age-related poorer performance in fast and long walking tasks. Published by Oxford University Press on behalf of The Gerontological Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Analysis of regional brain mitochondrial bioenergetics and susceptibility to mitochondrial inhibition utilizing a microplate based system

PubMed Central

Sauerbeck, Andrew; Pandya, Jignesh; Singh, Indrapal; Bittman, Kevin; Readnower, Ryan; Bing, Guoying; Sullivan, Patrick

2012-01-01

The analysis of mitochondrial bioenergetic function typically has required 50–100 μg of protein per sample and at least 15 min per run when utilizing a Clark-type oxygen electrode. In the present work we describe a method utilizing the Seahorse Biosciences XF24 Flux Analyzer for measuring mitochondrial oxygen consumption simultaneously from multiple samples and utilizing only 5 μg of protein per sample. Utilizing this method we have investigated whether regionally based differences exist in mitochondria isolated from the cortex, striatum, hippocampus, and cerebellum. Analysis of basal mitochondrial bioenergetics revealed that minimal differences exist between the cortex, striatum, and hippocampus. However, the cerebellum exhibited significantly slower basal rates of Complex I and Complex II dependent oxygen consumption (p < 0.05). Mitochondrial inhibitors affected enzyme activity proportionally across all samples tested and only small differences existed in the effect of inhibitors on oxygen consumption. Investigation of the effect of rotenone administration on Complex I dependent oxygen consumption revealed that exposure to 10 pM rotenone led to a clear time dependent decrease in oxygen consumption beginning 12 min after administration (p < 0.05). These studies show that the utilization of this microplate based method for analysis of mitochondrial bioenergetics is effective at quantifying oxygen consumption simultaneously from multiple samples. Additionally, these studies indicate that minimal regional differences exist in mitochondria isolated from the cortex, striatum, or hippocampus. Furthermore, utilization of the mitochondrial inhibitors suggests that previous work indicating regionally specific deficits following systemic mitochondrial toxin exposure may not be the result of differences in the individual mitochondria from the affected regions. PMID:21402103

Early bioenergetic evolution

PubMed Central

Sousa, Filipa L.; Thiergart, Thorsten; Landan, Giddy; Nelson-Sathi, Shijulal; Pereira, Inês A. C.; Allen, John F.; Lane, Nick; Martin, William F.

2013-01-01

Life is the harnessing of chemical energy in such a way that the energy-harnessing device makes a copy of itself. This paper outlines an energetically feasible path from a particular inorganic setting for the origin of life to the first free-living cells. The sources of energy available to early organic synthesis, early evolving systems and early cells stand in the foreground, as do the possible mechanisms of their conversion into harnessable chemical energy for synthetic reactions. With regard to the possible temporal sequence of events, we focus on: (i) alkaline hydrothermal vents as the far-from-equilibrium setting, (ii) the Wood–Ljungdahl (acetyl-CoA) pathway as the route that could have underpinned carbon assimilation for these processes, (iii) biochemical divergence, within the naturally formed inorganic compartments at a hydrothermal mound, of geochemically confined replicating entities with a complexity below that of free-living prokaryotes, and (iv) acetogenesis and methanogenesis as the ancestral forms of carbon and energy metabolism in the first free-living ancestors of the eubacteria and archaebacteria, respectively. In terms of the main evolutionary transitions in early bioenergetic evolution, we focus on: (i) thioester-dependent substrate-level phosphorylations, (ii) harnessing of naturally existing proton gradients at the vent–ocean interface via the ATP synthase, (iii) harnessing of Na+ gradients generated by H+/Na+ antiporters, (iv) flavin-based bifurcation-dependent gradient generation, and finally (v) quinone-based (and Q-cycle-dependent) proton gradient generation. Of those five transitions, the first four are posited to have taken place at the vent. Ultimately, all of these bioenergetic processes depend, even today, upon CO2 reduction with low-potential ferredoxin (Fd), generated either chemosynthetically or photosynthetically, suggesting a reaction of the type ‘reduced iron → reduced carbon’ at the beginning of bioenergetic evolution. PMID:23754820

Bioenergetics and diving activity of internesting leatherback turtles Dermochelys coriacea at Parque Nacional Marino Las Baulas, Costa Rica.

PubMed

Wallace, Bryan P; Williams, Cassondra L; Paladino, Frank V; Morreale, Stephen J; Lindstrom, R Todd; Spotila, James R

2005-10-01

Physiology, environment and life history demands interact to influence marine turtle bioenergetics and activity. However, metabolism and diving behavior of free-swimming marine turtles have not been measured simultaneously. Using doubly labeled water, we obtained the first field metabolic rates (FMRs; 0.20-0.74 W kg(-1)) and water fluxes (16-30% TBW day(-1), where TBW=total body water) for free-ranging marine turtles and combined these data with dive information from electronic archival tags to investigate the bioenergetics and diving activity of reproductive adult female leatherback turtles Dermochelys coriacea. Mean dive durations (7.8+/-2.4 min (+/-1 s.d.), bottom times (2.7+/-0.8 min), and percentage of time spent in water temperatures (Tw) < or =24 degrees C (9.5+/-5.7%) increased with increasing mean maximum dive depths (22.6+/-7.1 m; all P< or =0.001). The FMRs increased with longer mean dive durations, bottom times and surface intervals and increased time spent in Tw< or =24 degrees C (all r2> or =0.99). This suggests that low FMRs and activity levels, combined with shuttling between different water temperatures, could allow leatherbacks to avoid overheating while in warm tropical waters. Additionally, internesting leatherback dive durations were consistently shorter than aerobic dive limits calculated from our FMRs (11.7-44.3 min). Our results indicate that internesting female leatherbacks maintained low FMRs and activity levels, thereby spending relatively little energy while active at sea. Future studies should incorporate data on metabolic rate, dive patterns, water temperatures, and body temperatures to develop further the relationship between physiological and life history demands and marine turtle bioenergetics and activity.

Murine Mesenchymal Stem Cell Commitment to Differentiation is Regulated by Mitochondrial Dynamics

PubMed Central

Forni, Maria Fernanda; Peloggia, Julia; Trudeau, Kyle; Shirihai, Orian; Kowaltowski, Alicia J.

2015-01-01

Mouse skin mesenchymal stem cells (msMSCs) are dermis CD105+CD90+CD73+CD29+CD34− mesodermal precursors which, after in vitro induction, undergo chondro, adipo and osteogenesis. Extensive metabolic reconfiguration has been found to occur during differentiation, and the bioenergetic status of a cell is known to be dependent on the quality and abundance of the mitochondrial population, which may be regulated by fusion and fission. However, little is known regarding the impact of mitochondrial dynamics on the differentiation process. We addressed this knowledge gap by isolating MSCs from Swiss female mice, inducing these cells to differentiate into osteo, chondro and adipocytes and measuring changes in mass, morphology, dynamics and bioenergetics. Mitochondrial biogenesis was increased in adipogenesis, as evaluated through confocal microscopy, citrate synthase activity and mtDNA content. The early steps of adipo and osteogenesis involved mitochondrial elongation, as well as increased expression of mitochondrial fusion proteins Mfn1 and 2. Chondrogenesis involved a fragmented mitochondrial phenotype, increased expression of fission proteins Drp1, Fis1 and 2 and enhanced mitophagy. These events were accompanied by profound bioenergetic alterations during the commitment period. Moreover, knockdown of Mfn2 in adipo and osteogenesis and the overexpression of a dominant negative form of Drp1 during chondrogenesis resulted in a loss of differentiation ability. Overall, we find that mitochondrial morphology and its regulating processes of fission/fusion are modulated early on during commitment, leading to alterations in the bioenergetic profile that are important for differentiation. We thus propose a central role for mitochondrial dynamics in the maintenance/commitment of mesenchymal stem cells. PMID:26638184

Quantifying intracellular rates of glycolytic and oxidative ATP production and consumption using extracellular flux measurements

PubMed Central

Mookerjee, Shona A.; Gerencser, Akos A.; Nicholls, David G.; Brand, Martin D.

2017-01-01

Partitioning of ATP generation between glycolysis and oxidative phosphorylation is central to cellular bioenergetics but cumbersome to measure. We describe here how rates of ATP generation by each pathway can be calculated from simultaneous measurements of extracellular acidification and oxygen consumption. We update theoretical maximum ATP yields by mitochondria and cells catabolizing different substrates. Mitochondrial P/O ratios (mol of ATP generated per mol of [O] consumed) are 2.73 for oxidation of pyruvate plus malate and 1.64 for oxidation of succinate. Complete oxidation of glucose by cells yields up to 33.45 ATP/glucose with a maximum P/O of 2.79. We introduce novel indices to quantify bioenergetic phenotypes. The glycolytic index reports the proportion of ATP production from glycolysis and identifies cells as primarily glycolytic (glycolytic index > 50%) or primarily oxidative. The Warburg effect is a chronic increase in glycolytic index, quantified by the Warburg index. Additional indices quantify the acute flexibility of ATP supply. The Crabtree index and Pasteur index quantify the responses of oxidative and glycolytic ATP production to alterations in glycolysis and oxidative reactions, respectively; the supply flexibility index quantifies overall flexibility of ATP supply; and the bioenergetic capacity quantifies the maximum rate of total ATP production. We illustrate the determination of these indices using C2C12 myoblasts. Measurement of ATP use revealed no significant preference for glycolytic or oxidative ATP by specific ATP consumers. Overall, we demonstrate how extracellular fluxes quantitatively reflect intracellular ATP turnover and cellular bioenergetics. We provide a simple spreadsheet to calculate glycolytic and oxidative ATP production rates from raw extracellular acidification and respiration data. PMID:28270511

Bioenergetics model for estimating food requirements of female Pacific walruses (Odobenus rosmarus divergens)

USGS Publications Warehouse

Noren, S.R.; Udevitz, M.S.; Jay, C.V.

2012-01-01

Pacific walruses Odobenus rosmarus divergens use sea ice as a platform for resting, nursing, and accessing extensive benthic foraging grounds. The extent of summer sea ice in the Chukchi Sea has decreased substantially in recent decades, causing walruses to alter habitat use and activity patterns which could affect their energy requirements. We developed a bioenergetics model to estimate caloric demand of female walruses, accounting for maintenance, growth, activity (active in-water and hauled-out resting), molt, and reproductive costs. Estimates for non-reproductive females 0–12 yr old (65−810 kg) ranged from 16359 to 68960 kcal d−1 (74−257 kcal d−1 kg−1) for years with readily available sea ice for which we assumed animals spent 83% of their time in water. This translated into the energy content of 3200–5960 clams per day, equivalent to 7–8% and 14–9% of body mass per day for 5–12 and 2–4 yr olds, respectively. Estimated consumption rates of 12 yr old females were minimally affected by pregnancy, but lactation had a large impact, increasing consumption rates to 15% of body mass per day. Increasing the proportion of time in water to 93%, as might happen if walruses were required to spend more time foraging during ice-free periods, increased daily caloric demand by 6–7% for non-lactating females. We provide the first bioenergetics-based estimates of energy requirements for walruses and a first step towards establishing bioenergetic linkages between demography and prey requirements that can ultimately be used in predicting this population’s response to environmental change.

Modulation of Hypercholesterolemia-Induced Oxidative/Nitrative Stress in the Heart

PubMed Central

Sárközy, Márta; Pipicz, Márton; Dux, László; Csont, Tamás

2016-01-01

Hypercholesterolemia is a frequent metabolic disorder associated with increased risk for cardiovascular morbidity and mortality. In addition to its well-known proatherogenic effect, hypercholesterolemia may exert direct effects on the myocardium resulting in contractile dysfunction, aggravated ischemia/reperfusion injury, and diminished stress adaptation. Both preclinical and clinical studies suggested that elevated oxidative and/or nitrative stress plays a key role in cardiac complications induced by hypercholesterolemia. Therefore, modulation of hypercholesterolemia-induced myocardial oxidative/nitrative stress is a feasible approach to prevent or treat deleterious cardiac consequences. In this review, we discuss the effects of various pharmaceuticals, nutraceuticals, some novel potential pharmacological approaches, and physical exercise on hypercholesterolemia-induced oxidative/nitrative stress and subsequent cardiac dysfunction as well as impaired ischemic stress adaptation of the heart in hypercholesterolemia. PMID:26788247

Searching for Pedagogical Adaptations by Exploring Teacher's Tacit Knowledge and Interactional Co-Regulation in the Education of Pupils with Autism

ERIC Educational Resources Information Center

Rama, Irene; Kontu, Elina

2012-01-01

The purpose of this article is to introduce a research design, which aims to find useful pedagogical adaptations for teaching pupils with autism. Autism is a behavioural syndrome characterised by disabilities and dysfunctions in interaction and communication, which is why it is interesting to explore educational processes particularly from an…

Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes

PubMed Central

Smith, Darrell R.; Saleh, Ali; Schapansky, Jason; Marquez, Alexandra; Gomes, Suzanne; Akude, Eli; Morrow, Dwane; Calcutt, Nigel A.; Fernyhough, Paul

2012-01-01

Mitochondrial dysfunction occurs in sensory neurons and may contribute to distal axonopathy in animal models of diabetic neuropathy. The adenosine monophosphate-activated protein kinase and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling axis senses the metabolic demands of cells and regulates mitochondrial function. Studies in muscle, liver and cardiac tissues have shown that the activity of adenosine monophosphate-activated protein kinase and PGC-1α is decreased under hyperglycaemia. In this study, we tested the hypothesis that deficits in adenosine monophosphate-activated protein kinase/PGC-1α signalling in sensory neurons underlie impaired axonal plasticity, suboptimal mitochondrial function and development of neuropathy in rodent models of type 1 and type 2 diabetes. Phosphorylation and expression of adenosine monophosphate-activated protein kinase/PGC-1α and mitochondrial respiratory chain complex proteins were downregulated in dorsal root ganglia of both streptozotocin-diabetic rats and db/db mice. Adenoviral-mediated manipulation of endogenous adenosine monophosphate-activated protein kinase activity using mutant proteins modulated neurotrophin-directed neurite outgrowth in cultures of sensory neurons derived from adult rats. Addition of resveratrol to cultures of sensory neurons derived from rats after 3–5 months of streptozotocin-induced diabetes, significantly elevated adenosine monophosphate-activated protein kinase levels, enhanced neurite outgrowth and normalized mitochondrial inner membrane polarization in axons. The bioenergetics profile (maximal oxygen consumption rate, coupling efficiency, respiratory control ratio and spare respiratory capacity) was aberrant in cultured sensory neurons from streptozotocin-diabetic rats and was corrected by resveratrol treatment. Finally, resveratrol treatment for the last 2 months of a 5-month period of diabetes reversed thermal hypoalgesia and attenuated foot skin intraepidermal nerve fibre loss and reduced myelinated fibre mean axonal calibre in streptozotocin-diabetic rats. These data suggest that the development of distal axonopathy in diabetic neuropathy is linked to nutrient excess and mitochondrial dysfunction via defective signalling of the adenosine monophosphate-activated protein kinase/PGC-1α pathway. PMID:22561641

Barth Syndrome: From Mitochondrial Dysfunctions Associated with Aberrant Production of Reactive Oxygen Species to Pluripotent Stem Cell Studies

PubMed Central

Saric, Ana; Andreau, Karine; Armand, Anne-Sophie; Møller, Ian M.; Petit, Patrice X.

2016-01-01

Mutations in the gene encoding the enzyme tafazzin, TAZ, cause Barth syndrome (BTHS). Individuals with this X-linked multisystem disorder present cardiomyopathy (CM) (often dilated), skeletal muscle weakness, neutropenia, growth retardation, and 3-methylglutaconic aciduria. Biopsies of the heart, liver and skeletal muscle of patients have revealed mitochondrial malformations and dysfunctions. It is the purpose of this review to summarize recent results of studies on various animal or cell models of Barth syndrome, which have characterized biochemically the strong cellular defects associated with TAZ mutations. Tafazzin is a mitochondrial phospholipidlysophospholipid transacylase that shuttles acyl groups between phospholipids and regulates the remodeling of cardiolipin (CL), a unique inner mitochondrial membrane phospholipid dimer consisting of two phosphatidyl residues linked by a glycerol bridge. After their biosynthesis, the acyl chains of CLs may be modified in remodeling processes involving up to three different enzymes. Their characteristic acyl chain composition depends on the function of tafazzin, although the enzyme itself surprisingly lacks acyl specificity. CLs are crucial for correct mitochondrial structure and function. In addition to their function in the basic mitochondrial function of ATP production, CLs play essential roles in cardiac function, apoptosis, autophagy, cell cycle regulation and Fe-S cluster biosynthesis. Recent developments in tafazzin research have provided strong insights into the link between mitochondrial dysfunction and the production of reactive oxygen species (ROS). An important tool has been the generation of BTHS-specific induced pluripotent stem cells (iPSCs) from BTHS patients. In a complementary approach, disease-specific mutations have been introduced into wild-type iPSC lines enabling direct comparison with isogenic controls. iPSC-derived cardiomyocytes were then characterized using biochemical and classical bioenergetic approaches. The cells are tested in a “heart-on-chip” assay to model the pathophysiology in vitro, to characterize the underlying mechanism of BTHS deriving from TAZ mutations, mitochondrial deficiencies and ROS production and leading to tissue defects, and to evaluate potential therapies with the use of mitochondrially targeted antioxidants. PMID:26834781

Pathways and Bioenergetics of Anaerobic Carbon Monoxide Fermentation.

PubMed

Diender, Martijn; Stams, Alfons J M; Sousa, Diana Z

2015-01-01

Carbon monoxide can act as a substrate for different modes of fermentative anaerobic metabolism. The trait of utilizing CO is spread among a diverse group of microorganisms, including members of bacteria as well as archaea. Over the last decade this metabolism has gained interest due to the potential of converting CO-rich gas, such as synthesis gas, into bio-based products. Three main types of fermentative CO metabolism can be distinguished: hydrogenogenesis, methanogenesis, and acetogenesis, generating hydrogen, methane and acetate, respectively. Here, we review the current knowledge on these three variants of microbial CO metabolism with an emphasis on the potential enzymatic routes and bio-energetics involved.

1H and 31P spectroscopy and bioenergetics in the lateralization of seizures in temporal lobe epilepsy.

PubMed

Hetherington, Hoby P; Pan, Jullie W; Spencer, Dennis D

2002-10-01

Over the past decade, (1)H and (31)P spectroscopy measurements have demonstrated that significant metabolic alterations occur in temporal lobe epilepsy. However, to most accurately interpret these changes, metabolic heterogeneity and differences between gray and white matter must be accounted for. These alterations, decreased NAA and the ratio of phosphocreatine/inorganic phosphate, can be reversed with successful treatment of seizures. The reversibility of these two measures is consistent with the localization of NAA synthesis to neuronal mitochondria and the important role for bioenergetics in the pathophysiology of temporal lobe epilepsy. Copyright 2002 Wiley-Liss, Inc.

