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Sample records for abnormal mitochondrial distribution

  1. Abnormal Mitochondrial Dynamics and Neurodegenerative Diseases

    PubMed Central

    Su, Bo; Wang, Xinglong; Zheng, Ling; Perry, George; Smith, Mark A.; Zhu, Xiongwei

    2009-01-01

    Mitochondrial dysfunction is a prominent feature of various neurodegenerative diseases. A deeper understanding of the remarkably dynamic nature of mitochondria, characterized by a delicate balance of fission and fusion, has helped to fertilize a recent wave of new studies demonstrating abnormal mitochondrial dynamics in neurodegenerative diseases. This review highlights mitochondrial dysfunction and abnormal mitochondrial dynamics in Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease and discusses how these abnormal mitochondrial dynamics may contribute to mitochondrial and neuronal dysfunction. We propose that abnormal mitochondrial dynamics represents a key common pathway that mediates or amplifies mitochondrial dysfunction and neuronal dysfunction during the course of neurodegeneration. PMID:19799998

  2. Haematological abnormalities in mitochondrial disorders

    PubMed Central

    Finsterer, Josef; Frank, Marlies

    2015-01-01

    INTRODUCTION This study aimed to assess the kind of haematological abnormalities that are present in patients with mitochondrial disorders (MIDs) and the frequency of their occurrence. METHODS The blood cell counts of a cohort of patients with syndromic and non-syndromic MIDs were retrospectively reviewed. MIDs were classified as ‘definite’, ‘probable’ or ‘possible’ according to clinical presentation, instrumental findings, immunohistological findings on muscle biopsy, biochemical abnormalities of the respiratory chain and/or the results of genetic studies. Patients who had medical conditions other than MID that account for the haematological abnormalities were excluded. RESULTS A total of 46 patients (‘definite’ = 5; ‘probable’ = 9; ‘possible’ = 32) had haematological abnormalities attributable to MIDs. The most frequent haematological abnormality in patients with MIDs was anaemia. 27 patients had anaemia as their sole haematological problem. Anaemia was associated with thrombopenia (n = 4), thrombocytosis (n = 2), leucopenia (n = 2), and eosinophilia (n = 1). Anaemia was hypochromic and normocytic in 27 patients, hypochromic and microcytic in six patients, hyperchromic and macrocytic in two patients, and normochromic and microcytic in one patient. Among the 46 patients with a mitochondrial haematological abnormality, 78.3% had anaemia, 13.0% had thrombopenia, 8.7% had leucopenia and 8.7% had eosinophilia, alone or in combination with other haematological abnormalities. CONCLUSION MID should be considered if a patient’s abnormal blood cell counts (particularly those associated with anaemia, thrombopenia, leucopenia or eosinophilia) cannot be explained by established causes. Abnormal blood cell counts may be the sole manifestation of MID or a collateral feature of a multisystem problem. PMID:26243978

  3. Abnormal Mitochondrial Dynamics in the Pathogenesis of Alzheimer's Disease

    PubMed Central

    Zhu, Xiongwei; Perry, George; Smith, Mark A.; Wang, Xinglong

    2014-01-01

    Mitochondrial dysfunction is one of the most early and prominent features in vulnerable neurons in the brain of Alzheimer's disease (AD) patients. Recent studies suggest that mitochondria are highly dynamic organelles characterized by a delicate balance of fission and fusion, a concept that has revolutionized our basic understanding of the regulation of mitochondrial structure and function which has far-reaching significance in studies of health and disease. Tremendous progress has been made in studying changes in mitochondrial dynamics in AD brain and models and the potential underlying mechanisms. This review highlights the recent work demonstrating abnormal mitochondrial dynamics and distribution in AD models and discusses how these abnormalities may contribute to various aspects of mitochondrial dysfunction and the pathogenesis of AD. PMID:22531428

  4. Genetics and Mitochondrial Abnormalities in Autism Spectrum Disorders: A Review

    PubMed Central

    Dhillon, Sukhbir; Hellings, Jessica A; Butler, Merlin G

    2011-01-01

    We review the current status of the role and function of the mitochondrial DNA (mtDNA) in the etiology of autism spectrum disorders (ASD) and the interaction of nuclear and mitochondrial genes. High lactate levels reported in about one in five children with ASD may indicate involvement of the mitochondria in energy metabolism and brain development. Mitochondrial disturbances include depletion, decreased quantity or mutations of mtDNA producing defects in biochemical reactions within the mitochondria. A subset of individuals with ASD manifests copy number variation or small DNA deletions/duplications, but fewer than 20 percent are diagnosed with a single gene condition such as fragile X syndrome. The remaining individuals with ASD have chromosomal abnormalities (e.g., 15q11-q13 duplications), other genetic or multigenic causes or epigenetic defects. Next generation DNA sequencing techniques will enable better characterization of genetic and molecular anomalies in ASD, including defects in the mitochondrial genome particularly in younger children. PMID:22294875

  5. Methylene blue alleviates nuclear and mitochondrial abnormalities in progeria.

    PubMed

    Xiong, Zheng-Mei; Choi, Ji Young; Wang, Kun; Zhang, Haoyue; Tariq, Zeshan; Wu, Di; Ko, Eunae; LaDana, Christina; Sesaki, Hiromi; Cao, Kan

    2016-04-01

    Hutchinson-Gilford progeria syndrome (HGPS), a fatal premature aging disease, is caused by a single-nucleotide mutation in the LMNA gene. Previous reports have focused on nuclear phenotypes in HGPS cells, yet the potential contribution of the mitochondria, a key player in normal aging, remains unclear. Using high-resolution microscopy analysis, we demonstrated a significantly increased fraction of swollen and fragmented mitochondria and a marked reduction in mitochondrial mobility in HGPS fibroblast cells. Notably, the expression of PGC-1α, a central regulator of mitochondrial biogenesis, was inhibited by progerin. To rescue mitochondrial defects, we treated HGPS cells with a mitochondrial-targeting antioxidant methylene blue (MB). Our analysis indicated that MB treatment not only alleviated the mitochondrial defects but also rescued the hallmark nuclear abnormalities in HGPS cells. Additional analysis suggested that MB treatment released progerin from the nuclear membrane, rescued perinuclear heterochromatin loss and corrected misregulated gene expression in HGPS cells. Together, these results demonstrate a role of mitochondrial dysfunction in developing the premature aging phenotypes in HGPS cells and suggest MB as a promising therapeutic approach for HGPS. PMID:26663466

  6. Abnormalities in Mitochondrial Structure in Cells from Patients with Bipolar Disorder

    PubMed Central

    Cataldo, Anne M.; McPhie, Donna L.; Lange, Nicholas T.; Punzell, Steven; Elmiligy, Sarah; Ye, Nancy Z.; Froimowitz, Michael P.; Hassinger, Linda C.; Menesale, Emily B.; Sargent, Laura W.; Logan, David J.; Carpenter, Anne E.; Cohen, Bruce M.

    2010-01-01

    Postmortem, genetic, brain imaging, and peripheral cell studies all support decreased mitochondrial activity as a factor in the manifestation of Bipolar Disorder (BD). Because abnormal mitochondrial morphology is often linked to altered energy metabolism, we investigated whether changes in mitochondrial structure were present in brain and peripheral cells of patients with BD. Mitochondria from patients with BD exhibited size and distributional abnormalities compared with psychiatrically-healthy age-matched controls. Specifically, in brain, individual mitochondria profiles had significantly smaller areas, on average, in BD samples (P = 0.03). In peripheral cells, mitochondria in BD samples were concentrated proportionately more within the perinuclear region than in distal processes (P = 0.0008). These mitochondrial changes did not appear to be correlated with exposure to lithium. Also, these abnormalities in brain and peripheral cells were independent of substantial changes in the actin or tubulin cytoskeleton with which mitochondria interact. The observed changes in mitochondrial size and distribution may be linked to energy deficits and, therefore, may have consequences for cell plasticity, resilience, and survival in patients with BD, especially in brain, which has a high-energy requirement. The findings may have implications for diagnosis, if they are specific to BD, and for treatment, if they provide clues as to the underlying pathophysiology of BD. PMID:20566748

  7. Mitochondrial abnormalities-A link to idiosyncratic drug hepatotoxicity?

    SciTech Connect

    Boelsterli, Urs A. . E-mail: phcbua@nus.edu.sg; Lim, Priscilla L.K.

    2007-04-01

    Idiosyncratic drug-induced liver injury (DILI) is a major clinical problem and poses a considerable challenge for drug development as an increasing number of successfully launched drugs or new potential drugs have been implicated in causing DILI in susceptible patient subsets. Although the incidence for a particular drug is very low (yet grossly underestimated), the outcome of DILI can be serious. Unfortunately, prediction has remained poor (both for patients at risk and for new chemical entities). The underlying mechanisms and the determinants of susceptibility have largely remained ill-defined. The aim of this review is to provide both clinical and experimental evidence for a major role of mitochondria both as a target of drugs causing idiosyncratic DILI and as mediators of delayed liver injury. We develop a unifying hypothesis that involves underlying genetic or acquired mitochondrial abnormalities as a major determinant of susceptibility for a number of drugs that target mitochondria and cause DILI. The mitochondrial hypothesis, implying gradually accumulating and initially silent mitochondrial injury in heteroplasmic cells which reaches a critical threshold and abruptly triggers liver injury, is consistent with the findings that typically idiosyncratic DILI is delayed (by weeks or months), that increasing age and female gender are risk factors and that these drugs are targeted to the liver and clearly exhibit a mitochondrial hazard in vitro and in vivo. New animal models (e.g., the Sod2 {sup +/-} mouse) provide supporting evidence for this concept. However, genetic analyses of DILI patient samples are needed to ultimately provide the proof-of-concept.