Pathways and Bioenergetics of Anaerobic Carbon Monoxide Fermentation

PubMed Central

Diender, Martijn; Stams, Alfons J. M.; Sousa, Diana Z.

2015-01-01

Carbon monoxide can act as a substrate for different modes of fermentative anaerobic metabolism. The trait of utilizing CO is spread among a diverse group of microorganisms, including members of bacteria as well as archaea. Over the last decade this metabolism has gained interest due to the potential of converting CO-rich gas, such as synthesis gas, into bio-based products. Three main types of fermentative CO metabolism can be distinguished: hydrogenogenesis, methanogenesis, and acetogenesis, generating hydrogen, methane and acetate, respectively. Here, we review the current knowledge on these three variants of microbial CO metabolism with an emphasis on the potential enzymatic routes and bio-energetics involved. PMID:26635746

Transfer of computer software technology through workshops: The case of fish bioenergetics modeling

USGS Publications Warehouse

Johnson, B.L.

1992-01-01

A three-part program is proposed to promote the availability and use of computer software packages to fishery managers and researchers. The approach consists of journal articles that announce new technologies, technical reports that serve as user's guides, and hands-on workshops that provide direct instruction to new users. Workshops, which allow experienced users to directly instruct novices in software operation and application are important, but often neglected. The author's experience with organizing and conducting bioenergetics modeling workshops suggests the optimal workshop would take 2 days, have 10-15 participants, one computer for every two users, and one instructor for every 5-6 people.

Computational Analysis of AMPK-Mediated Neuroprotection Suggests Acute Excitotoxic Bioenergetics and Glucose Dynamics Are Regulated by a Minimal Set of Critical Reactions.

PubMed

Connolly, Niamh M C; D'Orsi, Beatrice; Monsefi, Naser; Huber, Heinrich J; Prehn, Jochen H M

2016-01-01

Loss of ionic homeostasis during excitotoxic stress depletes ATP levels and activates the AMP-activated protein kinase (AMPK), re-establishing energy production by increased expression of glucose transporters on the plasma membrane. Here, we develop a computational model to test whether this AMPK-mediated glucose import can rapidly restore ATP levels following a transient excitotoxic insult. We demonstrate that a highly compact model, comprising a minimal set of critical reactions, can closely resemble the rapid dynamics and cell-to-cell heterogeneity of ATP levels and AMPK activity, as confirmed by single-cell fluorescence microscopy in rat primary cerebellar neurons exposed to glutamate excitotoxicity. The model further correctly predicted an excitotoxicity-induced elevation of intracellular glucose, and well resembled the delayed recovery and cell-to-cell heterogeneity of experimentally measured glucose dynamics. The model also predicted necrotic bioenergetic collapse and altered calcium dynamics following more severe excitotoxic insults. In conclusion, our data suggest that a minimal set of critical reactions may determine the acute bioenergetic response to transient excitotoxicity and that an AMPK-mediated increase in intracellular glucose may be sufficient to rapidly recover ATP levels following an excitotoxic insult.

Computational Analysis of AMPK-Mediated Neuroprotection Suggests Acute Excitotoxic Bioenergetics and Glucose Dynamics Are Regulated by a Minimal Set of Critical Reactions

PubMed Central

Connolly, Niamh M. C.; D’Orsi, Beatrice; Monsefi, Naser; Huber, Heinrich J.; Prehn, Jochen H. M.

2016-01-01

Loss of ionic homeostasis during excitotoxic stress depletes ATP levels and activates the AMP-activated protein kinase (AMPK), re-establishing energy production by increased expression of glucose transporters on the plasma membrane. Here, we develop a computational model to test whether this AMPK-mediated glucose import can rapidly restore ATP levels following a transient excitotoxic insult. We demonstrate that a highly compact model, comprising a minimal set of critical reactions, can closely resemble the rapid dynamics and cell-to-cell heterogeneity of ATP levels and AMPK activity, as confirmed by single-cell fluorescence microscopy in rat primary cerebellar neurons exposed to glutamate excitotoxicity. The model further correctly predicted an excitotoxicity-induced elevation of intracellular glucose, and well resembled the delayed recovery and cell-to-cell heterogeneity of experimentally measured glucose dynamics. The model also predicted necrotic bioenergetic collapse and altered calcium dynamics following more severe excitotoxic insults. In conclusion, our data suggest that a minimal set of critical reactions may determine the acute bioenergetic response to transient excitotoxicity and that an AMPK-mediated increase in intracellular glucose may be sufficient to rapidly recover ATP levels following an excitotoxic insult. PMID:26840769

A new bioenergetic and thermodynamic approach to batch photoautotrophic growth of Arthrospira (Spirulina) platensis in different photobioreactors and under different light conditions.

PubMed

da Silva, Milena Fernandes; Casazza, Alessandro Alberto; Ferrari, Pier Francesco; Perego, Patrizia; Bezerra, Raquel Pedrosa; Converti, Attilio; Porto, Ana Lucia Figueiredo

2016-05-01

Photobioreactor configuration, mode of operation and light intensity are known to strongly impact on cyanobacteria growth. To shed light on these issues, kinetic, bioenergetic and thermodynamic parameters of batch Arthrospira platensis cultures were estimated along the time at photosynthetic photon flux density (PPFD) of 70μmolm(-2)s(-1) in different photobioreactors with different surface/volume ratio (S/V), namely open pond (0.25cm(-1)), shaken flask (0.48cm(-1)), horizontal photobioreactor (HoP) (1.94cm(-1)) and helicoidal photobioreactor (HeP) (3.88cm(-1)). Maximum biomass concentration and productivity remarkably increased with S/V up to 1.94cm(-1). HoP was shown to be the best-performing system throughout the whole runs, while HeP behaved better only at the start. Runs carried out in HoP increasing PPFD from 40 to 100μmolm(-2)s(-1) revealed a progressive enhancement of bioenergetics and thermodynamics likely because of favorable light distribution. HoP appeared to be a promising configuration to perform high-yield indoor cyanobacterial cultures. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evaluating the use of gas discharge visualization to measure massage therapy outcomes

PubMed Central

Haun, Jolie; Patel, Nitin; Schwartz, Gary; Ritenbaugh, Cheryl

2017-01-01

Background The purpose of this study was to evaluate the short-term effects of massage therapy using gas discharge visualization (GDV), a computerized biophysical electrophoton capture (EPC), in tandem with traditional self-report measures to evaluate the use of GDV measurement to assess the bioenergetic whole-person effects of massage therapy. Methods This study used a single treatment group, pre–post-repeated measures design with a sample of 23 healthy adults. This study utilized a single 50-min full-body relaxation massage with participants. GDV measurement method, an EPC, and traditional paper-based measures evaluating pain, stress, muscle tension, and well-being were used to assess intervention outcomes. Results Significant differences were found between pre- and post-measures of well-being, pain, stress, muscle tension, and GDV parameters. Pearson correlations indicate the GDV measure is correlated with pain and stress, variables that impact the whole person. Conclusions This study demonstrates that GDV parameters may be used to indicate significant bioenergetic change from pre- to post-massage. Findings warrant further investigation with a larger diverse sample size and control group to further explore GDV as a measure of whole-person bioenergetic effects associated with massage. PMID:26087069

Protecting Mitochondrial Bioenergetic Function during Resuscitation from Cardiac Arrest

PubMed Central

Gazmuri, Raúl J.; Radhakrishnan, Jeejabai

2012-01-01

Synopsis Successful resuscitation from cardiac arrest requires reestablishment of aerobic metabolism by reperfusion with oxygenated blood of tissues that have been deprived of oxygen for variables periods of time. However, reperfusion concomitantly activates pathogenic mechanisms known as “reperfusion injury.” At the core of reperfusion injury are mitochondria, playing a critical role as effectors and targets of such injury. Mitochondrial injury compromises oxidative phosphorylation and also prompts release of cytochrome c to the cytosol and bloodstream where it correlates with severity of injury. Main drivers of such injury include Ca2+ overload and oxidative stress. Preclinical work shows that limiting myocardial cytosolic Na+ overload at the time of reperfusion attenuates mitochondrial Ca2+ overload and maintains oxidative phosphorylation yielding functional myocardial benefits that include preservation of left ventricular distensibility. Preservation of left ventricular distensibility enables hemodynamically more effective chest compression. Similar myocardial effect have been reported using erythropoietin hypothesized to protect mitochondrial bioenergetic function presumably through activation of pathways similar to those activated during preconditioning. Incorporation of novel and clinical relevant strategies to protect mitochondrial bioenergetic function are expected to attenuate injury at the time of reperfusion and enhance organ viability ultimately improving resuscitation and survival from cardiac arrest. PMID:22433486

Sexual difference in mercury concentrations of lake trout (Salvelinus namaycush) from Lake Ontario

USGS Publications Warehouse

Madenjian, C.P.; Keir, M.J.; Whittle, D.M.

2011-01-01

We determined total mercury (Hg) concentrations in 50 female lake trout (Salvelinus namaycush) and 69 male lake trout from Lake Ontario (Ontario, Canada and New York, United States). Results showed that, on average, males were 8% higher in Hg concentration than females in Lake Ontario. We also used bioenergetics modeling to determine whether a sexual difference in gross growth efficiency (GGE) could explain the observed sexual difference in Hg concentrations. According to the bioenergetics modeling results, male GGE was about 3% higher than female GGE, on average. Although the bioenergetics modeling could not explain the higher Hg concentrations exhibited by the males, a sexual difference in GGE remained a plausible explanation for the sexual difference in Hg concentrations of the lake trout. In an earlier study, male lake trout from Lake Ontario were found to be 22% higher in polychlorinated biphenyl (PCB) concentration than females from Lake Ontario. Thus, although males were higher in both Hg and PCB concentrations, the degree of the sexual difference in concentration varied between the two contaminants. Further research on sexual differences in Hg excretion rates and Hg direct uptake rates may be needed to resolve the disparity in results between the two contaminants.

Sexual difference in PCB concentrations of coho salmon (Oncorhynchus kisutch)

USGS Publications Warehouse

Madenjian, Charles P.; Schrank, Candy S.; Begnoche, Linda J.; Elliott, Robert F.; Quintal, Richard T.

2010-01-01

We determined polychlorinated biphenyl (PCB) concentrations in 35 female coho salmon (Oncorhynchus kisutch) and 60 male coho salmon caught in Lake Michigan (Michigan and Wisconsin, United States) during the fall of 1994 and 1995. In addition, we determined PCB concentrations in the skin-on fillets of 26 female and 19 male Lake Michigan coho salmon caught during the fall of 2004 and 2006. All coho salmon were age-2 fish. These fish were caught prior to spawning, and therefore release of eggs could not account for sexual differences in PCB concentrations because female coho salmon spawn only once during their lifetime. To investigate whether gross growth efficiency (GGE) differed between the sexes, we applied bioenergetics modeling. Results showed that, on average, males were 19% higher in PCB concentration than females, based on the 1994–1995 dataset. Similarly, males averaged a 20% higher PCB concentration in their skin-on fillets compared with females. According to the bioenergetics modeling results, GGE of adult females was less than 1% higher than adult male GGE. Thus, bioenergetics modeling could not explain the 20% higher PCB concentration exhibited by the males. Nonetheless, a sexual difference in GGE remained a plausible explanation for the sexual difference in PCB concentrations.

Sexual difference in PCB concentrations of lake trout (Salvelinus namaycush) from Lake Ontario

USGS Publications Warehouse

Madenjian, Charles P.; Keir, Michael J.; Whittle, D. Michael; Noguchi, George E.

2010-01-01

We determined polychlorinated biphenyl (PCB) concentrations in 61 female lake trout (Salvelinus namaycush) and 71 male lake trout from Lake Ontario (Ontario, Canada and New York, United States). To estimate the expected change in PCB concentration due to spawning, PCB concentrations in gonads and in somatic tissue of lake trout were also determined. In addition, bioenergetics modeling was applied to investigate whether gross growth efficiency (GGE) differed between the sexes. Results showed that, on average, males were 22% higher in PCB concentration than females in Lake Ontario. Results from the PCB determinations of the gonads and somatic tissues revealed that shedding of the gametes led to 3% and 14% increases in PCB concentration for males and females, respectively. Therefore, shedding of the gametes could not explain the higher PCB concentration in male lake trout. According to the bioenergetics modeling results, GGE of males was about 2% higher than adult female GGE, on average. Thus, bioenergetics modeling could not explain the higher PCB concentrations exhibited by the males. Nevertheless, a sexual difference in GGE remained a plausible explanation for the sexual difference in PCB concentrations of the lake trout.

Antiproliferative effects of mitochondria-targeted cationic antioxidants and analogs: Role of mitochondrial bioenergetics and energy-sensing mechanism

PubMed Central

Cheng, Gang; Zielonka, Jacek; McAllister, Donna; Hardy, Micael; Ouari, Olivier; Joseph, Joy; Dwinell, Michael B.; Kalyanaraman, Balaraman

2015-01-01

One of the proposed mechanisms for tumor proliferation involves redox signaling mediated by reactive oxygen species such as superoxide and hydrogen peroxide generated at moderate levels. Thus, the antiproliferative and anti-tumor effects of certain antioxidants were attributed to their ability to mitigate intracellular reactive oxygen species (ROS). Recent reports support a role for mitochondrial ROS in stimulating tumor cell proliferation. In this study, we compared the antiproliferative effects and the effects on mitochondrial bioenergetic functions of a mitochondria-targeted cationic carboxyproxyl nitroxide (Mito-CP), exhibiting superoxide dismutase (SOD)-like activity and a synthetic cationic acetamide analog (Mito-CP-Ac) lacking the nitroxide moiety responsible for the SOD activity. Results indicate that both Mito-CP and Mito-CP-Ac potently inhibited tumor cell proliferation. Both compounds altered mitochondrial and glycolytic functions, and intracellular citrate levels. Both Mito-CP and Mito-CP-Ac synergized with 2-deoxy-glucose (2-DG) to deplete intracellular ATP, inhibit cell proliferation and induce apoptosis in pancreatic cancer cells. We conclude that mitochondria-targeted cationic agents inhibit tumor proliferation via modification of mitochondrial bioenergetics pathways rather than by dismutating and detoxifying mitochondrial superoxide. PMID:26004344

Evaluation of a chinook salmon (Oncorhynchus tshawytscha) bioenergetics model

USGS Publications Warehouse

Madenjian, Charles P.; O'Connor, Daniel V.; Chernyak, Sergei M.; Rediske, Richard R.; O'Keefe, James P.

2004-01-01

We evaluated the Wisconsin bioenergetics model for chinook salmon (Oncorhynchus tshawytscha) in both the laboratory and the field. Chinook salmon in laboratory tanks were fed alewife (Alosa pseudoharengus), the predominant food of chinook salmon in Lake Michigan. Food consumption and growth by chinook salmon during the experiment were measured. To estimate the efficiency with which chinook salmon retain polychlorinated biphenyls (PCBs) from their food in the laboratory, PCB concentrations of the alewife and of the chinook salmon at both the beginning and end of the experiment were determined. Based on our laboratory evaluation, the bioenergetics model was furnishing unbiased estimates of food consumption by chinook salmon. Additionally, from the laboratory experiment, we calculated that chinook salmon retained 75% of the PCBs contained within their food. In an earlier study, assimilation rate of PCBs to chinook salmon from their food in Lake Michigan was estimated at 53%, thereby suggesting that the model was substantially overestimating food consumption by chinook salmon in Lake Michigan. However, we concluded that field performance of the model could not be accurately assessed because PCB assimilation efficiency is dependent on feeding rate, and feeding rate of chinook salmon was likely much lower in our laboratory tanks than in Lake Michigan.

Bioenergetic evaluation of diel vertical migration by bull trout (Salvelinus confluentus) in a thermally stratified reservoir

USGS Publications Warehouse

Eckmann, Madeleine; Dunham, Jason B.; Connor, Edward J.; Welch, Carmen A.

2018-01-01

Many species living in deeper lentic ecosystems exhibit daily movements that cycle through the water column, generally referred to as diel vertical migration (DVM). In this study, we applied bioenergetics modelling to evaluate growth as a hypothesis to explain DVM by bull trout (Salvelinus confluentus) in a thermally stratified reservoir (Ross Lake, WA, USA) during the peak of thermal stratification in July and August. Bioenergetics model parameters were derived from observed vertical distributions of temperature, prey and bull trout. Field sampling confirmed that bull trout prey almost exclusively on recently introduced redside shiner (Richardsonius balteatus). Model predictions revealed that deeper (>25 m) DVMs commonly exhibited by bull trout during peak thermal stratification cannot be explained by maximising growth. Survival, another common explanation for DVM, may have influenced bull trout depth use, but observations suggest there may be additional drivers of DVM. We propose these deeper summertime excursions may be partly explained by an alternative hypothesis: the importance of colder water for gametogenesis. In Ross Lake, reliance of bull trout on warm water prey (redside shiner) for consumption and growth poses a potential trade-off with the need for colder water for gametogenesis.

A review of the basics of mitochondrial bioenergetics, metabolism, and related signaling pathways in cancer cells: Therapeutic targeting of tumor mitochondria with lipophilic cationic compounds.