  8. Redox metabolism abnormalities in autistic children associated with mitochondrial disease.

    PubMed

    Frye, R E; Delatorre, R; Taylor, H; Slattery, J; Melnyk, S; Chowdhury, N; James, S J

    2013-01-01

    Research studies have uncovered several metabolic abnormalities associated with autism spectrum disorder (ASD), including mitochondrial disease (MD) and abnormal redox metabolism. Despite the close connection between mitochondrial dysfunction and oxidative stress, the relation between MD and oxidative stress in children with ASD has not been studied. Plasma markers of oxidative stress and measures of cognitive and language development and ASD behavior were obtained from 18 children diagnosed with ASD who met criteria for probable or definite MD per the Morava et al. criteria (ASD/MD) and 18 age and gender-matched ASD children without any biological markers or symptoms of MD (ASD/NoMD). Plasma measures of redox metabolism included reduced free glutathione (fGSH), oxidized glutathione (GSSG), the fGSH/GSSG ratio and 3-nitrotyrosine (3NT). In addition, a plasma measure of chronic immune activation, 3-chlorotyrosine (3CT), was also measured. Language was measured using the preschool language scale or the expressive one-word vocabulary test (depending on the age), adaptive behaviour was measured using the Vineland Adaptive Behavior Scale (VABS) and core autism symptoms were measured using the Autism Symptoms Questionnaire and the Social Responsiveness Scale. Children with ASD/MD were found to have lower scores on the communication and daily living skill subscales of the VABS despite having similar language and ASD symptoms. Children with ASD/MD demonstrated significantly higher levels of fGSH/GSSG and lower levels of GSSG as compared with children with ASD/NoMD, suggesting an overall more favourable glutathione redox status in the ASD/MD group. However, compare with controls, both ASD groups demonstrated lower fGSH and fGSH/GSSG, demonstrating that both groups suffer from redox abnormalities. Younger ASD/MD children had higher levels of 3CT than younger ASD/NoMD children because of an age-related effect in the ASD/MD group. Both ASD groups demonstrated significantly

  9. Redox metabolism abnormalities in autistic children associated with mitochondrial disease

    PubMed Central

    Frye, R E; DeLaTorre, R; Taylor, H; Slattery, J; Melnyk, S; Chowdhury, N; James, S J

    2013-01-01

    Research studies have uncovered several metabolic abnormalities associated with autism spectrum disorder (ASD), including mitochondrial disease (MD) and abnormal redox metabolism. Despite the close connection between mitochondrial dysfunction and oxidative stress, the relation between MD and oxidative stress in children with ASD has not been studied. Plasma markers of oxidative stress and measures of cognitive and language development and ASD behavior were obtained from 18 children diagnosed with ASD who met criteria for probable or definite MD per the Morava et al. criteria (ASD/MD) and 18 age and gender-matched ASD children without any biological markers or symptoms of MD (ASD/NoMD). Plasma measures of redox metabolism included reduced free glutathione (fGSH), oxidized glutathione (GSSG), the fGSH/GSSG ratio and 3-nitrotyrosine (3NT). In addition, a plasma measure of chronic immune activation, 3-chlorotyrosine (3CT), was also measured. Language was measured using the preschool language scale or the expressive one-word vocabulary test (depending on the age), adaptive behaviour was measured using the Vineland Adaptive Behavior Scale (VABS) and core autism symptoms were measured using the Autism Symptoms Questionnaire and the Social Responsiveness Scale. Children with ASD/MD were found to have lower scores on the communication and daily living skill subscales of the VABS despite having similar language and ASD symptoms. Children with ASD/MD demonstrated significantly higher levels of fGSH/GSSG and lower levels of GSSG as compared with children with ASD/NoMD, suggesting an overall more favourable glutathione redox status in the ASD/MD group. However, compare with controls, both ASD groups demonstrated lower fGSH and fGSH/GSSG, demonstrating that both groups suffer from redox abnormalities. Younger ASD/MD children had higher levels of 3CT than younger ASD/NoMD children because of an age-related effect in the ASD/MD group. Both ASD groups demonstrated significantly

  10. Deficiency of Cardiolipin Synthase Causes Abnormal Mitochondrial Function and Morphology in Germ Cells of Caenorhabditis elegans*

    PubMed Central

    Sakamoto, Taro; Inoue, Takao; Otomo, Yukae; Yokomori, Nagaharu; Ohno, Motoki; Arai, Hiroyuki; Nakagawa, Yasuhito

    2012-01-01

    Cardiolipin (CL) is a major membrane phospholipid specifically localized in mitochondria. At the cellular level, CL has been shown to have a role in mitochondrial energy production, mitochondrial membrane dynamics, and the triggering of apoptosis. However, the in vivo role of CL in multicellular organisms is largely unknown. In this study, by analyzing deletion mutants of a CL synthase gene (crls-1) in Caenorhabditis elegans, we demonstrated that CL depletion selectively caused abnormal mitochondrial function and morphology in germ cells but not in somatic cell types such as muscle cells. crls-1 mutants reached adulthood but were sterile with reduced germ cell proliferation and impaired oogenesis. In the gonad of crls-1 mutants, mitochondrial membrane potential was significantly decreased, and the structure of the mitochondrial cristae was disrupted. Contrary to the abnormalities in the gonad, somatic tissues in crls-1 mutants appeared normal with respect to cell proliferation, mitochondrial function, and mitochondrial morphology. Increased susceptibility to CL depletion in germ cells was also observed in mutants of phosphatidylglycerophosphate synthase, an enzyme responsible for producing phosphatidylglycerol, a precursor phospholipid of CL. We propose that the contribution of CL to mitochondrial function and morphology is different among the cell types in C. elegans. PMID:22174409

  11. Human Misato regulates mitochondrial distribution and morphology

    SciTech Connect

    Kimura, Masashi . E-mail: yo@gifu-u.ac.jp; Okano, Yukio

    2007-04-15

    Misato of Drosophila melanogaster and Saccharomyces cerevisiae DML1 are conserved proteins having a homologous region with a part of the GTPase family that includes eukaryotic tubulin and prokaryotic FtsZ. We characterized human Misato sharing homology with Misato of D. melanogaster and S. cerevisiae DML1. Tissue distribution of Misato exhibited ubiquitous distribution. Subcellular localization of the protein studied using anti-Misato antibody suggested that it is localized to the mitochondria. Further experiments of fractionating mitochondria revealed that Misato was localized to the outer membrane. The transfection of Misato siRNA led to growth deficiencies compared with control siRNA transfected HeLa cells, and the Misato-depleted HeLa cells showed apoptotic nuclear fragmentation resulting in cell death. After silencing of Misato, the filamentous mitochondrial network disappeared and fragmented mitochondria were observed, indicating human Misato has a role in mitochondrial fusion. To examine the effects of overexpression, COS-7 cells were transfected with cDNA encoding EGFP-Misato. Its overexpression resulted in the formation of perinuclear aggregations of mitochondria in these cells. The Misato-overexpressing cells showed low viability and had no nuclei or a small and structurally unusual ones. These results indicated that human Misato has a role(s) in mitochondrial distribution and morphology and that its unregulated expression leads to cell death.

  12. Inhibition of NAPDH Oxidase 2 (NOX2) Prevents Oxidative Stress and Mitochondrial Abnormalities Caused by Saturated Fat in Cardiomyocytes

    PubMed Central

    Joseph, Leroy C.; Barca, Emanuele; Subramanyam, Prakash; Komrowski, Michael; Pajvani, Utpal; Colecraft, Henry M.; Hirano, Michio; Morrow, John P.

    2016-01-01

    Obesity and high saturated fat intake increase the risk of heart failure and arrhythmias. The molecular mechanisms are poorly understood. We hypothesized that physiologic levels of saturated fat could increase mitochondrial reactive oxygen species (ROS) in cardiomyocytes, leading to abnormalities of calcium homeostasis and mitochondrial function. We investigated the effect of saturated fat on mitochondrial function and calcium homeostasis in isolated ventricular myocytes. The saturated fatty acid palmitate causes a decrease in mitochondrial respiration in cardiomyocytes. Palmitate, but not the monounsaturated fatty acid oleate, causes an increase in both total cellular ROS and mitochondrial ROS. Palmitate depolarizes the mitochondrial inner membrane and causes mitochondrial calcium overload by increasing sarcoplasmic reticulum calcium leak. Inhibitors of PKC or NOX2 prevent mitochondrial dysfunction and the increase in ROS, demonstrating that PKC-NOX2 activation is also required for amplification of palmitate induced-ROS. Cardiomyocytes from mice with genetic deletion of NOX2 do not have palmitate-induced ROS or mitochondrial dysfunction. We conclude that palmitate induces mitochondrial ROS that is amplified by NOX2, causing greater mitochondrial ROS generation and partial depolarization of the mitochondrial inner membrane. The abnormal sarcoplasmic reticulum calcium leak caused by palmitate could promote arrhythmia and heart failure. NOX2 inhibition is a potential therapy for heart disease caused by diabetes or obesity. PMID:26756466

  13. Using Reduced Interference Distribution to Analyze Abnormal Cardiac Signal

    NASA Astrophysics Data System (ADS)

    Mousa, Allam; Saleem, Rashid

    2011-05-01

    Due to the non-stationary, multicomponent nature of biomedical signals, the use of time-frequency analysis can be inevitable for these signals. The choice and selection of the proper Time-Frequency Distribution (TFD) that can reveal the exact multicomponent structure of biological signals is vital in many applications, including the diagnosis of medical abnormalities. In this paper, the instantaneous frequency techniques using two distribution functions are applied for analysis of biological signals. These distributions are the Wigner-Ville Distribution and the Bessel Distribution. The simulation performed on normaland abnormal cardiac signals show that the Bessel Distribution can clearly detect the QRS complexes. However, Wigner-Ville Distribution was able to detect the QRS complexes in the normal signa, but fails to detect these complexes in the abnormal cardiac signal.

  14. Heart Failure and Mitochondrial Dysfunction: The Role of Mitochondrial Fission/Fusion Abnormalities and New Therapeutic Strategies

    PubMed Central

    Knowlton, A. A.; Chen, Le; Malik, Zulfiqar A.

    2013-01-01

    The treatment of heart failure has evolved during the last thirty years with recognition of neurohormonal activation and the effectiveness of its inhibition in improving quality of life and survival. Over the last twenty years there has been a revolution in the investigation of the mitochondrion with the development of new techniques and the finding that mitochondria are connected in networks and undergo constant division (fission) and fusion, even in cardiac myocytes. This has led to new molecular and cellular discoveries in heart failure, which offer the potential for the development of new molecular-based therapies. Reactive oxygen species (ROS) are an important cause of mitochondrial and cellular injury in heart failure, but there are other abnormalities, such as depressed mitochondrial fusion, that may eventually become targets of at least episodic treatment. The overall need for mitochondrial fission/fusion balance may preclude sustained change in either fission or fusion. In this review we will discuss current heart failure therapy and its impact on the mitochondria. In addition we will review some of the new drug targets under development. There is potential for effective, novel therapies for heart failure to arise from new molecular understanding. PMID:23884159