PubMed

Kalyanaraman, Balaraman; Cheng, Gang; Hardy, Micael; Ouari, Olivier; Lopez, Marcos; Joseph, Joy; Zielonka, Jacek; Dwinell, Michael B

2018-04-01

The present review is a sequel to the previous review on cancer metabolism published in this journal. This review focuses on the selective antiproliferative and cytotoxic effects of mitochondria-targeted therapeutics (MTTs) in cancer cells. Emerging research reveals a key role of mitochondrial respiration on tumor proliferation. Previously, a mitochondria-targeted nitroxide was shown to selectively inhibit colon cancer cell proliferation at submicromolar levels. This review is centered on the therapeutic use of MTTs and their bioenergetic profiling in cancer cells. Triphenylphosphonium cation conjugated to a parent molecule (e.g., vitamin-E or chromanol, ubiquinone, and metformin) via a linker alkyl chain is considered an MTT. MTTs selectively and potently inhibit proliferation of cancer cells and, in some cases, induce cytotoxicity. MTTs inhibit mitochondrial complex I activity and induce mitochondrial stress in cancer cells through generation of reactive oxygen species. MTTs in combination with glycolytic inhibitors synergistically inhibit tumor cell proliferation. This review discusses how signaling molecules traditionally linked to tumor cell proliferation affect tumor metabolism and bioenergetics (glycolysis, TCA cycle, and glutaminolysis). Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Treatment Approaches for Interoceptive Dysfunctions in Drug Addiction

PubMed Central

Paulus, Martin P.; Stewart, Jennifer L.; Haase, Lori

2013-01-01

There is emerging evidence that individuals with drug addiction have dysfunctions in brain systems that are important for interoceptive processing, which include, among others, the insular and the anterior cingulate cortices. These individuals may not be expending sufficient neural resources to process perturbations of the interoceptive state but may exert over-activation of these systems when processing drug-related stimuli. As a consequence, insufficient detection and processing of interoceptive state changes may result in inadequate anticipation and preparation to adapt to environmental challenges, e.g., adapt to abstinence in the presence of withdrawal symptoms. Here, we integrate interoceptive dysfunction in drug-addicted individuals, with the neural basis for meditation and exercise to develop a heuristic to target the interoceptive system as potential treatments for drug addiction. First, it is suggested that mindfulness-based approaches can modulate both interoceptive function and insular activation patterns. Second, there is an emerging literature showing that the regulation of physical exercise in the brain involves the insula and anterior cingulate cortex and that intense physical exercise is associated with a insula changes that may provide a window to attenuate the increased interoceptive response to drug-related stimuli. It is concluded that the conceptual framework of interoceptive dysfunctions in drug addiction and the experimental findings in meditation and exercise provide a useful approach to develop new interventions for drug addiction. PMID:24151471

Treatment approaches for interoceptive dysfunctions in drug addiction.

PubMed

Paulus, Martin P; Stewart, Jennifer L; Haase, Lori

2013-10-18

There is emerging evidence that individuals with drug addiction have dysfunctions in brain systems that are important for interoceptive processing, which include, among others, the insular and the anterior cingulate cortices. These individuals may not be expending sufficient neural resources to process perturbations of the interoceptive state but may exert over-activation of these systems when processing drug-related stimuli. As a consequence, insufficient detection and processing of interoceptive state changes may result in inadequate anticipation and preparation to adapt to environmental challenges, e.g., adapt to abstinence in the presence of withdrawal symptoms. Here, we integrate interoceptive dysfunction in drug-addicted individuals, with the neural basis for meditation and exercise to develop a heuristic to target the interoceptive system as potential treatments for drug addiction. First, it is suggested that mindfulness-based approaches can modulate both interoceptive function and insular activation patterns. Second, there is an emerging literature showing that the regulation of physical exercise in the brain involves the insula and anterior cingulate cortex and that intense physical exercise is associated with a insula changes that may provide a window to attenuate the increased interoceptive response to drug-related stimuli. It is concluded that the conceptual framework of interoceptive dysfunctions in drug addiction and the experimental findings in meditation and exercise provide a useful approach to develop new interventions for drug addiction.

Microtubule Actin Cross-Linking Factor 1 Regulates Cardiomyocyte Microtubule Distribution and Adaptation to Hemodynamic Overload

PubMed Central

Kwak, Dongmin; Wang, Huan; Liu, Xiaoyu; Hu, Xinli; Bache, Robert J.; Chen, Yingjie

2013-01-01

Aberrant cardiomyocyte microtubule growth is a feature of pressure overload induced cardiac hypertrophy believed to contribute to left ventricular (LV) dysfunction. Microtubule Actin Cross-linking Factor 1 (MACF1/Acf7) is a 600 kd spectraplakin that stabilizes and guides microtubule growth along actin filaments. MACF1 is expressed in the heart, but its impact on cardiac microtubules, and how this influences cardiac structure, function, and adaptation to hemodynamic overload is unknown. Here we used inducible cardiac-specific MACF1 knockout mice (MACF1 KO) to determine the impact of MACF1 on cardiac microtubules and adaptation to pressure overload (transverse aortic constriction (TAC).In adult mouse hearts, MACF1 expression was low under basal conditions, but increased significantly in response to TAC. While MACF1 KO had no observable effect on heart size or function under basal conditions, MACF1 KO exacerbated TAC induced LV hypertrophy, LV dilation and contractile dysfunction. Interestingly, subcellular fractionation of ventricular lysates revealed that MACF1 KO altered microtubule distribution in response to TAC, so that more tubulin was associated with the cell membrane fraction. Moreover, TAC induced microtubule redistribution into this cell membrane fraction in both WT and MACF1 KO mice correlated strikingly with the level of contractile dysfunction (r2 = 0.786, p<.001). MACF1 disruption also resulted in reduction of membrane caveolin 3 levels, and increased levels of membrane PKCα and β1 integrin after TAC, suggesting MACF1 function is important for spatial regulation of several physiologically relevant signaling proteins during hypertrophy. Together, these data identify for the first time, a role for MACF1 in cardiomyocyte microtubule distribution and in adaptation to hemodynamic overload. PMID:24086300

Microtubule Actin Cross-linking Factor 1 regulates cardiomyocyte microtubule distribution and adaptation to hemodynamic overload.

PubMed

Fassett, John T; Xu, Xin; Kwak, Dongmin; Wang, Huan; Liu, Xiaoyu; Hu, Xinli; Bache, Robert J; Chen, Yingjie

2013-01-01

Aberrant cardiomyocyte microtubule growth is a feature of pressure overload induced cardiac hypertrophy believed to contribute to left ventricular (LV) dysfunction. Microtubule Actin Cross-linking Factor 1 (MACF1/Acf7) is a 600 kd spectraplakin that stabilizes and guides microtubule growth along actin filaments. MACF1 is expressed in the heart, but its impact on cardiac microtubules, and how this influences cardiac structure, function, and adaptation to hemodynamic overload is unknown. Here we used inducible cardiac-specific MACF1 knockout mice (MACF1 KO) to determine the impact of MACF1 on cardiac microtubules and adaptation to pressure overload (transverse aortic constriction (TAC).In adult mouse hearts, MACF1 expression was low under basal conditions, but increased significantly in response to TAC. While MACF1 KO had no observable effect on heart size or function under basal conditions, MACF1 KO exacerbated TAC induced LV hypertrophy, LV dilation and contractile dysfunction. Interestingly, subcellular fractionation of ventricular lysates revealed that MACF1 KO altered microtubule distribution in response to TAC, so that more tubulin was associated with the cell membrane fraction. Moreover, TAC induced microtubule redistribution into this cell membrane fraction in both WT and MACF1 KO mice correlated strikingly with the level of contractile dysfunction (r(2) = 0.786, p<.001). MACF1 disruption also resulted in reduction of membrane caveolin 3 levels, and increased levels of membrane PKCα and β1 integrin after TAC, suggesting MACF1 function is important for spatial regulation of several physiologically relevant signaling proteins during hypertrophy. Together, these data identify for the first time, a role for MACF1 in cardiomyocyte microtubule distribution and in adaptation to hemodynamic overload.

31P-nuclear magnetic resonance spectroscopy in vivo of six human melanoma xenograft lines: tumour bioenergetic status and blood supply.

PubMed Central

Lyng, H.; Olsen, D. R.; Southon, T. E.; Rofstad, E. K.

1993-01-01

Six human melanoma xenograft lines grown s.c. in BALB/c-nu/nu mice were subjected to 31P-nuclear magnetic resonance (31P-NMR) spectroscopy in vivo. The following resonances were detected: phosphomonoesters (PME), inorganic phosphate (Pi), phosphodiesters (PDE), phosphocreatine (PCr) and nucleoside triphosphate gamma, alpha and beta (NTP gamma, alpha and beta). The main purpose of the work was to search for possible relationships between 31P-NMR resonance ratios and tumour pH on the one hand and blood supply per viable tumour cell on the other. The latter parameter was measured by using the 86Rb uptake method. Tumour bioenergetic status [the (PCr + NTP beta)/Pi resonance ratio], tumour pH and blood supply per viable tumour cell decreased with increasing tumour volume for five of the six xenograft lines. The decrease in tumour bioenergetic status was due to a decrease in the (PCr + NTP beta)/total resonance ratio as well as an increase in the Pi/total resonance ratio. The decrease in the (PCr + NTP beta)/total resonance ratio was mainly a consequence of a decrease in the PCr/total resonance ratio for two lines and mainly a consequence of a decrease in the NTP beta/total resonance ratio for three lines. The magnitude of the decrease in the (PCr + NTP beta)/total resonance ratio and the magnitude of the decrease in tumour pH were correlated to the magnitude of the decrease in blood supply per viable tumour cell. Tumour pH decreased with decreasing tumour bioenergetic status, and the magnitude of this decrease was larger for the tumour lines showing a high than for those showing a low blood supply per viable tumour cell. No correlations across the tumour lines were found between tumour pH and tumour bioenergetic status or any other resonance ratio on the one hand and blood supply per viable tumour cell on the other. The differences in the 31P-NMR spectrum between the tumour lines were probably caused by differences in the intrinsic biochemical properties of the tumour cells rather than by the differences in blood supply per viable tumour cell. Biochemical properties of particular importance included rate of respiration, glycolytic capacity and tolerance to hypoxic stress. On the other hand, tumour bioenergetic status and tumour pH were correlated to blood supply per viable tumour cell within individual tumour lines. These observations suggest that 31P-NMR spectroscopy may be developed to be a clinically useful method for monitoring tumour blood supply and parameters related to tumour blood supply during and after physiological intervention and tumour treatment. However, clinically useful parameters for prediction of tumour treatment resistance caused by insufficient blood supply can probably not be derived from a single 31P-NMR spectrum since correlations across tumour lines were not detected; additional information is needed. PMID:8260356

Leadership Behaviors of Management for Complex Adaptive Systems

DTIC Science & Technology

2010-04-01

arson • The Five Dysfunctions of a Team - Patrick M. Lencioni Agile Development Practices • Agile Project Management with Scrum – Ken Schwaber...and down to the individual and team level – Relationships are not defined hierarchically, but rather through interactions across References: Mike...n – Consisting of parts intricately combined © Copyright 2009 Northrop GrummanCopyright 2010 Northrop Grumman 5 Predictable or Adaptive Software/IT

Analysis of pain behavior profiles and functional disability in outpatient physical therapy clinics.

PubMed

Hankin, H A; Spencer, T; Kegerreis, S; Worrell, T; Rice, J M

2001-02-01

Descriptive, ex post facto. To determine the proportion of physical therapy outpatients with pain who exhibit various pain behavior profiles, and to determine whether there are differences in functional disability across the profiles. Physical therapists treat many patients who have chronic pain. Research suggests that early identification and multidisciplinary treatment are effective and economical for these patients. The Multidimensional Pain Inventory (MPI) and the Pain Disability Index (PDI) are potential screening tools that could be used in physical therapy clinics to determine which patients should be referred for multidisciplinary treatment. MPI and PDI data were gathered on 57 physical therapy outpatients (mean age 44.3 +/- 14.5 years, 22 men and 35 women) with pain of 3 or more months duration. ANOVA was used to analyze differences in mean PDI scores across the MPI profiles. Of all patients, 42.1% fit the Adaptive Coper profile, 29.8% fit the Interpersonally Distressed profile, and 28.1% fit the Dysfunctional profile. There were significant differences in PDI scores among profile groups. Post hoc analysis showed that the PDI scores of the Adaptive Coper and Interpersonally Distressed groups were different from the Dysfunctional group, but that there was no difference between the Adaptive Coper and Interpersonally Distressed groups. Many patients in outpatient physical therapy settings exhibit behavioral, affective, and cognitive characteristics associated with chronic pain. Thirty-three patients (57.9%) had MPI profiles (interpersonally distressed and dysfunctional) that suggest they might benefit from multidisciplinary treatment.

Dietary Antioxidants as Modifiers of Physiologic Adaptations to Exercise

PubMed Central

Mankowski, Robert T.; Anton, Stephen D.; Buford, Thomas W.; Leeuwenburgh, Christiaan

2015-01-01

Adaptive responses to exercise training (ET) are crucial in maintaining physiological homeostasis and health span. Exercise-induced aerobic bioenergetic reactions in mitochondria and cytosol increase production of reactive oxygen species (ROSs), where excess of ROS can be scavenged by enzymatic as well as non-enzymatic antioxidants to protect against deleterious oxidative stress. Free radicals, however, have recently been recognized as crucial signaling agents that promote adaptive mechanisms to ET, such as mitochondrial biogenesis, antioxidant (AO) enzyme activity defense system upregulation, insulin sensitivity, and glucose uptake in skeletal muscle. Commonly used non-enzymatic AO supplements, such as vitamins C and E, a-lipoic acid, and polyphenols, in combination with ET, have been proposed as ways to prevent exercise-induced oxidative stress and hence improve adaptation responses to endurance training. Preclinical and clinical studies to date have shown inconsistent results indicating either positive or negative effects of endurance training combined with different blends of AO supplements (mostly vitamins C and E and a-lipoic acid) on redox status, mitochondrial biogenesis pathways, and insulin sensitivity. Preclinical reports on ET combined with resveratrol, however, have shown consistent positive effects on exercise performance, mitochondrial biogenesis, and insulin sensitivity, with clinical trials reporting mixed effects. Relevant clinical studies have been few and have used inconsistent results and methodology (types of compounds, combinations, and supplementation time). The future studies would investigate the effects of specific antioxidants and other popular supplements, such as a-lipoic acid and resveratrol, on training effects in humans. Of particular importance are older adults who may be at higher risk of age-related increased oxidative stress, an impaired AO enzyme defense system, and comorbidities such as hypertension, insulin resistance, and diabetes. PMID:25606815

Reducing RBM20 activity improves diastolic dysfunction and cardiac atrophy.

PubMed

Hinze, Florian; Dieterich, Christoph; Radke, Michael H; Granzier, Henk; Gotthardt, Michael

2016-12-01

Impaired diastolic filling is a main contributor to heart failure with preserved ejection fraction (HFpEF), a syndrome with increasing prevalence and no treatment. Both collagen and the giant sarcomeric protein titin determine diastolic function. Since titin's elastic properties can be adjusted physiologically, we evaluated titin-based stiffness as a therapeutic target. We adjusted RBM20-dependent cardiac isoform expression in the titin N2B knockout mouse with increased ventricular stiffness. A ~50 % reduction of RBM20 activity does not only maintain cardiac filling in diastole but also ameliorates cardiac atrophy and thus improves cardiac function in the N2B-deficient heart. Reduced RBM20 activity partially normalized gene expression related to muscle development and fatty acid metabolism. The adaptation of cardiac growth was related to hypertrophy signaling via four-and-a-half lim-domain proteins (FHLs) that translate mechanical input into hypertrophy signals. We provide a novel link between cardiac isoform expression and trophic signaling via FHLs and suggest cardiac splicing as a therapeutic target in diastolic dysfunction. Increasing the length of titin isoforms improves ventricular filling in heart disease. FHL proteins are regulated via RBM20 and adapt cardiac growth. RBM20 is a therapeutic target in diastolic dysfunction.

Near-shore and off-shore habitat use by endangered juvenile Lost River and Shortnose Suckers in Upper Klamath Lake, Oregon: 2006 data summary

USGS Publications Warehouse

Burdick, Summer M.; Wilkens, Alexander X.; VanderKooi, Scott P.

2008-01-01

We continued sampling juvenile suckers in 2006 as part of an effort to develop bioenergetics models for juvenile Lost River and shortnose suckers. This study required us to collect fish to determine growth rates and energy content of juvenile suckers. We followed the sampling protocols and methods described by Hendrixson et al. (2007b) to maintain continuity and facilitate comparisons with data collected in recent years, but sampled at a reduced level of effort compared to previous years (approximately one-third) due to limited funding. Here we present a summary of catch data collected in 2006. Bioenergetics models will be reported separately

BNIP3 contributes to the glutamine-driven aggressive behavior of melanoma cells.

PubMed

Vara-Perez, Monica; Maes, Hannelore; Van Dingenen, Sarah; Agostinis, Patrizia

2018-06-01

Aerobic glycolysis (Warburg effect) is used by cancer cells to fuel tumor growth. Interestingly, metastatic melanoma cells rely on glutaminolysis rather than aerobic glycolysis for their bioenergetic needs through the tricarboxylic acid cycle. Here, we compared the effects of glucose or glutamine on melanoma cell proliferation, migration and oxidative phosphorylation in vitro. We found that glutamine-driven melanoma cell's aggressive traits positively correlated with increased expression of HIF1α and its pro-autophagic target BNIP3. BNIP3 silencing reduced glutamine-mediated effects on melanoma cell growth, migration and bioenergetics. Hence, BNIP3 is a vital component of the mitochondria quality control required for glutamine-driven melanoma aggressiveness.

Cardiovascular adaptation to extrauterine life after intrauterine growth restriction.

PubMed

Rodriguez-Guerineau, Luciana; Perez-Cruz, Miriam; Gomez Roig, María D; Cambra, Francisco J; Carretero, Juan; Prada, Fredy; Gómez, Olga; Crispi, Fátima; Bartrons, Joaquim

2018-02-01

Introduction The adaptive changes of the foetal heart in intrauterine growth restriction can persist postnatally. Data regarding its consequences for early circulatory adaptation to extrauterine life are scarce. The aim of this study was to assess cardiac morphometry and function in newborns with late-onset intrauterine growth restriction to test the hypothesis that intrauterine growth restriction causes cardiac shape and functional changes at birth. A comprehensive echocardiographic study was performed in 25 neonates with intrauterine growth restriction and 25 adequate-for-gestational-age neonates. Compared with controls, neonates with intrauterine growth restriction had more globular ventricles, lower longitudinal tricuspid annular motion, and higher left stroke volume without differences in the heart rate. Neonates with intrauterine growth restriction also showed subclinical signs of diastolic dysfunction in the tissue Doppler imaging with lower values of early (e') diastolic annular peak velocities in the septal annulus. Finally, the Tei index in the tricuspid annulus was higher in the intrauterine growth restriction group. Neonates with history of intrauterine growth restriction showed cardiac remodelling and signs of systolic and diastolic dysfunction. Overall, there was a significant tendency to worse cardiac function results in the right heart. The adaptation to extrauterine life occurred with more globular hearts, higher stroke volumes but a similar heart rate compared to adequate-for-gestational-age neonates.

The impact of pediatric traumatic brain injury (TBI) on family functioning: a systematic review.