  15. Nicotine in Combination With a High-Fat Diet Causes Intramyocellular Mitochondrial Abnormalities in Male Mice

    PubMed Central

    Sinha-Hikim, Indrani; Friedman, Theodore C.; Shin, Chang-Sung; Lee, Desean; Ivey, Rasheed

    2014-01-01

    Smoking is a major risk factor for diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. The health risk associated with smoking can be exaggerated by obesity. We hypothesize that nicotine when combined with a high-fat diet (HFD) can also cause ectopic lipid accumulation in skeletal muscle, similar to recently observed hepatic steatosis. Adult C57BL6 male mice were fed a normal chow diet or HFD and received twice-daily ip injections of nicotine (0.75 mg/kg body weight) or saline for 10 weeks. Transmission electron microscopy of the gastrocnemius muscle revealed substantial intramyocellular lipid accumulation in close association with intramyofibrillar mitochondria along with intramyofibrillar mitochondrial swelling and vacuolization in nicotine-treated mice on an HFD compared with mice on an HFD treated with saline. These abnormalities were reversed by acipimox, an inhibitor of lipolysis. Mechanistically, the detrimental effect of nicotine plus HFD on skeletal muscle was associated with significantly increased oxidative stress, plasma free fatty acid, and muscle triglyceride levels coupled with inactivation of AMP-activated protein kinase and activation of its downstream target, acetyl-coenzyme A-carboxylase. We conclude that 1) greater oxidative stress together with inactivation of AMP-activated protein kinase mediates the effect of nicotine on skeletal muscle abnormalities in diet-induced obesity and 2) adipose tissue lipolysis is an important contributor of muscle steatosis and mitochondrial abnormalities. PMID:24424058

  16. [Dysfunction of mitochondrial dynamic and distribution in Amyotrophic Lateral Sclerosis].

    PubMed

    Walczak, Jarosław; Szczepanowska, Joanna

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a complex disease leading to degradation of motor neurons. One of the early symptoms of many neurodegenerative disorders are mitochondrial dysfunctions. Since few decades mitochondrial morphology changes have been observed in tissues of patients with ALS. Mitochondria are highly dynamic organelles which constantly undergo continuous process of fusion and fission and are actively transported within the cell. Proper functioning of mitochondrial dynamics and distribution is crucial for cell survival, especially neuronal cells that have long axons. This article summarizes the current knowledge about the role of mitochondrial dynamics and distribution in pathophysiology of familial and sporadic form of ALS. PMID:26689011

  17. Mutant prenyltransferase-like mitochondrial protein (PLMP) and mitochondrial abnormalities in kd/kd mice

    PubMed Central

    Peng, Min; Jarett, Leonard; Meade, Ray; Madaio, Michael P.; Hancock, Wayne W.; George, Alfred L.; Neilson, Eric G.; Gasser, David L.

    2008-01-01

    Background Mice that are homozygous for the kidney disease (kd) mutation are apparently healthy for the first 8 weeks of life, but spontaneously develop a severe form of interstitial nephritis that progresses to end-stage renal disease (ESRD) by 4 to 8 months of age. By testing for linkage to microsatellite markers, we previously localized the kd gene to a YAC/BAC contig. Methods The sequence of the entire critical region was examined, and candidate genes were identified. These candidate genes were sequenced in both mutant (kd/kd) mice and normal controls. The phenotype was further characterized by immunohistochemistry and electron microscopy. Transgenic mice were constructed that carried the wild-type allele of the prime candidate gene, and this transgene was transferred to a kd/kd background by breeding. Results We have obtained evidence that kd is a mutant allele of a novel gene for a prenyltransferase-like mitochondrial protein (PLMP). This gene is alternatively spliced, with the larger gene product having one domain that resembles transprenyltransferase and another that is similar to geranylgeranyl pyrophosphate synthase. The smaller gene product includes only the first domain. An antiserum to PLMP localizes to mitochondria, and ultrastructural defects are present in the mitochondria of renal tubular epithelial cells, and to a lesser extent, hepatocytes and heart cells from kd/kd mice. In a line of kd/kd mice that carried the wild-type PLMP allele as a transgene, only 1 out of 13 animals expressed the disease by 120 days of age. Conclusion The kd allele codes for a novel protein that localizes to the mitochondria, and the kd/kd mouse has dysmorphic mitochondria in the renal tubular epithelial cells. This mouse is therefore a unique animal model for studying mechanisms that lead to tubulointerstitial nephritis. PMID:15200409

  18. Abnormally activated one-carbon metabolic pathway is associated with mtDNA hypermethylation and mitochondrial malfunction in the oocytes of polycystic gilt ovaries

    PubMed Central

    Jia, Longfei; Li, Juan; He, Bin; Jia, Yimin; Niu, Yingjie; Wang, Chenfei; Zhao, Ruqian

    2016-01-01

    Polycystic ovarian syndrome (PCOS) is associated with hyperhomocysteinemia and polycystic ovaries (PCO) usually produce oocytes of poor quality. However, the intracellular mechanism linking hyperhomocysteinemia and oocyte quality remains elusive. In this study, the quality of the oocytes isolated from healthy and polycystic gilt ovaries was evaluated in vitro in association with one-carbon metabolism, mitochondrial DNA (mtDNA) methylation, and mitochondrial function. PCO oocytes demonstrated impaired polar body extrusion, and significantly decreased cleavage and blastocyst rates. The mitochondrial distribution was disrupted in PCO oocytes, together with decreased mitochondrial membrane potential and deformed mitochondrial structure. The mtDNA copy number and the expression of mtDNA-encoded genes were significantly lower in PCO oocytes. Homocysteine concentration in follicular fluid was significantly higher in PCO group, which was associated with significantly up-regulated one-carbon metabolic enzymes betaine homocysteine methyltransferase (BHMT), glycine N-methyltransferase (GNMT) and the DNA methyltransferase DNMT1. Moreover, mtDNA sequences coding for 12S, 16S rRNA and ND4, as well as the D-loop region were significantly hypermethylated in PCO oocytes. These results indicate that an abnormal activation of one-carbon metabolism and hypermethylation of mtDNA may contribute, largely, to the mitochondrial malfunction and decreased quality of PCO-derived oocytes in gilts. PMID:26758245

  19. Abnormal Mitochondrial Function and Impaired Granulosa Cell Differentiation in Androgen Receptor Knockout Mice

    PubMed Central

    Wang, Ruey-Sheng; Chang, Heng-Yu; Kao, Shu-Huei; Kao, Cheng-Heng; Wu, Yi-Chen; Yeh, Shuyuan; Tzeng, Chii-Reuy; Chang, Chawnshang

    2015-01-01

    In the ovary, the paracrine interactions between the oocyte and surrounded granulosa cells are critical for optimal oocyte quality and embryonic development. Mice lacking the androgen receptor (AR−/−) were noted to have reduced fertility with abnormal ovarian function that might involve the promotion of preantral follicle growth and prevention of follicular atresia. However, the detailed mechanism of how AR in granulosa cells exerts its effects on oocyte quality is poorly understood. Comparing in vitro maturation rate of oocytes, we found oocytes collected from AR−/− mice have a significantly poor maturating rate with 60% reached metaphase II and 30% remained in germinal vesicle breakdown stage, whereas 95% of wild-type AR (AR+/+) oocytes had reached metaphase II. Interestingly, we found these AR−/− female mice also had an increased frequency of morphological alterations in the mitochondria of granulosa cells with reduced ATP generation (0.18 ± 0.02 vs. 0.29 ± 0.02 µM/mg protein; p < 0.05) and aberrant mitochondrial biogenesis. Mechanism dissection found loss of AR led to a significant decrease in the expression of peroxisome proliferator-activated receptor γ (PPARγ) co-activator 1-β (PGC1-β) and its sequential downstream genes, nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM), in controlling mitochondrial biogenesis. These results indicate that AR may contribute to maintain oocyte quality and fertility via controlling the signals of PGC1-β-mediated mitochondrial biogenesis in granulosa cells. PMID:25941928

  20. Abnormal intermediate filament organization alters mitochondrial motility in giant axonal neuropathy fibroblasts

    PubMed Central

    Lowery, Jason; Jain, Nikhil; Kuczmarski, Edward R.; Mahammad, Saleemulla; Goldman, Anne; Gelfand, Vladimir I.; Opal, Puneet; Goldman, Robert D.

    2016-01-01

    Giant axonal neuropathy (GAN) is a rare disease caused by mutations in the GAN gene, which encodes gigaxonin, an E3 ligase adapter that targets intermediate filament (IF) proteins for degradation in numerous cell types, including neurons and fibroblasts. The cellular hallmark of GAN pathology is the formation of large aggregates and bundles of IFs. In this study, we show that both the distribution and motility of mitochondria are altered in GAN fibroblasts and this is attributable to their association with vimentin IF aggregates and bundles. Transient expression of wild-type gigaxonin in GAN fibroblasts reduces the number of IF aggregates and bundles, restoring mitochondrial motility. Conversely, silencing the expression of gigaxonin in control fibroblasts leads to changes in IF organization similar to that of GAN patient fibroblasts and a coincident loss of mitochondrial motility. The inhibition of mitochondrial motility in GAN fibroblasts is not due to a global inhibition of organelle translocation, as lysosome motility is normal. Our findings demonstrate that it is the pathological changes in IF organization that cause the loss of mitochondrial motility. PMID:26700320

  1. Transfer of beta-amyloid precursor protein gene using adenovirus vector causes mitochondrial abnormalities in cultured normal human muscle.

    PubMed Central

    Askanas, V; McFerrin, J; Baqué, S; Alvarez, R B; Sarkozi, E; Engel, W K

    1996-01-01

    As in Alzheimer-disease (AD) brain, vacuolated muscle fibers of inclusion-body myositis (IBM) contain abnormally accumulated beta-amyloid precursor protein (beta APP), including its beta-amyloid protein epitope, and increased beta APP-751 mRNA. Other similarities between IBM muscle and AD brain phenotypes include paired helical filaments, hyperphosphorylated tau protein, apolipoprotein E, and mitochondrial abnormalities, including decreased cytochrome-c oxidase (COX) activity. The pathogenesis of these abnormalities in IBM muscle and AD brain is not known. We now report that direct transfer of the beta APP gene, using adenovirus vector, into cultured normal human muscle fibers causes structural abnormalities of mitochondria and decreased COX activity. In this adenovirus-mediated beta APP gene transfer, we demonstrated that beta APP overproduction can induce mitochondrial abnormalities. The data suggest that excessive beta APP may be responsible for mitochondrial and COX abnormalities in IBM muscle and perhaps AD brain. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:8577761

  2. Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock in mice

    PubMed Central

    Yue, M.; Hinkle, K.; Davies, P.; Trushina, E.; Fiesel, F.; Christenson, T.; Schroeder, A.; Zhang, L.; Bowles, E.; Behrouz, B.; Lincoln, S.; Beevers, J.; Milnerwood, A.; Kurti, A.; McLean, P. J.; Fryer, J. D.; Springer, W.; Dickson, D.; Farrer, M.; Melrose, H.