PubMed

Rashid, Marghalara; Goez, Helly R; Mabood, Neelam; Damanhoury, Samah; Yager, Jerome Y; Joyce, Anthony S; Newton, Amanda S

2014-01-01

To explore the impact moderate to severe traumatic brain injury (TBI) in a child has on family functioning. The search was conducted using 9 bibliographic databases for articles published between 1980 and 2013. Two reviewers independently screened for inclusion and assessed study quality. Two reviewers extracted study data and a third checked for completeness and accuracy. Findings are presented by three domains: injury-related burden and stress, family adaptability, and family cohesion. Nine observational studies were included. Across the studies, differences between study groups for family functioning varied, but there was a trend for more dysfunction in families whose child had a severe TBI as compared to families whose child had a moderate TBI or orthopedic injury. In three studies, injury-associated burden was persistent post-injury and was highest in families whose child had a severe TBI followed by families with a child who had a moderate TBI. One study found fathers reported more family dysfunction caused by their child's injury compared to mothers. Two studies found that mothers' adaptability depended on social support and stress levels while fathers' adaptability was independent of these factors and injury severity. Moderate to severe TBI has a significant, long-standing impact on family functioning. Factors associated with family adaptability vary by parental role.

Phylogeny of Rieske/cytb Complexes with a Special Focus on the Haloarchaeal Enzymes

PubMed Central

Baymann, Frauke; Schoepp-Cothenet, Barbara; Lebrun, Evelyne; van Lis, Robert; Nitschke, Wolfgang

2012-01-01

Rieske/cytochrome b (Rieske/cytb) complexes are proton pumping quinol oxidases that are present in most bacteria and Archaea. The phylogeny of their subunits follows closely the 16S-rRNA phylogeny, indicating that chemiosmotic coupling was already present in the last universal common ancestor of Archaea and bacteria. Haloarchaea are the only organisms found so far that acquired Rieske/cytb complexes via interdomain lateral gene transfer. They encode two Rieske/cytb complexes in their genomes; one of them is found in genetic context with nitrate reductase genes and has its closest relatives among Actinobacteria and the Thermus/Deinococcus group. It is likely to function in nitrate respiration. The second Rieske/cytb complex of Haloarchaea features a split cytochrome b sequence as do Cyanobacteria, chloroplasts, Heliobacteria, and Bacilli. It seems that Haloarchaea acquired this complex from an ancestor of the above-mentioned phyla. Its involvement in the bioenergetic reaction chains of Haloarchaea is unknown. We present arguments in favor of the hypothesis that the ancestor of Haloarchaea, which relied on a highly specialized bioenergetic metabolism, that is, methanogenesis, and was devoid of quinones and most enzymes of anaerobic or aerobic bioenergetic reaction chains, integrated laterally transferred genes into its genome to respond to a change in environmental conditions that made methanogenesis unfavorable. PMID:22798450

Citrobacter freundii impairs the phosphoryl transfer network in the gills of Rhamdia quelen: Impairment of bioenergetics homeostasis.

PubMed

Baldissera, Matheus D; Souza, Carine F; Junior, Guerino B; Moreira, Karen Luise S; da Veiga, Marcelo L; da Rocha, Maria Izabel U M; Baldisserotto, Bernardo

2018-04-01

The precise coupling of spatially separated intracellular adenosine triphosphate (ATP)-producing and ATP-consuming, catalyzed by creatine kinase (CK), adenylate kinase (AK), and pyruvate kinase (PK), is a critical process in the bioenergetics of tissues with high energy demand, such as the branchial tissue. The effects of Citrobacter freundii infection on gills remain poorly understood, limited only to histopathological studies. Thus, the aim of this study was to evaluate whether experimental infection by C. freundii impairs the enzymes of the phosphoryl transfer network in gills of silver catfish (Rhamdia quelen). The CK (cytosolic and mitochondrial) and AK activities decreased in infected compared to uninfected animals, while the PK activity did not differ between groups. The gill histopathology of infected animals revealed extensive degeneration with fusion and necrosis of secondary lamellae, detachment of superficial epithelium, aneurysm, vessel congestion and inflammatory process. Based on these evidences, the inhibition and absence of an efficient communication between CK compartments caused the impairment of the branchial bioenergetics homeostasis, which was not compensated by the augmentation on branchial AK activity in an attempt to restore energy homeostasis. In summary, these alterations contribute to disease pathogenesis linked to branchial tissue in animals infected with C. freundii. Copyright © 2018. Published by Elsevier Ltd.

Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A and Leigh Syndrome Muscle Cells

PubMed Central

Fontes-Oliveira, Cibely C.; Steinz, Maarten; Schneiderat, Peter; Mulder, Hindrik; Durbeej, Madeleine

2017-01-01

Skeletal muscle has high energy requirement and alterations in metabolism are associated with pathological conditions causing muscle wasting and impaired regeneration. Congenital muscular dystrophy type 1A (MDC1A) is a severe muscle disorder caused by mutations in the LAMA2 gene. Leigh syndrome (LS) is a neurometabolic disease caused by mutations in genes related to mitochondrial function. Skeletal muscle is severely affected in both diseases and a common feature is muscle weakness that leads to hypotonia and respiratory problems. Here, we have investigated the bioenergetic profile in myogenic cells from MDC1A and LS patients. We found dysregulated expression of genes related to energy production, apoptosis and proteasome in myoblasts and myotubes. Moreover, impaired mitochondrial function and a compensatory upregulation of glycolysis were observed when monitored in real-time. Also, alterations in cell cycle populations in myoblasts and enhanced caspase-3 activity in myotubes were observed. Thus, we have for the first time demonstrated an impairment of the bioenergetic status in human MDC1A and LS muscle cells, which could contribute to cell cycle disturbance and increased apoptosis. Our findings suggest that skeletal muscle metabolism might be a promising pharmacological target in order to improve muscle function, energy efficiency and tissue maintenance of MDC1A and LS patients. PMID:28367954

A stochastic bioenergetics model based approach to translating large river flow and temperature in to fish population responses: The pallid sturgeon example

USGS Publications Warehouse

Wildhaber, Mark L.; Dey, Rima; Wikle, Christopher K.; Moran, Edward H.; Anderson, Christopher J.; Franz, Kristie J.

2015-01-01

In managing fish populations, especially at-risk species, realistic mathematical models are needed to help predict population response to potential management actions in the context of environmental conditions and changing climate while effectively incorporating the stochastic nature of real world conditions. We provide a key component of such a model for the endangered pallid sturgeon (Scaphirhynchus albus) in the form of an individual-based bioenergetics model influenced not only by temperature but also by flow. This component is based on modification of a known individual-based bioenergetics model through incorporation of: the observed ontogenetic shift in pallid sturgeon diet from marcroinvertebrates to fish; the energetic costs of swimming under flowing-water conditions; and stochasticity. We provide an assessment of how differences in environmental conditions could potentially alter pallid sturgeon growth estimates, using observed temperature and velocity from channelized portions of the Lower Missouri River mainstem. We do this using separate relationships between the proportion of maximum consumption and fork length and swimming cost standard error estimates for fish captured above and below the Kansas River in the Lower Missouri River. Critical to our matching observed growth in the field with predicted growth based on observed environmental conditions was a two-step shift in diet from macroinvertebrates to fish.

Magnetic resonance spectroscopy in congenital heart disease.

PubMed Central

Miall-Allen, V. M.; Kemp, G. J.; Rajagopalan, B.; Taylor, D. J.; Radda, G. K.; Haworth, S. G.

1996-01-01

OBJECTIVE: To determine the feasibility of studying myocardial and skeletal muscle bioenergetics using 31P magnetic resonance spectroscopy (MRS) in babies and young children with congenital heart disease. SUBJECTS: 16 control subjects aged 5 months to 24 years and 18 patients with CHD, aged 7 months to 23 years, of whom 11 had cyanotic CHD, five had cardiac failure, and two had had a Senning procedure. DESIGN: 31P MRS was carried out using a 1.9 Tesla horizontal 65 cm bore whole body magnet to study the myocardium in 10 patients and skeletal muscle (gastrocnemius) in 14 patients, eight of whom were exercised, together with appropriate controls. RESULTS: In hypoxaemic patients, in skeletal muscle at rest intracellular pH (pHi) was abnormally high [7.06 (SEM 0.04) v 7.04 (0.05), P < 0.01] and showed a positive correlation with haemoglobin (P < 0.03). On exercise, hypoxaemic patients fatigued more quickly but end-exercise pHi and phosphocreatine recovery were normal, implying that an equivalent but smaller amount of work had been performed. End-exercise ADP concentration was lower. On recovery, the initial rate of phosphocreatine resynthesis was low. Skeletal muscle bioenergetics were within normal limits in those in heart failure. In the myocardium, the phosphocreatine/ATP ratio was similar in controls and hypoxaemic subjects, but low in those in heart failure. CONCLUSIONS: In heart failure, the myocardial phosphocreatine/ATP ratio was reduced, as in adults, while resting skeletal muscle studies were normal. By contrast, hypoxaemic children had normal myocardial bioenergetics, but showed skeletal muscle alkalinity, and energy reserves were more readily depleted on exercise. On recovery, the initially slow phosphocreatine resynthesis rate reflects a low rate of mitochondrial ATP synthesis, probably due to an inadequate oxygen supply. 31P MRS offers a safe, non-invasive method of studying myocardial and skeletal muscle bioenergetics in children as young as 5 months. PMID:8697167

Derangements of liver tissue bioenergetics in concanavalin A-induced hepatitis.

PubMed

Al-Shamsi, Mariam; Shahin, Allen; Mensah-Brown, Eric P K; Souid, Abdul-Kader

2013-01-12

A novel in vitro system was employed to investigate liver tissue respiration (mitochondrial O2 consumption) in mice treated with concanavalin A (Con A). This study aimed to investigate hepatocyte bioenergetics in this well-studied hepatitis model. C57Bl/6 and C57Bl/6 IFN-γ-/- mice were injected intravenously with 12 mg ConA/kg. Liver specimens were collected at various timepoints after injection and analyzed for cellular respiration and caspase activation. Serum was analyzed for interferon-gamma (IFN-γ) and aminotransferases. Fluorescence activated cell sorting analysis was used to determine the phenotype of infiltrating cells, and light and electron microscopy were used to monitor morphological changes. Phosphorescence analyzer that measured dissolved O2 as function of time was used to evaluate respiration. In sealed vials, O2 concentrations in solutions containing liver specimen and glucose declined linearly with time, confirming zero-order kinetics of hepatocyte respiration. O2 consumption was inhibited by cyanide, confirming the oxidation occurred in the respiratory chain. Enhanced liver respiration (by ≈68%, p<0.02) was noted 3 hr after ConA treatment, and occurred in conjunction with limited cellular infiltrations around the blood vessels. Diminished respiration (by ≈30%, p=0.005) was noted 12 hr after ConA treatment, and occurred in conjunction with deranged mitochondria, areas of necrosis, and prominent infiltrations with immune cells, most significantly, CD3+NKT+ cells. Increases in intracellular caspase activity and serum IFN-γ and aminotransferase levels were noted 3 hr after ConA treatment and progressed with time. The above-noted changes were less pronounced in C57Bl/6 IFN-γ-/- mice treated with ConA. Based on these results, liver tissue bioenergetics is increased 3 hr after ConA exposure. This effect is driven by the pathogenesis of the disease, in which IFN-γ and other cytokines contribute to. Subsequent declines in liver bioenergetics appear to be a result of necrosis and active caspases targeting the mitochondria within hepatocytes.

For better or for worse? The effects of alcohol use on marital functioning.

PubMed

Marshal, Michael P

2003-12-01

Two competing hypotheses propose opposite effects for the relation between alcohol use and marital functioning. One hypothesis conceptualizes alcohol use as maladaptive and proposes that it serves as a chronic stressor that causes marital dysfunction and subsequent dissolution. An opposing hypothesis proposes that alcohol use is adaptive and serves to temporarily relieve stressors that cause marital dysfunction, stabilizing the marital relationship, and perhaps preventing dissolution. Sixty studies were reviewed that tested the relation between alcohol use and one of three marital functioning domains (satisfaction, interaction, and violence). Results provide overwhelming support for the notion that alcohol use is maladaptive, and that it is associated with dissatisfaction, negative marital interaction patterns, and higher levels of marital violence. A small subset of studies found that light drinking patterns are associated with adaptive marital functioning; however, more research is necessary to replicate these effects and identify specific conditions under which they occur.

Positive Feedback Amplifies the Response of Mitochondrial Membrane Potential to Glucose Concentration in Clonal Pancreatic Beta Cells.

PubMed

Gerencser, Akos A; Mookerjee, Shona A; Jastroch, Martin; Brand, Martin D

2017-05-01

Analysis of the cellular mechanisms of metabolic disorders, including type 2 diabetes mellitus, is complicated by the large number of reactions and interactions in metabolic networks. Metabolic control analysis with appropriate modularization is a powerful method for simplifying and analyzing these networks. To analyze control of cellular energy metabolism in adherent cell cultures of the INS-1 832/13 pancreatic β-cell model we adapted our microscopy assay of absolute mitochondrial membrane potential (ΔψM) to a fluorescence microplate reader format, and applied it in conjunction with cell respirometry. In these cells the sensitive response of ΔψM to extracellular glucose concentration drives glucose-stimulated insulin secretion. Using metabolic control analysis we identified the control properties that generate this sensitive response. Force-flux relationships between ΔψM and respiration were used to calculate kinetic responses to ΔψM of processes both upstream (glucose oxidation) and downstream (proton leak and ATP turnover) of ΔψM. The analysis revealed that glucose-evoked ΔψM hyperpolarization is amplified by increased glucose oxidation activity caused by factors downstream of ΔψM. At high glucose, the hyperpolarized ΔψM is stabilized almost completely by the action of glucose oxidation, whereas proton leak also contributes to the homeostatic control of ΔψM at low glucose. These findings suggest a strong positive feedback loop in the regulation of β-cell energetics, and a possible regulatory role of proton leak in the fasting state. Analysis of islet bioenergetics from published cases of type 2 diabetes suggests that disruption of this feedback can explain the damaged bioenergetic response of β-cells to glucose. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy. Copyright © 2016 Elsevier B.V. All rights reserved.

Cell Death and Heart Failure in Obesity: Role of Uncoupling Proteins

PubMed Central

Ruiz-Ramírez, Angélica; López-Acosta, Ocarol; Barrios-Maya, Miguel Angel

2016-01-01

Metabolic diseases such as obesity, metabolic syndrome, and type II diabetes are often characterized by increased reactive oxygen species (ROS) generation in mitochondrial respiratory complexes, associated with fat accumulation in cardiomyocytes, skeletal muscle, and hepatocytes. Several rodents studies showed that lipid accumulation in cardiac myocytes produces lipotoxicity that causes apoptosis and leads to heart failure, a dynamic pathological process. Meanwhile, several tissues including cardiac tissue develop an adaptive mechanism against oxidative stress and lipotoxicity by overexpressing uncoupling proteins (UCPs), specific mitochondrial membrane proteins. In heart from rodent and human with obesity, UCP2 and UCP3 may protect cardiomyocytes from death and from a state progressing to heart failure by downregulating programmed cell death. UCP activation may affect cytochrome c and proapoptotic protein release from mitochondria by reducing ROS generation and apoptotic cell death. Therefore the aim of this review is to discuss recent findings regarding the role that UCPs play in cardiomyocyte survival by protecting against ROS generation and maintaining bioenergetic metabolism homeostasis to promote heart protection. PMID:27642497

Population energetics and ecology of the rock grasshopper, Trimerotropis saxatilis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Duke, K.M.; Crossley, D.A. Jr.

The ecology and bioenergetics of a population of Trimerotropis saxatilis (Acrididae) were examined in field and laboratory studies. This grasshopper species occurs on harsh, desert-like rock outcrops in the southeastern United States and constitutes one of the important consumers in those ecosystems. The rock grasshopper population studied was located on Panola Mountain, approximately 16 km southeast of Atlanta, Georgia, USA. Supplemental population data were collected from a nearby granite outcrop, Mt. Arabia. The energy budget equation used was: Production = Ingestion - Egestion - Respiration. Production, ingestion and respiration were measured, and egestion was determined by difference. The energy budgetmore » and population ecology parameters for T. saxatilis were compared with those reported for other orthopteran species. The parameters for T. saxatilis were smaller than for any other population studied, reflecting their adaptation to the harsh environment in which they live. Efficiencies, including production/ingestion and assimilation/ingestion, calculated for several orthopteran populations, were found to be relatively constant, indicating that herbivorous orthopterans function similarly in different ecosystems.« less

Import, maturation, and function of SOD1 and its copper chaperone CCS in the mitochondrial intermembrane space.

PubMed

Kawamata, Hibiki; Manfredi, Giovanni

2010-11-01

Cu, Zn, superoxide dismutase (SOD1) is a ubiquitous enzyme localized in multiple cellular compartments, including mitochondria, where it concentrates in the intermembrane space (IMS). Similar to other small IMS proteins, the import and retention of SOD1 in the IMS is linked to its folding and maturation, involving the formation of critical intra- and intermolecular disulfide bonds. Therefore, the cysteine residues of SOD1 play a fundamental role in its IMS localization. IMS import of SOD1 involves its copper chaperone, CCS, whose mitochondrial distribution is regulated by the Mia40/Erv1 disulfide relay system in a redox-dependent manner: CCS promotes SOD1 maturation and retention in the IMS. The function of SOD1 in the IMS is still unknown, but it is plausible that it serves to remove superoxide released from the mitochondrial respiratory chain. Mutations in SOD1 cause familial amyotrophic lateral sclerosis (ALS), whose pathologic features include mitochondrial bioenergetic dysfunction. Mutant SOD1 localization in the IMS is not dictated by oxygen concentration and the Mia40/Erv1 system, but is primarily dependent on aberrant protein folding and aggregation. Mutant SOD1 localization and aggregation in the IMS might cause the mitochondrial abnormalities observed in familial ALS and could play a significant role in disease pathogenesis.

Rapeseed oil-rich diet alters in vitro menadione and nimesulide hepatic mitochondrial toxicity.

PubMed

Monteiro, João P; Silva, Ana M; Jurado, Amália S; Oliveira, Paulo J

2013-10-01

Diet-induced changes in the lipid composition of mitochondrial membranes have been shown to influence physiological processes. However, the modulation effect of diet on mitochondrially-active drugs has not yet received the deserved attention. Our hypothesis is that modulation of membrane dynamics by diet impacts drug-effects on liver mitochondrial functioning. In a previous work, we have shown that a diet rich in rapeseed oil altered mitochondrial membrane composition and bioenergetics in Wistar rats. In the present work, we investigated the influence of the modified diet on hepatic mitochondrial activity of two drugs, menadione and nimesulide, and FCCP, a classic protonophore, was used for comparison. The results showed that the effects of menadione and nimesulide were less severe on liver mitochondria for rats fed the modified diet than on rats fed the control diet. A specific effect on complex I seemed to be involved in drug-induced mitochondria dysfunction. Liver mitochondria from the modified diet group were more susceptible to nimesulide effects on MPT induction. The present work demonstrates that diet manipulation aimed at modifying mitochondrial membrane properties alters the toxicity of mitochondria active agents. This work highlights that diet may potentiate mitochondrial pharmacologic effects or increase drug-induced liabilities. Copyright © 2013 Elsevier Ltd. All rights reserved.