    2015-01-01

    Mutations in the LRRK2 gene represent the most common genetic cause of late onset Parkinson’s disease. The physiological and pathological roles of LRRK2 are yet to be fully determined but evidence points towards LRRK2 mutations causing a gain in kinase function, impacting on neuronal maintenance, vesicular dynamics and neurotransmitter release. To explore the role of physiological levels of mutant LRRK2, we created knock in mice harboring the most common LRRK2 mutation G2019S in their own genome. We have performed comprehensive dopaminergic, behavioral and neuropathological analyses in this model up to 24 months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6 months, by 12 months of age, basal and pharmacologically induced extracellular release of dopamine is impaired in both heterozygous and homozygous mice, corroborating previous findings in transgenic models over-expressing mutant LRRK2. Via in vivo microdialysis measurement of basal and drug- evoked extracellular release of dopamine and its metabolites, our findings indicate that exocytotic release from the vesicular pool is impaired. Furthermore, profound mitochondrial abnormalities are evident in the striatum of older homozygous G2019S mice, which are consistent with mitochondrial fission arrest. We anticipate the G2019S will be a useful pre-clinical model for further evaluation of early mechanistic events in LRRK2 pathogenesis and for second-hit approaches to model disease progression. PMID:25836420

  3. Mitochondria-Targeted Antioxidant SS31 Prevents Amyloid Beta-Induced Mitochondrial Abnormalities and Synaptic Degeneration in Alzheimer's Disease.

    PubMed

    Calkins, Marcus J; Manczak, Maria; Reddy, P Hemachandra

    2012-01-01

    In neuronal systems, the health and activity of mitochondria and synapses are tightly coupled. For this reason, it has been postulated that mitochondrial abnormalities may, at least in part, drive neurodegeneration in conditions such as Alzheimer's disease (AD). Mounting evidence from multiple Alzheimer's disease cell and mouse models and postmortem brains suggest that loss of mitochondrial integrity may be a key factor that mediates synaptic loss. Therefore, the prevention or rescue of mitochondrial dysfunction may help delay or altogether prevent AD-associated neurodegeneration. Since mitochondrial health is heavily dependent on antioxidant defenses, researchers have begun to explore the use of mitochondria-targeted antioxidants as therapeutic tools to prevent neurodegenerative diseases. This review will highlight advances made using a model mitochondria-targeted antioxidant peptide, SS31, as a potential treatment for AD. PMID:23226091

  4. Fourier analysis of mitochondrial distribution in oocytes

    NASA Astrophysics Data System (ADS)

    Hollmann, Joseph L.; Brooks, Dana H.; Newmark, Judith A.; Warner, Carol M.; DiMarzio, Charles A.

    2011-03-01

    This paper describes a novel approach to quantifying mitochondrial patterns which are typically described using the qualitative terms "diffuse" "aggregated" and are potentially key indicators for an oocyte's health and survival potential post-implantation. An oocyte was isolated in a confocal image and a coarse grid was superimposed upon it. The spatial spectrum was calculated and an aggregation factor was generated. A classifier for healthy cells was developed and verified. The aggregation factor showed a clear distinction between the healthy and unhealthy oocytes. The ultimate goal is to screen oocytes for viability preimplantation, thus improving the outcome of in vitro fertilization (IVF) treatments.

  5. Integrity of the yeast mitochondrial genome, but not its distribution and inheritance, relies on mitochondrial fission and fusion

    PubMed Central

    Osman, Christof; Noriega, Thomas R.; Okreglak, Voytek; Fung, Jennifer C.; Walter, Peter

    2015-01-01

    Mitochondrial DNA (mtDNA) is essential for mitochondrial and cellular function. In Saccharomyces cerevisiae, mtDNA is organized in nucleoprotein structures termed nucleoids, which are distributed throughout the mitochondrial network and are faithfully inherited during the cell cycle. How the cell distributes and inherits mtDNA is incompletely understood although an involvement of mitochondrial fission and fusion has been suggested. We developed a LacO-LacI system to noninvasively image mtDNA dynamics in living cells. Using this system, we found that nucleoids are nonrandomly spaced within the mitochondrial network and observed the spatiotemporal events involved in mtDNA inheritance. Surprisingly, cells deficient in mitochondrial fusion and fission distributed and inherited mtDNA normally, pointing to alternative pathways involved in these processes. We identified such a mechanism, where we observed fission-independent, but F-actin–dependent, tip generation that was linked to the positioning of mtDNA to the newly generated tip. Although mitochondrial fusion and fission were dispensable for mtDNA distribution and inheritance, we show through a combination of genetics and next-generation sequencing that their absence leads to an accumulation of mitochondrial genomes harboring deleterious structural variations that cluster at the origins of mtDNA replication, thus revealing crucial roles for mitochondrial fusion and fission in maintaining the integrity of the mitochondrial genome. PMID:25730886

  6. NLRP3 deletion protects against renal fibrosis and attenuates mitochondrial abnormality in mouse with 5/6 nephrectomy.