Enterocin AS-48 as Evidence for the Use of Bacteriocins as New Leishmanicidal Agents.

PubMed

Abengózar, María Ángeles; Cebrián, Rubén; Saugar, José María; Gárate, Teresa; Valdivia, Eva; Martínez-Bueno, Manuel; Maqueda, Mercedes; Rivas, Luis

2017-04-01

We report the feasibility of enterocin AS-48, a circular cationic peptide produced by Enterococcus faecalis , as a new leishmanicidal agent. AS-48 is lethal to Leishmania promastigotes as well as to axenic and intracellular amastigotes at low micromolar concentrations, with scarce cytotoxicity to macrophages. AS-48 induced a fast bioenergetic collapse of L. donovani promastigotes but only a partial permeation of their plasma membrane with limited entrance of vital dyes, even at concentrations beyond its full lethality. Fluoresceinated AS-48 was visualized inside parasites by confocal microscopy and seen to cause mitochondrial depolarization and reactive oxygen species production. Altogether, AS-48 appeared to have a mixed leishmanicidal mechanism that includes both plasma membrane permeabilization and additional intracellular targets, with mitochondrial dysfunctionality being of special relevance. This complex leishmanicidal mechanism of AS-48 persisted even for the killing of intracellular amastigotes, as evidenced by transmission electron microscopy. We demonstrated the potentiality of AS-48 as a new and safe leishmanicidal agent, expanding the growing repertoire of eukaryotic targets for bacteriocins, and our results provide a proof of mechanism for the search of new leishmanicidal bacteriocins, whose diversity constitutes an almost endless source for new structures at moderate production cost and whose safe use on food preservation is well established. Copyright © 2017 American Society for Microbiology.

Enterocin AS-48 as Evidence for the Use of Bacteriocins as New Leishmanicidal Agents

PubMed Central

Abengózar, María Ángeles; Cebrián, Rubén; Saugar, José María; Gárate, Teresa; Valdivia, Eva; Martínez-Bueno, Manuel; Maqueda, Mercedes

2017-01-01

ABSTRACT We report the feasibility of enterocin AS-48, a circular cationic peptide produced by Enterococcus faecalis, as a new leishmanicidal agent. AS-48 is lethal to Leishmania promastigotes as well as to axenic and intracellular amastigotes at low micromolar concentrations, with scarce cytotoxicity to macrophages. AS-48 induced a fast bioenergetic collapse of L. donovani promastigotes but only a partial permeation of their plasma membrane with limited entrance of vital dyes, even at concentrations beyond its full lethality. Fluoresceinated AS-48 was visualized inside parasites by confocal microscopy and seen to cause mitochondrial depolarization and reactive oxygen species production. Altogether, AS-48 appeared to have a mixed leishmanicidal mechanism that includes both plasma membrane permeabilization and additional intracellular targets, with mitochondrial dysfunctionality being of special relevance. This complex leishmanicidal mechanism of AS-48 persisted even for the killing of intracellular amastigotes, as evidenced by transmission electron microscopy. We demonstrated the potentiality of AS-48 as a new and safe leishmanicidal agent, expanding the growing repertoire of eukaryotic targets for bacteriocins, and our results provide a proof of mechanism for the search of new leishmanicidal bacteriocins, whose diversity constitutes an almost endless source for new structures at moderate production cost and whose safe use on food preservation is well established. PMID:28167557

Rejuvenating cellular respiration for optimizing respiratory function: targeting mitochondria.

PubMed

Agrawal, Anurag; Mabalirajan, Ulaganathan

2016-01-15

Altered bioenergetics with increased mitochondrial reactive oxygen species production and degradation of epithelial function are key aspects of pathogenesis in asthma and chronic obstructive pulmonary disease (COPD). This motif is not unique to obstructive airway disease, reported in related airway diseases such as bronchopulmonary dysplasia and parenchymal diseases such as pulmonary fibrosis. Similarly, mitochondrial dysfunction in vascular endothelium or skeletal muscles contributes to the development of pulmonary hypertension and systemic manifestations of lung disease. In experimental models of COPD or asthma, the use of mitochondria-targeted antioxidants, such as MitoQ, has substantially improved mitochondrial health and restored respiratory function. Modulation of noncoding RNA or protein regulators of mitochondrial biogenesis, dynamics, or degradation has been found to be effective in models of fibrosis, emphysema, asthma, and pulmonary hypertension. Transfer of healthy mitochondria to epithelial cells has been associated with remarkable therapeutic efficacy in models of acute lung injury and asthma. Together, these form a 3R model--repair, reprogramming, and replacement--for mitochondria-targeted therapies in lung disease. This review highlights the key role of mitochondrial function in lung health and disease, with a focus on asthma and COPD, and provides an overview of mitochondria-targeted strategies for rejuvenating cellular respiration and optimizing respiratory function in lung diseases. Copyright © 2016 the American Physiological Society.

The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis.

PubMed

Loeffler, Jean-Philippe; Picchiarelli, Gina; Dupuis, Luc; Gonzalez De Aguilar, Jose-Luis

2016-03-01

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease primarily characterized by upper and lower motor neuron degeneration, muscle wasting and paralysis. It is increasingly accepted that the pathological process leading to ALS is the result of multiple disease mechanisms that operate within motor neurons and other cell types both inside and outside the central nervous system. The implication of skeletal muscle has been the subject of a number of studies conducted on patients and related animal models. In this review, we describe the features of ALS muscle pathology and discuss on the contribution of muscle to the pathological process. We also give an overview of the therapeutic strategies proposed to alleviate muscle pathology or to deliver curative agents to motor neurons. ALS muscle mainly suffers from oxidative stress, mitochondrial dysfunction and bioenergetic disturbances. However, the way by which the disease affects different types of myofibers depends on their contractile and metabolic features. Although the implication of muscle in nourishing the degenerative process is still debated, there is compelling evidence suggesting that it may play a critical role. Detailed understanding of the muscle pathology in ALS could, therefore, lead to the identification of new therapeutic targets. © 2016 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.

Review of methods to probe single cell metabolism and bioenergetics

PubMed Central

Vasdekis, Andreas E.; Stephanopoulos, Gregory

2015-01-01

Single cell investigations have enabled unexpected discoveries, such as the existence of biological noise and phenotypic switching in infection, metabolism and treatment. Herein, we review methods that enable such single cell investigations specific to metabolism and bioenergetics. Firstly, we discuss how to isolate and immobilize individuals from a cell suspension, including both permanent and reversible approaches. We also highlight specific advances in microbiology for its implications in metabolic engineering. Methods for probing single cell physiology and metabolism are subsequently reviewed. The primary focus therein is on dynamic and high-content profiling strategies based on label-free and fluorescence microspectroscopy and microscopy. Non-dynamic approaches, such as mass spectrometry and nuclear magnetic resonance, are also briefly discussed. PMID:25448400

Linking mitochondrial bioenergetics to insulin resistance via redox biology

PubMed Central

Fisher-Wellman, Kelsey H.; Neufer, P. Darrell

2012-01-01

Chronic overnutrition and physical inactivity are major risk factors for insulin resistance and type 2 diabetes. Recent research indicates that overnutrition generates an increase in hydrogen peroxide (H2O2) emission from mitochondria, serving as a release valve to relieve the reducing pressure created by fuel overload, as well as a primary signal to ultimately decrease insulin sensitivity. H2O2 is a major input to cellular redox circuits that link to cysteine residues throughout the entire proteome to regulate cell function. Here we review the principles of mitochondrial bioenergetics and redox systems biology and offer new insight as to how H2O2 emission may be linked via redox biology to the etiology of insulin resistance. PMID:22305519

Autism as an adaptive common variant pathway for human brain development.

PubMed

Johnson, Mark H

2017-06-01

While research on focal perinatal lesions has provided evidence for recovery of function, much less is known about processes of brain adaptation resulting from mild but widespread disturbances to neural processing over the early years (such as alterations in synaptic efficiency). Rather than being viewed as a direct behavioral consequence of life-long neural dysfunction, I propose that autism is best viewed as the end result of engaging adaptive processes during a sensitive period. From this perspective, autism is not appropriately described as a disorder of neurodevelopment, but rather as an adaptive common variant pathway of human functional brain development. Copyright © 2017 The Author. Published by Elsevier Ltd.. All rights reserved.

Oxytocin and Social Adaptation: Insights from Neuroimaging Studies of Healthy and Clinical Populations.

PubMed

Ma, Yina; Shamay-Tsoory, Simone; Han, Shihui; Zink, Caroline F

2016-02-01

Adaptation to the social environment is critical for human survival. The neuropeptide oxytocin (OT), implicated in social cognition and emotions pivotal to sociality and well-being, is a promising pharmacological target for social and emotional dysfunction. We suggest here that the multifaceted role of OT in socio-affective processes improves the capability for social adaptation. We review OT effects on socio-affective processes, with a focus on OT-neuroimaging studies, to elucidate neuropsychological mechanisms through which OT promotes social adaptation. We also review OT-neuroimaging studies of individuals with social deficits and suggest that OT ameliorates impaired social adaptation by normalizing hyper- or hypo-brain activity. The social adaption model (SAM) provides an integrative understanding of discrepant OT effects and the modulations of OT action by personal milieu and context. Copyright © 2015 Elsevier Ltd. All rights reserved.

Defective cerebellar control of cortical plasticity in writer’s cramp

PubMed Central

Hubsch, Cecile; Roze, Emmanuel; Popa, Traian; Russo, Margherita; Balachandran, Ammu; Pradeep, Salini; Mueller, Florian; Brochard, Vanessa; Quartarone, Angelo; Degos, Bertrand; Vidailhet, Marie; Kishore, Asha

2013-01-01

A large body of evidence points to a role of basal ganglia dysfunction in the pathophysiology of dystonia, but recent studies indicate that cerebellar dysfunction may also be involved. The cerebellum influences sensorimotor adaptation by modulating sensorimotor plasticity of the primary motor cortex. Motor cortex sensorimotor plasticity is maladaptive in patients with writer’s cramp. Here we examined whether putative cerebellar dysfunction in dystonia is linked to these patients’ maladaptive plasticity. To that end we compared the performances of patients and healthy control subjects in a reaching task involving a visuomotor conflict generated by imposing a random deviation (−40° to 40°) on the direction of movement of the mouse/cursor. Such a task is known to involve the cerebellum. We also compared, between patients and healthy control subjects, how the cerebellum modulates the extent and duration of an ongoing sensorimotor plasticity in the motor cortex. The cerebellar cortex was excited or inhibited by means of repeated transcranial magnetic stimulation before artificial sensorimotor plasticity was induced in the motor cortex by paired associative stimulation. Patients with writer’s cramp were slower than the healthy control subjects to reach the target and, after having repeatedly adapted their trajectories to the deviations, they were less efficient than the healthy control subjects to perform reaching movement without imposed deviation. It was interpreted as impaired washing-out abilities. In healthy subjects, cerebellar cortex excitation prevented the paired associative stimulation to induce a sensorimotor plasticity in the primary motor cortex, whereas cerebellar cortex inhibition led the paired associative stimulation to be more efficient in inducing the plasticity. In patients with writer’s cramp, cerebellar cortex excitation and inhibition were both ineffective in modulating sensorimotor plasticity. In patients with writer’s cramp, but not in healthy subjects, behavioural parameters reflecting their capacity for adapting to the rotation and for washing-out of an earlier adaptation predicted the efficacy of inhibitory cerebellar conditioning to influence sensorimotor plasticity: the better the online adaptation, the smaller the influence of cerebellar inhibitory stimulation on motor cortex plasticity. Altered cerebellar encoding of incoming afferent volleys may result in decoupling the motor component from the afferent information flow, and also in maladjusted sensorimotor calibration. The loss of cerebellar control over sensorimotor plasticity might also lead to building up an incorrect motor program to specific adaptation tasks such as writing. PMID:23801734

The Paradox of Mitochondrial Dysfunction and Extended Longevity

PubMed Central

Munkácsy, Erin; Rea, Shane L.

2014-01-01

Mitochondria play numerous, essential roles in the life of eukaryotes. Disruption of mitochondrial function in humans is often pathological or even lethal. Surprisingly, in some organisms mitochondrial dysfunction can result in life extension. This paradox has been studied most extensively in the long-lived Mit mutants of the nematode Caenorhabditis elegans. In this review, we explore the major responses that are activated following mitochondrial dysfunction in these animals and how these responses potentially act to extend their life. We focus our attention on five broad areas of current research – reactive oxygen species signaling, the mitochondrial unfolded protein response, autophagy, metabolic adaptation, and the roles played by various transcription factors. Lastly, we also examine why disruption of complexes I and II differ in their ability to induce the Mit phenotype and extend lifespan. PMID:24699406

Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction

PubMed Central

Bavli, Danny; Prill, Sebastian; Ezra, Elishai; Levy, Gahl; Cohen, Merav; Vinken, Mathieu; Vanfleteren, Jan; Jaeger, Magnus; Nahmias, Yaakov

2016-01-01

Microfluidic organ-on-a-chip technology aims to replace animal toxicity testing, but thus far has demonstrated few advantages over traditional methods. Mitochondrial dysfunction plays a critical role in the development of chemical and pharmaceutical toxicity, as well as pluripotency and disease processes. However, current methods to evaluate mitochondrial activity still rely on end-point assays, resulting in limited kinetic and prognostic information. Here, we present a liver-on-chip device capable of maintaining human tissue for over a month in vitro under physiological conditions. Mitochondrial respiration was monitored in real time using two-frequency phase modulation of tissue-embedded phosphorescent microprobes. A computer-controlled microfluidic switchboard allowed contiguous electrochemical measurements of glucose and lactate, providing real-time analysis of minute shifts from oxidative phosphorylation to anaerobic glycolysis, an early indication of mitochondrial stress. We quantify the dynamics of cellular adaptation to mitochondrial damage and the resulting redistribution of ATP production during rotenone-induced mitochondrial dysfunction and troglitazone (Rezulin)-induced mitochondrial stress. We show troglitazone shifts metabolic fluxes at concentrations previously regarded as safe, suggesting a mechanism for its observed idiosyncratic effect. Our microfluidic platform reveals the dynamics and strategies of cellular adaptation to mitochondrial damage, a unique advantage of organ-on-chip technology. PMID:27044092

Renal Hypoxia and Dysoxia After Reperfusion of the Ischemic Kidney

PubMed Central

Legrand, Matthieu; Mik, Egbert G; Johannes, Tanja; Payen, Didier; Ince, Can

2008-01-01

Ischemia is the most common cause of acute renal failure. Ischemic-induced renal tissue hypoxia is thought to be a major component in the development of acute renal failure in promoting the initial tubular damage. Renal oxygenation originates from a balance between oxygen supply and consumption. Recent investigations have provided new insights into alterations in oxygenation pathways in the ischemic kidney. These findings have identified a central role of microvascular dysfunction related to an imbalance between vasoconstrictors and vasodilators, endothelial damage and endothelium–leukocyte interactions, leading to decreased renal oxygen supply. Reduced microcirculatory oxygen supply may be associated with altered cellular oxygen consumption (dysoxia), because of mitochondrial dysfunction and activity of alternative oxygen-consuming pathways. Alterations in oxygen utilization and/or supply might therefore contribute to the occurrence of organ dysfunction. This view places oxygen pathways’ alterations as a potential central player in the pathogenesis of acute kidney injury. Both in regulation of oxygen supply and consumption, nitric oxide seems to play a pivotal role. Furthermore, recent studies suggest that, following acute ischemic renal injury, persistent tissue hypoxia contributes to the development of chronic renal dysfunction. Adaptative mechanisms to renal hypoxia may be ineffective in more severe cases and lead to the development of chronic renal failure following ischemia-reperfusion. This paper is aimed at reviewing the current insights into oxygen transport pathways, from oxygen supply to oxygen consumption in the kidney and from the adaptation mechanisms to renal hypoxia. Their role in the development of ischemia-induced renal damage and ischemic acute renal failure are discussed. PMID:18488066

Dominant Species in Subtropical Forests Could Decrease Photosynthetic N Allocation to Carboxylation and Bioenergetics and Enhance Leaf Construction Costs during Forest Succession

PubMed Central

Xiao, Yihua; Liu, Shirong; Tong, Fuchun; Chen, Bufeng; Kuang, Yuanwen

2018-01-01

It is important to understand how eco-physiological characteristics shift in forests when elucidating the mechanisms underlying species replacement and the process of succession and stabilization. In this study, the dominant species at three typical successional stages (early-, mid-, and late-succession) in the subtropical forests of China were selected. At each stage, we compared the leaf construction costs (CC), payback time (PBT), leaf area based N content (NA), maximum CO2 assimilation rate (Pmax), specific leaf area (SLA), photosynthetic nitrogen use efficiency (PNUE), and leaf N allocated to carboxylation (NC), and to bioenergetics (NB). The relationships between these leaf functional traits were also determined. The results showed that the early-succession forest is characterized with significantly lower leaf CC, PBT, NA, but higher Pmax, SLA, PNUE, NC, and NB, in relation to the late-succession forest. From the early- to the late-succession forests, the relationship between Pmax and leaf CC strengthened, whereas the relationships between NB, NC, PNUE, and leaf CC weakened. Thus, the dominant species are able to decrease the allocation of the photosynthetic N fraction to carboxylation and bioenergetics during forest succession. The shift in these leaf functional traits and their linkages might represent a fundamental physiological mechanism that occurs during forest succession and stabilization. PMID:29472939

Dominant Species in Subtropical Forests Could Decrease Photosynthetic N Allocation to Carboxylation and Bioenergetics and Enhance Leaf Construction Costs during Forest Succession.

PubMed

Xiao, Yihua; Liu, Shirong; Tong, Fuchun; Chen, Bufeng; Kuang, Yuanwen

2018-01-01

It is important to understand how eco-physiological characteristics shift in forests when elucidating the mechanisms underlying species replacement and the process of succession and stabilization. In this study, the dominant species at three typical successional stages (early-, mid-, and late-succession) in the subtropical forests of China were selected. At each stage, we compared the leaf construction costs (CC), payback time (PBT), leaf area based N content ( N A ), maximum CO 2 assimilation rate ( P max ), specific leaf area (SLA), photosynthetic nitrogen use efficiency (PNUE), and leaf N allocated to carboxylation ( N C ), and to bioenergetics ( N B ). The relationships between these leaf functional traits were also determined. The results showed that the early-succession forest is characterized with significantly lower leaf CC, PBT, N A , but higher P max , SLA, PNUE, N C , and N B , in relation to the late-succession forest. From the early- to the late-succession forests, the relationship between P max and leaf CC strengthened, whereas the relationships between N B , N C , PNUE, and leaf CC weakened. Thus, the dominant species are able to decrease the allocation of the photosynthetic N fraction to carboxylation and bioenergetics during forest succession. The shift in these leaf functional traits and their linkages might represent a fundamental physiological mechanism that occurs during forest succession and stabilization.

Effects of Recent Concussion on Brain Bioenergetics: A Phosphorus-31 Magnetic Resonance Spectroscopy Study.

PubMed

Sikoglu, Elif M; Liso Navarro, Ana A; Czerniak, Suzanne M; McCafferty, Joseph; Eisenstock, Jordan; Stevenson, J Herbert; King, Jean A; Moore, Constance M

2015-12-01

Although clinical evaluations and neurocognitive assessments are commonly used to evaluate the extent of and recovery from concussion, brain bioenergetics could provide a more quantitative marker. The neurometabolic response to a concussion is thought to increase neuronal energy consumption and thus the demand for nucleoside triphosphate (NTP). We investigated the possible disruption in high-energy metabolism within the prefrontal cortex of college athletes who had either had a concussion within the past 6 months (n=14) or had never had a concussion (n=13). We hypothesized that concussed athletes would have imbalanced brain bioenergetics resulting from increased NTP consumption, and these biochemical changes would correspond to impaired cognitive abilities. We used phosphorus-31 magnetic resonance spectroscopy to quantify high-energy phosphates. We performed the neuroimaging in conjunction with neurocognitive assessments targeting prefrontal cortex-mediated tasks. Our results revealed significantly lower γ-NTP levels in the athletes after concussion. Although the concussed and non-concussed participants performed similarly in neurocognitive assessments, lower levels of γ-NTP were associated with worse scores on neurocognitive tasks. Our results support the concept of increased energy demand in the prefrontal cortex of a concussed brain, and we found that while neurocognitive assessments appear normal, brain energetics may be abnormal. A longitudinal study could help establish brain NTP levels as a biomarker to aid in diagnosis and to assess recovery in concussed patients.

Cannabidiol attenuates OGD/R-induced damage by enhancing mitochondrial bioenergetics and modulating glucose metabolism via pentose-phosphate pathway in hippocampal neurons.

PubMed

Sun, Shanshan; Hu, Fangyuan; Wu, Jihong; Zhang, Shenghai

2017-04-01

Deficient bioenergetics and diminished redox conservation have been implicated in the development of cerebral ischemia/reperfusion injury. In this study, the mechanisms underlying the neuroprotective effects of cannabidiol (CBD), a nonpsychotropic compound derived from Cannabis sativa with FDA-approved antiepilepsy properties, were studied in vitro using an oxygen-glucose-deprivation/reperfusion (OGD/R) model in a mouse hippocampal neuronal cell line. CBD supplementation during reperfusion rescued OGD/R-induced cell death, attenuated intracellular ROS generation and lipid peroxidation, and simultaneously reversed the abnormal changes in antioxidant biomarkers. Using the Seahorse XF e 24 Extracellular Flux Analyzer, we found that CBD significantly improved basal respiration, ATP-linked oxygen consumption rate, and the spare respiratory capacity, and augmented glucose consumption in OGD/R-injured neurons. The activation of glucose 6-phosphate dehydrogenase and the preservation of the NADPH/NADP + ratio implies that the pentose-phosphate pathway is stimulated by CBD, thus protecting hippocampal neurons from OGD/R injury. This study is the first to document the neuroprotective effects of CBD against OGD/R insult, which depend in part on attenuating oxidative stress, enhancing mitochondrial bioenergetics, and modulating glucose metabolism via the pentose-phosphate pathway, thus preserving both energy and the redox balance. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Cellular bioenergetics is impaired in patients with chronic fatigue syndrome.

PubMed

Tomas, Cara; Brown, Audrey; Strassheim, Victoria; Elson, Joanna L; Newton, Julia; Manning, Philip

2017-01-01

Chronic fatigue syndrome (CFS) is a highly debilitating disease of unknown aetiology. Abnormalities in bioenergetic function have been cited as one possible cause for CFS. Preliminary studies were performed to investigate cellular bioenergetic abnormalities in CFS patients. A series of assays were conducted using peripheral blood mononuclear cells (PBMCs) from CFS patients and healthy controls. These experiments investigated cellular patterns in oxidative phosphorylation (OXPHOS) and glycolysis. Results showed consistently lower measures of OXPHOS parameters in PBMCs taken from CFS patients compared with healthy controls. Seven key parameters of OXPHOS were calculated: basal respiration, ATP production, proton leak, maximal respiration, reserve capacity, non-mitochondrial respiration, and coupling efficiency. While many of the parameters differed between the CFS and control cohorts, maximal respiration was determined to be the key parameter in mitochondrial function to differ between CFS and control PBMCs due to the consistency of its impairment in CFS patients found throughout the study (p≤0.003). The lower maximal respiration in CFS PBMCs suggests that when the cells experience physiological stress they are less able to elevate their respiration rate to compensate for the increase in stress and are unable to fulfil cellular energy demands. The metabolic differences discovered highlight the inability of CFS patient PBMCs to fulfil cellular energetic demands both under basal conditions and when mitochondria are stressed during periods of high metabolic demand.

Lung toxicities of core–shell nanoparticles composed of carbon, cobalt, and silica

PubMed Central

Al Samri, Mohammed T; Silva, Rafael; Almarzooqi, Saeeda; Albawardi, Alia; Othman, Aws Rashad Diab; Al Hanjeri, Ruqayya SMS; Al Dawaar, Shaikha KM; Tariq, Saeed; Souid, Abdul-Kader; Asefa, Tewodros

2013-01-01

We present here comparative assessments of murine lung toxicity (biocompatibility) after in vitro and in vivo exposures to carbon (C–SiO2-etched), carbon–silica (C–SiO2), carbon–cobalt–silica (C–Co–SiO2), and carbon–cobalt oxide–silica (C–Co3O4–SiO2) nanoparticles. These nanoparticles have potential applications in clinical medicine and bioimaging, and thus their possible adverse events require thorough investigation. The primary aim of this work was to explore whether the nanoparticles are biocompatible with pneumatocyte bioenergetics (cellular respiration and adenosine triphosphate content). Other objectives included assessments of caspase activity, lung structure, and cellular organelles. Pneumatocyte bioenergetics of murine lung remained preserved after treatment with C–SiO2-etched or C–SiO2 nanoparticles. C–SiO2-etched nanoparticles, however, increased caspase activity and altered lung structure more than C–SiO2 did. Consistent with the known mitochondrial toxicity of cobalt, both C–Co–SiO2 and C–Co3O4–SiO2 impaired lung tissue bioenergetics. C–Co–SiO2, however, increased caspase activity and altered lung structure more than C–Co3O4–SiO2. The results indicate that silica shell is essential for biocompatibility. Furthermore, cobalt oxide is the preferred phase over the zerovalent Co(0) phase to impart biocompatibility to cobalt-based nanoparticles. PMID:23658487

Redox biology and the interface between bioenergetics, autophagy and circadian control of metabolism.

PubMed

Wende, Adam R; Young, Martin E; Chatham, John; Zhang, Jianhua; Rajasekaran, Namakkal S; Darley-Usmar, Victor M

2016-11-01

Understanding molecular mechanisms that underlie the recent emergence of metabolic diseases such as diabetes and heart failure has revealed the need for a multi-disciplinary research integrating the key metabolic pathways which change the susceptibility to environmental or pathologic stress. At the physiological level these include the circadian control of metabolism which aligns metabolism with temporal demand. The mitochondria play an important role in integrating the redox signals and metabolic flux in response to the changing activities associated with chronobiology, exercise and diet. At the molecular level this involves dynamic post-translational modifications regulating transcription, metabolism and autophagy. In this review we will discuss different examples of mechanisms which link these processes together. An important pathway capable of linking signaling to metabolism is the post-translational modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc). This is a nutrient regulated protein modification that plays an important role in impaired cellular stress responses. Circadian clocks have also emerged as critical regulators of numerous cardiometabolic processes, including glucose/lipid homeostasis, hormone secretion, redox status and cardiovascular function. Central to these pathways are the response of autophagy, bioenergetics to oxidative stress, regulated by Keap1/Nrf2 and mechanisms of metabolic control. The extension of these ideas to the emerging concept of bioenergetic health will be discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis.

PubMed

Wilkins, Heather M; Harris, Janna L; Carl, Steven M; E, Lezi; Lu, Jianghua; Eva Selfridge, J; Roy, Nairita; Hutfles, Lewis; Koppel, Scott; Morris, Jill; Burns, Jeffrey M; Michaelis, Mary L; Michaelis, Elias K; Brooks, William M; Swerdlow, Russell H

2014-12-15

Brain bioenergetic function declines in some neurodegenerative diseases, this may influence other pathologies and administering bioenergetic intermediates could have therapeutic value. To test how one intermediate, oxaloacetate (OAA) affects brain bioenergetics, insulin signaling, inflammation and neurogenesis, we administered intraperitoneal OAA, 1-2 g/kg once per day for 1-2 weeks, to C57Bl/6 mice. OAA altered levels, distributions or post-translational modifications of mRNA and proteins (proliferator-activated receptor-gamma coactivator 1α, PGC1 related co-activator, nuclear respiratory factor 1, transcription factor A of the mitochondria, cytochrome oxidase subunit 4 isoform 1, cAMP-response element binding, p38 MAPK and adenosine monophosphate-activated protein kinase) in ways that should promote mitochondrial biogenesis. OAA increased Akt, mammalian target of rapamycin and P70S6K phosphorylation. OAA lowered nuclear factor κB nucleus-to-cytoplasm ratios and CCL11 mRNA. Hippocampal vascular endothelial growth factor mRNA, doublecortin mRNA, doublecortin protein, doublecortin-positive neuron counts and neurite length increased in OAA-treated mice. (1)H-MRS showed OAA increased brain lactate, GABA and glutathione thereby demonstrating metabolic changes are detectable in vivo. In mice, OAA promotes brain mitochondrial biogenesis, activates the insulin signaling pathway, reduces neuroinflammation and activates hippocampal neurogenesis. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Bioenergetics and the role of soluble cytochromes C for alkaline adaptation in gram-negative alkaliphilic Pseudomonas.

PubMed

Matsuno, T; Yumoto, I

2015-01-01

Very few studies have been conducted on alkaline adaptation of Gram-negative alkaliphiles. The reversed difference of H(+) concentration across the membrane will make energy production considerably difficult for Gram-negative as well as Gram-positive bacteria. Cells of the alkaliphilic Gram-negative bacterium Pseudomonas alcaliphila AL15-21(T) grown at pH 10 under low-aeration intensity have a soluble cytochrome c content that is 3.6-fold higher than that of the cells grown at pH 7 under high-aeration intensity. Cytochrome c-552 content was higher (64% in all soluble cytochromes c) than those of cytochrome c-554 and cytochrome c-551. In the cytochrome c-552-dificient mutant grown at pH 10 under low-aeration intensity showed a marked decrease in μ max⁡ [h(-1)] (40%) and maximum cell turbidity (25%) relative to those of the wild type. Considering the high electron-retaining abilities of the three soluble cytochromes c, the deteriorations in the growth of the cytochrome c-552-deficient mutant could be caused by the soluble cytochromes c acting as electron storages in the periplasmic space of the bacterium. These electron-retaining cytochromes c may play a role as electron and H(+) condenser, which facilitate terminal oxidation at high pH under air-limited conditions, which is difficult to respire owing to less oxygen and less H(+).

Bioenergetics and the Role of Soluble Cytochromes c for Alkaline Adaptation in Gram-Negative Alkaliphilic Pseudomonas

PubMed Central

Matsuno, T.; Yumoto, I.

2015-01-01

Very few studies have been conducted on alkaline adaptation of Gram-negative alkaliphiles. The reversed difference of H+ concentration across the membrane will make energy production considerably difficult for Gram-negative as well as Gram-positive bacteria. Cells of the alkaliphilic Gram-negative bacterium Pseudomonas alcaliphila AL15-21T grown at pH 10 under low-aeration intensity have a soluble cytochrome c content that is 3.6-fold higher than that of the cells grown at pH 7 under high-aeration intensity. Cytochrome c-552 content was higher (64% in all soluble cytochromes c) than those of cytochrome c-554 and cytochrome c-551. In the cytochrome c-552-dificient mutant grown at pH 10 under low-aeration intensity showed a marked decrease in μ max⁡ [h−1] (40%) and maximum cell turbidity (25%) relative to those of the wild type. Considering the high electron-retaining abilities of the three soluble cytochromes c, the deteriorations in the growth of the cytochrome c-552-deficient mutant could be caused by the soluble cytochromes c acting as electron storages in the periplasmic space of the bacterium. These electron-retaining cytochromes c may play a role as electron and H+ condenser, which facilitate terminal oxidation at high pH under air-limited conditions, which is difficult to respire owing to less oxygen and less H+. PMID:25705691

Single Fiber Electromyographic Jitter to Detect Acute Changes in Neuromuscular Function in Young and Adult Rats

EPA Science Inventory

Introduction: Exposure to irreversible cholinesterase (ChE)-inhibiting compounds, such as organophosphates may produce neuromuscular dysfunction. However, less is known about changes in neuromuscular transmission after treatment with reversible ChE-inhibitors. These studies adapt...

The Microbiology of Subsurface, Salt-Based Nuclear Waste Repositories: Using Microbial Ecology, Bioenergetics, and Projected Conditions to Help Predict Microbial Effects on Repository Performance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Swanson, Juliet S.; Cherkouk, Andrea; Arnold, Thuro

This report summarizes the potential role of microorganisms in salt-based nuclear waste repositories using available information on the microbial ecology of hypersaline environments, the bioenergetics of survival under high ionic strength conditions, and “repository microbiology” related studies. In areas where microbial activity is in question, there may be a need to shift the research focus toward feasibility studies rather than studies that generate actual input for performance assessments. In areas where activity is not necessary to affect performance (e.g., biocolloid transport), repository-relevant data should be generated. Both approaches will lend a realistic perspective to a safety case/performance scenario that willmore » most likely underscore the conservative value of that case.« less

Organ-specific effects of low-dose zinc pre-exposure on high-dose zinc induced mitochondrial dysfunction in large yellow croaker Pseudosciaena crocea.

PubMed

Zheng, Jia-Lang; Yuan, Shuang-Shuang; Shen, Bin; Wu, Chang-Wen

2017-04-01

The study was carried out to evaluate the effects of low-dose zinc (Zn) pre-exposure on survival rate, new Zn accumulation, and mitochondrial bioenergetics in the liver and spleen of large yellow croaker exposed to high-dose Zn. To the end, fish were pre-exposed to 0 and 2 mg L -1 Zn for 48 h and post-exposed to 0 and 12 mg L -1 Zn for 48 h. Twelve milligrams Zn per liter exposure alone reduced survival rate, but the effect did not appear in the 2 mg L -1 Zn pre-exposure groups. Two milligrams per liter Zn pre-exposure also ameliorated 12 mg Zn L -1 induced new Zn accumulation, reactive oxygen species (ROS) levels, and mitochondrial swelling in the liver. However, these effects did not appear in the spleen. In the liver, 2 mg L -1 Zn pre-exposure apparently relieved 12 mg L -1 Zn induced down-regulation of activities of ATP synthase (F-ATPase), succinate dehydrogenase (SDH), and malate dehydrogenase (MDH). The mRNA levels of these genes remained relatively stable in fish exposed to 12 mg L -1 Zn alone, but increased in fish exposed to 12 mg L -1 Zn with 2 mg L -1 Zn pre-treatment. In the spleen, 2 mg Zn L -1 pre-exposure did not mitigate the down-regulation of mRNA levels of genes and activities of relative enzymes induced by 12 mg L -1 Zn. In conclusion, our study demonstrated low-dose zinc pre-exposure ameliorated high-dose zinc induced mitochondrial dysfunction in the liver but not in the spleen of large yellow croaker, indicating an organ-specific effect.

Locomotor Dysfunction after Long-Duration Space Flight and Development of Countermeasures to Facilitate Faster Recovery

NASA Technical Reports Server (NTRS)

Mulavara, A. P.; Wood, S. J.; Cohen, H. S.; Bloomberg, J. J.

2012-01-01

Exposure to the microgravity conditions of space flight induces adaptive modification in sensorimotor function allowing astronauts to operate in this unique environment. This adaptive state, however, is inappropriate for a 1-g environment. Consequently astronauts must spend time readapting to Earth s gravity following their return to Earth. During this readaptation period, alterations in sensorimotor function cause various disturbances in astronaut gait during postflight walking. They often rely more on vision for postural and gait stability and many report the need for greater cognitive supervision of motor actions that previous to space flight were fully automated. Over the last several years our laboratory has investigated postflight astronaut locomotion with the aim of better understanding how adaptive changes in underlying sensorimotor mechanisms contribute to postflight gait dysfunction. Exposure to the microgravity conditions of space flight induces adaptive modification in the control of vestibularly-mediated reflexive head movement during locomotion after space flight. Furthermore, during motor learning, adaptive transitions are composed of two main mechanisms: strategic and plastic. Strategic mechanisms represent immediate and transitory modifications in control to deal with changes in the prevailing environment that, if prolonged, induce plastic mechanisms designed to automate new behavioral responses. The goal of the present study was to examine the contributions of sensorimotor subsystems such as the vestibular and body load sensing (BLS) somatosensory influences on head movement control during locomotion after long-duration space flight. Further we present data on the two motor learning processes during readaptation of locomotor function after long-duration space flight.

Magnetic Resonance Characterization of Cardiac Adaptation and Myocardial Fibrosis in Pulmonary Hypertension Secondary to Systemic-To-Pulmonary Shunt.

PubMed

Pereda, Daniel; García-Lunar, Inés; Sierra, Federico; Sánchez-Quintana, Damián; Santiago, Evelyn; Ballesteros, Constanza; Encalada, Juan F; Sánchez-González, Javier; Fuster, Valentín; Ibáñez, Borja; García-Álvarez, Ana

2016-09-01

Pulmonary hypertension (PH) and right ventricular (RV) dysfunction are strong predictors of morbidity and mortality among patients with congenital heart disease. Early detection of RV involvement may be useful in the management of these patients. We aimed to assess progressive cardiac adaptation and quantify myocardial extracellular volume in an experimental porcine model of PH because of aorto-pulmonary shunt using cardiac magnetic resonance (CMR). To characterize serial cardiac adaptation, 12 pigs (aorto-pulmonary shunt [n=6] or sham operation [n=6]) were evaluated monthly with right heart catheterization, CMR, and computed tomography during 4 months, followed by pathology analysis. Extracellular volume by CMR in different myocardial regions was studied in 20 animals (aorto-pulmonary shunt [n=10] or sham operation [n=10]) 3 months after the intervention. All shunted animals developed PH. CMR evidenced progressive RV hypertrophy and dysfunction secondary to increased afterload and left ventricular dilatation secondary to volume overload. Shunt flow by CMR strongly correlated with PH severity, left ventricular end-diastolic pressure, and left ventricular dilatation. T1-mapping sequences demonstrated increased extracellular volume at the RV insertion points, the interventricular septum, and the left ventricular lateral wall, reproducing the pattern of fibrosis found on pathology. Extracellular volume at the RV insertion points strongly correlated with pulmonary hemodynamics and RV dysfunction. Prolonged systemic-to-pulmonary shunting in growing piglets induces PH with biventricular remodeling and myocardial fibrosis that can be detected and monitored using CMR. These results may be useful for the diagnosis and management of congenital heart disease patients with pulmonary overcirculation. © 2016 American Heart Association, Inc.

Which thoughts can kill a boxer? naive theories about cognitive and emotional antecedents of suicide.

PubMed

Spörrle, Matthias; Försterling, Friedrich

2007-12-01

We investigated naive theories regarding the association among beliefs, emotions and behaviours to test Rational Emotive Behaviour Therapy's (REBT) assumption that rational cognitions and adaptive emotions lead to functional behaviours whereas irrational cognitions and maladaptive emotions trigger dysfunctional reactions. We applied an experimental between-subjects design. Participants read newspaper articles about the defeat of a boxer. In one condition, the authentic article informed participants that he committed suicide and in the other, a fictitious article about the same defeat described the athlete as successfully continuing his career. Different question formats were employed to assess participants' assumptions about the stimulus person's defeat-related cognitions and emotions: rating scales, sentence completion and free responses. Participants assumed significantly more irrational beliefs (e.g. I absolutely have to win) on the side of the boxer in the suicide scenario than in the non-suicide version. This finding was obtained by directive and non-directive assessment methods. Additionally, participants expected the suicidal stimulus person to be experiencing maladaptive emotions (e.g. depression, guilt) whereas a successful resumption of his career lead to expectations of adaptive affects (e.g. sadness, concern). Ratings of the functionality revealed that sadness, fear, annoyance and concern were expected to be more functional than depression, anxiety, rage and guilt. The results show that naive psychological theories about the antecedents of dysfunctional behaviour are in accordance with theoretical assumptions of REBT: Irrational beliefs are viewed to be connected with maladaptive emotions and to result in dysfunctional behaviour, and adaptive emotions are thought to be of higher functional value than their maladaptive counterparts. The use of different question formats and a between-subject design excluded that results are due to methodological artifacts or contrast effects.

Normal movement selectivity in autism.

PubMed

Dinstein, Ilan; Thomas, Cibu; Humphreys, Kate; Minshew, Nancy; Behrmann, Marlene; Heeger, David J

2010-05-13

It has been proposed that individuals with autism have difficulties understanding the goals and intentions of others because of a fundamental dysfunction in the mirror neuron system. Here, however, we show that individuals with autism exhibited not only normal fMRI responses in mirror system areas during observation and execution of hand movements but also exhibited typical movement-selective adaptation (repetition suppression) when observing or executing the same movement repeatedly. Movement selectivity is a defining characteristic of neurons involved in movement perception, including mirror neurons, and, as such, these findings argue against a mirror system dysfunction in autism. Copyright 2010 Elsevier Inc. All rights reserved.

Assessment of the psychosocial and mental health needs, dysfunction and coping mechanisms of violence affected populations in Bireuen Aceh. A qualitative study.

PubMed

Poudyal, Bhava; Bass, Judith; Subyantoro, Theodora; Jonathan, Abraham; Erni, Theresia; Bolton, Paul

2009-01-01

Qualitative research is important due to the shortage of literature in understanding cultural influences on psychosocial and mental health syndromes and their presentation, especially in developing countries. This qualitative study aims to investigate the psychosocial and mental health needs of populations in Aceh, Indonesia affected by over 30 years of conflict, their dysfunction, and their positive coping mechanisms. Results from this qualitative assessment indicate the presence of depression, anxiety and somatic symptoms. The data provide local terminology and ways in which the local population describes their own distress, which is an important addition to the understanding of the mental health consequences of this conflict. The data has been used to develop appropriate intervention strategies and adapt and validate assessment tools to measure psychological distress, dysfunction and coping mechanisms.

Custodial Grandmothers' Psychological Distress, Dysfunctional Parenting, and Grandchildren's Adjustment

ERIC Educational Resources Information Center

Smith, Gregory C.; Palmieri, Patrick A.; Hancock, Gregory R.; Richardson, Rhonda A.

2008-01-01

An adaptation of the Family Stress Model (FSM) with hypothesized linkages between family contextual factors, custodial grandmothers' psychological distress, parenting practices, and grandchildren's adjustment was tested with structural equation modeling. Interview data from 733 custodial grandmothers of grandchildren between ages 4-17 revealed…

ACUTE PHARMACOLOGICAL INHIBITION OF CHOLINESTERASE RESULTS IN MINIMAL NEUROMUSCULAR JITTER CHANGES.

EPA Science Inventory

Concern over the lack of available endpoints to assess peripheral nervous system dysfunction after pesticide exposure has led to the search for new laboratory models. Recently our lab adapted the in vivo clinical practice of stimulation single fiber electromyography (SFEMG) for u...

Use of Single Fiber Electromyographic Jitter to Detect Acute Changes in Neuromuscular Function in Young and Adult Rats

EPA Science Inventory

INTRODUCTION: Exposure to irreversible cholinesterase (ChE)-inhibiting compounds, such as organophosphates may produce neuromuscular dysfunction. However, less is known about changes in neuromuscular transmission after treatment with reversible ChE-inhibitors. These studies adapt...

Hypoglycaemia and hypoxic-ischaemic encephalopathy.

PubMed

Boardman, James P; Hawdon, Jane M

2015-04-01

The transition from fetal to neonatal life requires metabolic adaptation to ensure that energy supply to vital organs and systems is maintained after separation from the placental circulation. Under normal conditions, this is achieved through the mobilization and use of alternative cerebral fuels (fatty acids, ketone bodies, and lactate) when blood glucose concentration falls. Severe hypoxia-ischaemia is associated with impaired metabolic adaptation, and animal and human data suggest that levels of hypoglycaemia that are tolerated under normal conditions can be harmful in association with hypoxia-ischaemia. The optimal target blood glucose level for ensuring adequate energy provision in hypoxic-ischaemic encephalopathy (HIE) remains unknown. However, recent data support guidance to maintain a blood glucose concentration of 2.5 mmol/L or more in neonates with signs of acute neurological dysfunction, which includes those with HIE, and this is higher than the accepted threshold of 2 mmol/L in infants without signs of neurological dysfunction or hyperinsulinism. © The Authors. Journal compilation © 2015 Mac Keith Press.

T cell deficiency leads to cognitive dysfunction: Implications for therapeutic vaccination for schizophrenia and other psychiatric conditions

PubMed Central

Kipnis, Jonathan; Cohen, Hagit; Cardon, Michal; Ziv, Yaniv; Schwartz, Michal

2004-01-01

The effects of the adaptive immune system on the cognitive performance and abnormal behaviors seen in mental disorders such as schizophrenia have never been documented. Here, we show that mice deprived of mature T cells manifested cognitive deficits and behavioral abnormalities, which were remediable by T cell restoration. T cell-based vaccination, using glatiramer acetate (copolymer-1, a weak agonist of numerous self-reactive T cells), can overcome the behavioral and cognitive abnormalities that accompany neurotransmitter imbalance induced by (+)dizocilpine maleate (MK-801) or amphetamine. The results, by suggesting that peripheral T cell deficit can lead to cognitive and behavioral impairment, highlight the importance of properly functioning adaptive immunity in the maintenance of mental activity and in coping with conditions leading to cognitive deficits. These findings point to critical factors likely to contribute to age- and AIDS-related dementias and might herald the development of a therapeutic vaccination for fighting off cognitive dysfunction and psychiatric conditions. PMID:15141078

Physiologic Dysfunction Scores and Cognitive Function Test Performance in United States Adults

PubMed Central

Kobrosly, Roni W; Seplaki, Christopher L; Jones, Courtney M; van Wijngaarden, Edwin

2013-01-01

Objective To investigate the relationship between a measure of cumulative physiologic dysfunction and specific domains of cognitive function. Methods We examined a summary score measuring physiological dysfunction, a multisystem measure of the body’s ability to effectively adapt to physical and psychological demands, in relation to cognitive function deficits in a population of 4511 adults aged 20 to 59 who participated in the third National Health and Nutrition Examination Survey (1988–1994). Measures of cognitive function comprised three domains: working memory, visuomotor speed, and perceptual-motor speed. ‘Physiologic dysfunction’ scores summarizing measures of cardiovascular, immunologic, kidney, and liver function were explored. We used multiple linear regression models to estimate associations between cognitive function measures and physiological dysfunction scores, adjusting for socioeconomic factors, test conditions, and self-reported health factors. Results We noted a dose-response relationship between physiologic dysfunction and working memory (coefficient = 0.207, 95% CI = (0.066, 0.348), p < 0.0001) that persisted after adjustment for all covariates (p = 0.03). We did not observe any significant relationships between dysfunction scores and visuomotor (p = 0.37) or perceptual-motor ability (p = 0.33). Conclusions Our findings suggest that multisystem physiologic dysfunction is associated with working memory. Future longitudinal studies are needed to clarify the underlying mechanisms and explore the persistency of this association into later life. We suggest that such studies should incorporate physiologic data, neuroendocrine parameters, and a wide range of specific cognitive domains. PMID:22155941

Immune dysfunction in cirrhosis.

PubMed

Sipeki, Nora; Antal-Szalmas, Peter; Lakatos, Peter L; Papp, Maria

2014-03-14

Innate and adaptive immune dysfunction, also referred to as cirrhosis-associated immune dysfunction syndrome, is a major component of cirrhosis, and plays a pivotal role in the pathogenesis of both the acute and chronic worsening of liver function. During the evolution of the disease, acute decompensation events associated with organ failure(s), so-called acute-on chronic liver failure, and chronic decompensation with progression of liver fibrosis and also development of disease specific complications, comprise distinct clinical entities with different immunopathology mechanisms. Enhanced bacterial translocation associated with systemic endotoxemia and increased occurrence of systemic bacterial infections have substantial impacts on both clinical situations. Acute and chronic exposure to bacteria and/or their products, however, can result in variable clinical consequences. The immune status of patients is not constant during the illness; consequently, alterations of the balance between pro- and anti-inflammatory processes result in very different dynamic courses. In this review we give a detailed overview of acquired immune dysfunction and its consequences for cirrhosis. We demonstrate the substantial influence of inherited innate immune dysfunction on acute and chronic inflammatory processes in cirrhosis caused by the pre-existing acquired immune dysfunction with limited compensatory mechanisms. Moreover, we highlight the current facts and future perspectives of how the assessment of immune dysfunction can assist clinicians in everyday practical decision-making when establishing treatment and care strategies for the patients with end-stage liver disease. Early and efficient recognition of inappropriate performance of the immune system is essential for overcoming complications, delaying progression and reducing mortality.

Immune dysfunction in cirrhosis

PubMed Central

Sipeki, Nora; Antal-Szalmas, Peter; Lakatos, Peter L; Papp, Maria

2014-01-01

Innate and adaptive immune dysfunction, also referred to as cirrhosis-associated immune dysfunction syndrome, is a major component of cirrhosis, and plays a pivotal role in the pathogenesis of both the acute and chronic worsening of liver function. During the evolution of the disease, acute decompensation events associated with organ failure(s), so-called acute-on chronic liver failure, and chronic decompensation with progression of liver fibrosis and also development of disease specific complications, comprise distinct clinical entities with different immunopathology mechanisms. Enhanced bacterial translocation associated with systemic endotoxemia and increased occurrence of systemic bacterial infections have substantial impacts on both clinical situations. Acute and chronic exposure to bacteria and/or their products, however, can result in variable clinical consequences. The immune status of patients is not constant during the illness; consequently, alterations of the balance between pro- and anti-inflammatory processes result in very different dynamic courses. In this review we give a detailed overview of acquired immune dysfunction and its consequences for cirrhosis. We demonstrate the substantial influence of inherited innate immune dysfunction on acute and chronic inflammatory processes in cirrhosis caused by the pre-existing acquired immune dysfunction with limited compensatory mechanisms. Moreover, we highlight the current facts and future perspectives of how the assessment of immune dysfunction can assist clinicians in everyday practical decision-making when establishing treatment and care strategies for the patients with end-stage liver disease. Early and efficient recognition of inappropriate performance of the immune system is essential for overcoming complications, delaying progression and reducing mortality. PMID:24627592

The bioenergetic consequences of invasive-induced food web disruption to Lake Ontario alewives

USGS Publications Warehouse

Stewart, Thomas J.; O'Gorman, Robert; Sprules, W. Gary; Lantry, B.F.

2010-01-01

Alewives Alosa pseudoharengus are the dominant prey fish in Lake Ontario, and their response to ecological change can alter the structure and function of the Lake Ontario food web. Using stochastic population-based bioenergetic models of Lake Ontario alewives for 1987–1991 and 2001–2005, we evaluated changes to alewife production, consumption, and associated bioenergetic ratios after invasive-induced food web disruption. After the disruption, mean biomass of alewives declined from 28.0 to 14.6 g/m2, production declined from 40.8 to 13.6 g·m−2·year−1, and consumption declined from 342.1 to 137.2 g·m−2·year−1, but bootstrapping of error sources suggested that the changes were not statistically significant. Population-based bioenergetic ratios of production to biomass (P/B ratio), total consumption to biomass (Q/B ratio), and production efficiency did not change. Pathways of energy flow measured as prey-group-specific Q/B ratios changed significantly between the two time periods for invasive predatory cladocerans (from 0.6 to 1.3), Mysis diluviana (from 0.4 to 2.5), and other prey (from 0.8 to 0.1), but the observed decline in the zooplankton Q/B ratio (from 10.6 to 5.5) was not significant. Gross production efficiency did not change; values ranged from 8% to 15%. Age-group mean gross conversion efficiency (GCE) declined with age; GCE ranged from 7.5% to 11.0% for yearlings, was approximately 5% for age-2 alewives, and was less than 2% for age-3 and older alewives. The GCE increased significantly between the time periods for yearling alewives. Our analyses support the hypothesis that after 2003, alewives could not sustain their growth while feeding on zooplankton closer to shore. Modeling of observed spatial variation in diet and alternative occupied temperatures demonstrates the potential for reducing consumption by alewives. Our results suggest that Lake Ontario alewives can exploit spatial heterogeneity in resource patches and thermal habitat to partially mitigate the effects of food web disruption. Fish management implications are discussed.

Modeling Late-State Serpentinization on Enceladus and Implications for Methane-Utilizing Microbial Metabolisms

NASA Astrophysics Data System (ADS)

Hart, R.; Cardace, D.

2017-12-01

Modeling investigations of Enceladus and other icy-satellites have included physicochemical properties (Sohl et al., 2010; Glein et al., 2015; Neveu et al., 2015), geophysical prospects of serpentinization (Malamud and Prialnik, 2016; Vance et al., 2016), and aqueous geochemistry across different antifreeze fluid-rock scenarios (Neveu et al., 2017). To more effectively evaluate the habitability of Enceladus, in the context of recent observations (Waite et al., 2017), we model the potential bioenergetic pathways that would be thermodynamically favorable at the interface of hydrothermal water-rock reactions resulting from late stage serpentinization (>90% serpentinized), hypothesized on Enceladus. Building on previous geochemical model outputs of Enceladus (Neveu et al., 2017), and bioenergetic modeling (as in Amend and Shock, 2001; Cardace et al., 2015), we present a model of late stage serpentinization possible at the water-rock interface of Enceladus, and report changing activities of chemical species related to methane utilization by microbes over the course of serpentinization using the Geochemist's Workbench REACT code [modified Extended Debye-Hückel (Helgeson, 1969) using the thermodynamic database of SUPCRT92 (Johnson et al., 1992)]. Using a model protolith speculated to exist at Enceladus's water-rock boundary, constrained by extraterrestrial analog analytical data for subsurface serpentinites of the Coast Range Ophiolite (Lower Lake, CA, USA) mélange rocks, we deduce evolving habitability conditions as the model protolith reacts with feasible, though hypothetical, planetary ocean chemistries (from Glien et al., 2015, and Neveu et al., 2017). Major components of modeled oceans, Na-Cl, Mg-Cl, and Ca-Cl, show shifts in the feasibility of CO2-CH4-H2 driven microbial habitability, occurring early in the reaction progress, with methanogenesis being bioenergetically favored. Methanotrophy was favored late in the reaction progress of some Na-Cl systems and in the Mg-Cl systems, with shifts in Gibbs Energy values for Mg-Cl systems progressing in the middle of the reaction process. In sum, we show that the bioenergetic yield of fundamental methanogenetic and methanotrophic reactions changes as late stage serpentinization progresses under different Enceladus seawater conditions.

Dysfunctional stress responses in chronic pain.

PubMed

Woda, Alain; Picard, Pascale; Dutheil, Frédéric

2016-09-01

Many dysfunctional and chronic pain conditions overlap. This review describes the different modes of chronic deregulation of the adaptive response to stress which may be a common factor for these conditions. Several types of dysfunction can be identified within the hypothalamo-pituitary-adrenal axis: basal hypercortisolism, hyper-reactivity, basal hypocortisolism and hypo-reactivity. Neuroactive steroid synthesis is another component of the adaptive response to stress. Dehydroepiandrosterone (DHEA) and its sulfated form DHEA-S, and progesterone and its derivatives are synthetized in cutaneous, nervous, and adipose cells. They are neuroactive factors that act locally. They may have a role in the localization of the symptoms and their levels can vary both in the central nervous system and in the periphery. Persistent changes in neuroactive steroid levels or precursors can induce localized neurodegeneration. The autonomic nervous system is another component of the stress response. Its dysfunction in chronic stress responses can be expressed by decreased basal parasympathethic activity, increased basal sympathetic activity or sympathetic hyporeactivity to a stressful stimulus. The immune and genetic systems also participate. The helper-T cells Th1 secrete pro-inflammatory cytokines such as IL-1-β, IL-2, IL-6, IL-8, IL-12, IFN-γ, and TNF-α, whereas Th2 secrete anti-inflammatory cytokines: IL-4, IL-10, IGF-10, IL-13. Chronic deregulation of the Th1/Th2 balance can occur in favor of anti- or pro-inflammatory direction, locally or systemically. Individual vulnerability to stress can be due to environmental factors but can also be genetically influenced. Genetic polymorphisms and epigenetics are the main keys to understanding the influence of genetics on the response of individuals to constraints. Copyright © 2016 Elsevier Ltd. All rights reserved.

Indochina Refugees: Families in Turmoil.

ERIC Educational Resources Information Center

Okura, K. Patrick

Many Indochinese refugees in the United States suffer from serious social adjustment problems. These adjustment problems appear to reflect the stress of adapting to American life rather than chronic dysfunction. Particular groups of Indochinese who appear to experience social adjustment problems that are more severe in terms of intensity,…

Can protective factors moderate the detrimental effects of child maltreatment on personality functioning?

PubMed

Hengartner, Michael P; Müller, Mario; Rodgers, Stephanie; Rössler, Wulf; Ajdacic-Gross, Vladeta

2013-09-01

The aim of this study was to examine whether, and if so, to what extent, education and coping strategies may reduce the detrimental effects of childhood maltreatment on personality functioning. We assessed dimensional trait-scores of all 10 DSM-IV personality disorders (PDs), childhood maltreatment, education and three coping styles in 511 subjects of the general population of Zurich, Switzerland, using data from the ZInEP Epidemiology Survey. Childhood maltreatment was associated with all 10 PDs. Low education was related to antisocial, borderline and histrionic PD. Low emotion-focused coping was associated with paranoid, schizoid, borderline, avoidant, and obsessive-compulsive PD. Low problem-focused coping was related to schizoid PD and high problem-focused coping to histrionic PD. High dysfunctional coping was significantly related to all 10 PD dimensions. Obsessive-compulsive trait scores were significantly lower in maltreated subjects with high emotion-focused coping. Antisocial, borderline and narcissistic trait scores were significantly higher in maltreated subjects with high dysfunctional coping. Education and adaptive coping may have a protective effect on PD symptomatology. Promotion of adaptive coping and suppression of dysfunctional coping may additionally reduce PD symptoms specifically in maltreated subjects. Those findings have important clinical implications. Longitudinal research is needed to address questions of causality and to evaluate potential effects of treatment and intervention. Copyright © 2013 Elsevier Ltd. All rights reserved.

RAAS inhibition and cardiorenal syndrome.

PubMed

Onuigbo, Macaulay Amechi C

2014-01-01

The consensus conference on cardio-renal syndromes (2008) defined 'cardio-renal syndromes' as 'disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other' and identified five subtypes of the syndromes. Various pathophysiologic mechanisms underlie cardiorenal syndrome including hemodynamic derangements, reduced cardiac output leading to impaired renal perfusion, reduced stroke volume, raised atrial filling pressures, elevated atrial pressures, sodium and water retention, venous congestion, right ventricular dysfunction and venous hypertension causing increased renal venous pressure, intra-abdominal hypertension, various neurohormonal adaptations including activation of the renin-angiotensin-aldosterone system, adaptive activation of the sympathetic nervous system, cytokine release and oxidative stress. Although there are standardized clinical guidelines for the management of heart failure, and chronic kidney disease, respectively, there are no similar consensus clinical guidelines for the management of the cardiorenal syndromes. RAAS inhibition is advocated in treating systolic heart failure. There is evidence that RAAS inhibition is also useful in cardiorenal syndrome. However, RAAS inhibition, while potentially useful in the management of cardiorenal syndrome, is not the 'magic bullet', is sometimes limited by adverse renal events, is not applicable to all patients, and must be applied by physicians with due diligence and caution. Nevertheless, a more comprehensive multidisciplinary multipronged approach to managing patients with cardiorenal syndrome is even more pragmatic and commonsense given the multiple mechanisms and pathogenetic pathways implicated in the causation and perpetuation of cardiorenal syndrome.

Bioenergetics | Bioenergy | NREL

Science.gov Websites

technologies, and working to understand the capture of solar energy in photosynthetic systems and the and attached to sensors, hoses, and valves Photosynthetic Energy Transduction Woman working with a

A design automation framework for computational bioenergetics in biological networks.

PubMed

Angione, Claudio; Costanza, Jole; Carapezza, Giovanni; Lió, Pietro; Nicosia, Giuseppe

2013-10-01

The bioenergetic activity of mitochondria can be thoroughly investigated by using computational methods. In particular, in our work we focus on ATP and NADH, namely the metabolites representing the production of energy in the cell. We develop a computational framework to perform an exhaustive investigation at the level of species, reactions, genes and metabolic pathways. The framework integrates several methods implementing the state-of-the-art algorithms for many-objective optimization, sensitivity, and identifiability analysis applied to biological systems. We use this computational framework to analyze three case studies related to the human mitochondria and the algal metabolism of Chlamydomonas reinhardtii, formally described with algebraic differential equations or flux balance analysis. Integrating the results of our framework applied to interacting organelles would provide a general-purpose method for assessing the production of energy in a biological network.

Upregulation of Krebs cycle and anaerobic glycolysis activity early after onset of liver ischemia.

PubMed

Chan, Tom S; Cassim, Shamir; Raymond, Valérie-Ann; Gottschalk, Sven; Merlen, Grégory; Zwingmann, Claudia; Lapierre, Pascal; Darby, Peter; Mazer, Cyril David; Bilodeau, Marc

2018-01-01

The liver is a highly vascularized organ receiving a dual input of oxygenated blood from the hepatic artery and portal vein. The impact of decreased blood flow on glucose metabolism and how hepatocytes could adapt to this restrictive environment are still unclear. Using the left portal vein ligation (LPVL) rat model, we found that cellular injury was delayed after the onset of liver ischemia. We hypothesized that a metabolic adaptation by hepatocytes to maintain energy homeostasis could account for this lag phase. Liver glucose metabolism was characterized by 13C- and 1H-NMR spectroscopy and analysis of high-energy metabolites. ALT levels and caspase 3 activity in LPVL animals remained normal during the first 12 h following surgery (P<0.05). Ischemia rapidly led to decreased intrahepatic tissue oxygen tension and blood flow (P<0.05) and increased expression of Hypoxia-inducible factor 1-alpha. Intrahepatic glucose uptake, ATP/ADP ratio and energy charge level remained stable for up to 12 h after ligation. Entry of glucose in the Krebs cycle was impaired with lowered incorporation of 13C from [U-13C]glucose into glutamate and succinate from 0.25 to 12 h after LPVL. However, total hepatic succinate and glutamate increased 6 and 12 h after ischemia (P<0.05). Glycolysis was initially reduced (P<0.05) but reached maximum 13C-lactate (P<0.001) and 13C-alanine (P<0.01) enrichments 12 h after LPVL. In conclusion, early liver homeostasis stems from an inherent ability of ischemic hepatocytes to metabolically adapt through increased Krebs cycle and glycolysis activity to preserve bioenergetics and cell viability. This metabolic plasticity of hepatocytes could be harnessed to develop novel metabolic strategies to prevent ischemic liver damage.

Effects of activity and energy budget balancing algorithm on laboratory performance of a fish bioenergetics model

USGS Publications Warehouse

Madenjian, Charles P.; David, Solomon R.; Pothoven, Steven A.

2012-01-01

We evaluated the performance of the Wisconsin bioenergetics model for lake trout Salvelinus namaycush that were fed ad libitum in laboratory tanks under regimes of low activity and high activity. In addition, we compared model performance under two different model algorithms: (1) balancing the lake trout energy budget on day t based on lake trout energy density on day t and (2) balancing the lake trout energy budget on day t based on lake trout energy density on day t + 1. Results indicated that the model significantly underestimated consumption for both inactive and active lake trout when algorithm 1 was used and that the degree of underestimation was similar for the two activity levels. In contrast, model performance substantially improved when using algorithm 2, as no detectable bias was found in model predictions of consumption for inactive fish and only a slight degree of overestimation was detected for active fish. The energy budget was accurately balanced by using algorithm 2 but not by using algorithm 1. Based on the results of this study, we recommend the use of algorithm 2 to estimate food consumption by fish in the field. Our study results highlight the importance of accurately accounting for changes in fish energy density when balancing the energy budget; furthermore, these results have implications for the science of evaluating fish bioenergetics model performance and for more accurate estimation of food consumption by fish in the field when fish energy density undergoes relatively rapid changes.

Sex difference in polychlorinated biphenyl concentrations of burbot Lota lota from Lake Erie

USGS Publications Warehouse

Madenjian, C.P.; Stapanian, M.A.; Rediske, R.R.; O’Keefe, J. P.

2013-01-01

Whole-fish polychlorinated biphenyl (PCB) concentrations were determined for 25 female and 25 male burbot Lota lota from Lake Erie. Bioenergetics modeling was used to investigate whether the sex difference in growth rate resulted in a difference in gross growth efficiency (GGE) between the sexes. For ages 6–13 years, male burbot averaged 28 % greater PCB concentrations than female burbot. The sex difference in PCB concentrations widened for ages 14–17 years, with male burbot having, on average, 71 % greater PCB concentrations than female burbot. Bioenergetics modeling results showed that the faster growth rate exhibited by female burbot did not lead to greater GGE in female individuals of the younger burbot and that the faster growth by female fish led to female GGE being only 2 % greater than male GGE in older burbot. Although our bioenergetics modeling could not explain the observed sex difference in PCB concentrations, we concluded that a sex difference in GGE was the most plausible explanation for the sex difference in PCB concentrations of burbot ages 6–13 years. Not only are male fish likely to be more active than female fish, but the resting metabolic rate of male fish may be greater than that of female fish. We also concluded that the widening of the sex difference in PCB concentrations for the older burbot may be due to many of the older male burbot spending a substantial amount of time in the vicinity of mouths of rivers contaminated with PCBs.

Nicotinamide Forestalls Pathology and Cognitive Decline in Alzheimer Mice: Evidence for Improved Neuronal Bioenergetics and Autophagy Procession

PubMed Central

Liu, Dong; Pitta, Michael; Jiang, Haiyang; Lee, Jong-Hwan; Zhang, Guofeng; Chen, Xinzhi; Kawamoto, Elisa M.; Mattson, Mark P.

2012-01-01

Impaired brain energy metabolism and oxidative stress are implicated in cognitive decline and the pathological accumulations of amyloid β-peptide (Aβ) and hyperphosphorylated Tau (p-Tau) in Alzheimer's disease (AD). To determine whether improving brain energy metabolism will forestall disease progress in AD, the impact of the NAD+ precursor nicotinamide on brain cell mitochondrial function and macroautophagy, bioenergetics-related signaling and cognitive performance were studied in cultured neurons and in a mouse model of AD. Oxidative stress resulted in decreased mitochondrial mass, mitochondrial degeneration and autophagosome accumulation in neurons. Nicotinamide preserved mitochondrial integrity and autophagy function, and reduced neuronal vulnerability to oxidative/metabolic insults and Aβ toxicity. NAD+ biosynthesis, autophagy and PI3K signaling were required for the neuroprotective action of nicotinamide. Treatment of 3xTgAD mice with nicotinamide for 8 months resulted in improved cognitive performance, and reduced Aβ and p-Tau pathologies in hippocampus and cerebral cortex. Nicotinamide treatment preserved mitochondrial integrity, and improved autophagy-lysosome procession by enhancing lysosome/autolysosome acidification to reduce autophagosome accumulation. Treatment of 3xTgAD mice with nicotinamide resulted in elevated levels of activated neuroplasticity-related kinases (Akt and ERKs) and the transcription factor cyclic AMP response element-binding protein in the hippocampus and cerebral cortex. Thus, nicotinamide suppresses AD pathology and cognitive decline in a mouse model of AD by a mechanism involving improved brain bioenergetics with preserved functionality of mitochondria and the autophagy system. PMID:23273573

Oncogene-induced senescence results in marked metabolic and bioenergetic alterations

PubMed Central

Quijano, Celia; Cao, Liu; Fergusson, Maria M; Romero, Hector; Liu, Jie; Gutkind, Sarah; Rovira, Ilsa I; Mohney, Robert P; Karoly, Edward D

2012-01-01

Oncogene-induced senescence (OIS) is characterized by permanent growth arrest and the acquisition of a secretory, pro-inflammatory state. Increasingly, OIS is viewed as an important barrier to tumorgenesis. Surprisingly, relatively little is known about the metabolic changes that accompany and therefore may contribute to OIS. Here, we have performed a metabolomic and bioenergetic analysis of Ras-induced senescence. Profiling approximately 300 different intracellular metabolites reveals that cells that have undergone OIS develop a unique metabolic signature that differs markedly from cells undergoing replicative senescence. A number of lipid metabolites appear uniquely increased in OIS cells, including a marked increase in the level of certain intracellular long chain fatty acids. Functional studies reveal that this alteration in the metabolome reflects substantial changes in overall lipid metabolism. In particular, Ras-induced senescent cells manifest a decline in lipid synthesis and a significant increase in fatty acid oxidation. Increased fatty acid oxidation results in an unexpectedly high rate of basal oxygen consumption in cells that have undergone OIS. Pharmacological or genetic inhibition of carnitine palmitoyltransferase 1, the rate-limiting step in mitochondrial fatty acid oxidation, restores a presenescent metabolic rate and, surprisingly, selectively inhibits the secretory, pro-inflammatory state that accompanies OIS. Thus, Ras-induced senescent cells demonstrate profound alterations in their metabolic and bioenergetic profiles, particularly with regards to the levels, synthesis and oxidation of free fatty acids. Furthermore, the inflammatory phenotype that accompanies OIS appears to be related to these underlying changes in cellular metabolism. PMID:22421146

Ancient Systems of Sodium/Potassium Homeostasis as Predecessors of Membrane Bioenergetics.

PubMed

Dibrova, D V; Galperin, M Y; Koonin, E V; Mulkidjanian, A Y

2015-05-01

Cell cytoplasm of archaea, bacteria, and eukaryotes contains substantially more potassium than sodium, and potassium cations are specifically required for many key cellular processes, including protein synthesis. This distinct ionic composition and requirements have been attributed to the emergence of the first cells in potassium-rich habitats. Different, albeit complementary, scenarios have been proposed for the primordial potassium-rich environments based on experimental data and theoretical considerations. Specifically, building on the observation that potassium prevails over sodium in the vapor of inland geothermal systems, we have argued that the first cells could emerge in the pools and puddles at the periphery of primordial anoxic geothermal fields, where the elementary composition of the condensed vapor would resemble the internal milieu of modern cells. Marine and freshwater environments generally contain more sodium than potassium. Therefore, to invade such environments, while maintaining excess of potassium over sodium in the cytoplasm, primordial cells needed means to extrude sodium ions. The foray into new, sodium-rich habitats was the likely driving force behind the evolution of diverse redox-, light-, chemically-, or osmotically-dependent sodium export pumps and the increase of membrane tightness. Here we present a scenario that details how the interplay between several, initially independent sodium pumps might have triggered the evolution of sodium-dependent membrane bioenergetics, followed by the separate emergence of the proton-dependent bioenergetics in archaea and bacteria. We also discuss the development of systems that utilize the sodium/potassium gradient across the cell membranes.

Bioenergetics models to estimate numbers of larval lampreys consumed by smallmouth bass in Elk Creek, Oregon

USGS Publications Warehouse

Schultz, Luke; Heck, Michael; Kowalski, Brandon M; Eagles-Smith, Collin A.; Coates, Kelly C.; Dunham, Jason B.

2017-01-01

Nonnative fishes have been increasingly implicated in the decline of native fishes in the Pacific Northwest. Smallmouth Bass Micropterus dolomieu were introduced into the Umpqua River in southwest Oregon in the early 1960s. The spread of Smallmouth Bass throughout the basin coincided with a decline in counts of upstream-migrating Pacific Lampreys Entosphenus tridentatus. This suggested the potential for ecological interactions between Smallmouth Bass and Pacific Lampreys, as well as freshwater-resident Western Brook Lampreys Lampetra richardsoni. To evaluate the potential effects of Smallmouth Bass on lampreys, we sampled diets of Smallmouth Bass and used bioenergetics models to estimate consumption of larval lampreys in a segment of Elk Creek, a tributary to the lower Umpqua River. We captured 303 unique Smallmouth Bass (mean: 197 mm and 136 g) via angling in July and September. We combined information on Smallmouth Bass diet and energy density with other variables (temperature, body size, growth, prey energy density) in a bioenergetics model to estimate consumption of larval lampreys. Larval lampreys were found in 6.2% of diet samples, and model estimates indicated that the Smallmouth Bass we captured consumed 925 larval lampreys in this 2-month study period. When extrapolated to a population estimate of Smallmouth Bass in this segment, we estimated 1,911 larval lampreys were consumed between July and September. Although the precision of these estimates was low, this magnitude of consumption suggests that Smallmouth Bass may negatively affect larval lamprey populations.

Direct effects of phenformin on metabolism/bioenergetics and viability of SH-SY5Y neuroblastoma cells.

PubMed

Geoghegan, Fintan; Chadderton, Naomi; Farrar, G Jane; Zisterer, Daniela M; Porter, Richard K

2017-11-01

Phenformin, a member of the biguanides class of drugs, has been reported to be efficacious in cancer treatment. The focus of the current study was to establish whether there were direct effects of phenformin on the metabolism and bioenergetics of neuroblastoma SH-SY5Y cancer cells. Cell viability was assessed using the alamar blue assay, flow cytometry analysis using propidium iodide and annexin V stain and poly (ADP-ribose) polymerase analysis. Cellular and mitochondrial oxygen consumption was determined using a Seahorse Bioscience Flux analyser and an Oroboros Oxygraph respirometer. Cells were transfected using electroporation and permeabilized for in situ mitochondrial functional analysis using digitonin. Standard protocols were used for immunoblotting and proteins were separated on denaturing gels. Phenformin was effective in reducing the viability of SH-SY5Y cells, causing G 1 cell cycle arrest and inducing apoptosis. Bioenergetic analysis demonstrated that phenformin significantly decreased oxygen consumption in a dose- and time-dependent manner. The sensitivity of oxygen consumption in SH-SY5Y cells to phenformin was circumvented by the expression of NADH-quinone oxidoreductase 1, a ubiquinone oxidoreductase, suggesting that complex I may be a target of phenformin. As a result of this inhibition, adenosine monophosphate protein kinase is activated and acetyl-coenzyme A carboxylase is inhibited. To the best of our knowledge, the current study is the first to demonstrate the efficacy and underlying mechanism by which phenformin directly effects the survival of neuroblastoma cancer cells.