    PubMed

    Gong, Wei; Mao, Song; Yu, Jing; Song, Jiayu; Jia, Zhanjun; Huang, Songming; Zhang, Aihua

    2016-05-15

    Progressive fibrosis in chronic kidney disease (CKD) is the well-recognized cause leading to the progressive loss of renal function. Emerging evidence indicated a pathogenic role of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome in mediating kidney injury. However, the role of NLRP3 in the remnant kidney disease model is still undefined. The present study was undertaken to evaluate the function of NLRP3 in modulating renal fibrosis in a CKD model of 5/6 nephrectomy (5/6 Nx) and the potential involvement of mitochondrial dysfunction in the pathogenesis. Employing NLRP3(+/+) and NLRP3(-/-) mice with or without 5/6 Nx, we examined renal fibrotic response and mitochondrial function. Strikingly, tubulointerstitial fibrosis was remarkably attenuated in NLRP3(-/-) mice as evidenced by the blockade of extracellular matrix deposition. Meanwhile, renal tubular cells in NLRP3(-/-) mice maintained better mitochondrial morphology and higher mitochondrial DNA copy number, indicating an amelioration of mitochondrial abnormality. Moreover, NLRP3 deletion also blunted the severity of proteinuria and CKD-related hypertension. To further evaluate the direct role of NLRP3 in triggering fibrogenesis, mouse proximal tubular cells (PTCs) were subjected to transforming growth factor β1 (TGF-β1), and the cellular phenotypic changes were detected. As expected, TGF-β1-induced alterations of PTC phenotype were abolished by NLRP3 small interfering RNA, in line with a protection of mitochondrial function. Taken together, NLRP3 deletion protected against renal fibrosis in the 5/6 Nx disease model, possibly via inhibiting mitochondrial dysfunction. PMID:26887832

  7. Diastolic Dysfunction Induced by a High-Fat Diet Is Associated with Mitochondrial Abnormality and Adenosine Triphosphate Levels in Rats

    PubMed Central

    Kang, Ki-Woon; Kim, Ok-Soon; Chin, Jung Yeon; Kim, Won Ho; Park, Sang Hyun; Choi, Yu Jeong; Shin, Jong Ho; Jung, Kyung Tae; Lim, Do-Seon

    2015-01-01

    Background Obesity is well-known as a risk factor for heart failure, including diastolic dysfunction. However, this mechanism in high-fat diet (HFD)-induced obese rats remain controversial. The purpose of this study was to investigate whether cardiac dysfunction develops when rats are fed with a HFD for 10 weeks; additionally, we sought to investigate the association between mitochondrial abnormalities, adenosine triphosphate (ATP) levels and cardiac dysfunction. Methods We examined myocardia in Wistar rats after 10 weeks of HFD (45 kcal% fat, n=6) or standard diet (SD, n=6). Echocardiography, histomorphologic analysis, and electron microscopy were performed. The expression levels of mitochondrial oxidative phosphorylation (OXPHOS) subunit genes, peroxisome-proliferator-activated receptor γ co-activator-1α (PGC1α) and anti-oxidant enzymes were assessed. Markers of oxidative stress damage, mitochondrial DNA copy number and myocardial ATP level were also examined. Results After 10 weeks, the body weight of the HFD group (349.6±22.7 g) was significantly higher than that of the SD group (286.8±14.9 g), and the perigonadal and epicardial fat weights of the HFD group were significantly higher than that of the SD group. Histomorphologic and electron microscopic images were similar between the two groups. However, in the myocardium of the HFD group, the expression levels of OXPHOS subunit NDUFB5 in complex I and PGC1α, and the mitochondrial DNA copy number were decreased and the oxidative stress damage marker 8-hydroxydeoxyguanosine was increased, accompanied by reduced ATP levels. Conclusion Diastolic dysfunction was accompanied by the mitochondrial abnormality and reduced ATP levels in the myocardium of 10 weeks-HFD-induced rats. PMID:26790384

  8. Heterogeneous base distribution in mitochondrial DNA of Neurospora crassa.

    PubMed Central

    Terpstra, P; Holtrop, M; Kroon, A

    1977-01-01

    The mitochondrial DNA of Neurospora crassa has a heterogeneous intramolecular base distribution. A contiguous piece, representing at least 30% of the total genome, has a G+C content that is 6% lower than the overall G+C content of the DNA. The genes for both ribosomal RNAs are contained in the remaining, relatively G+C rich, part of the genome. PMID:141040

  9. Maintenance of mitochondrial genome distribution by mitochondrial AAA+ protein ClpX.

    PubMed

    Kasashima, Katsumi; Sumitani, Megumi; Endo, Hitoshi

    2012-11-01

    The segregation of mitochondrial DNA (mtDNA) is important for the maintenance and transmission of the genome between generations. Recently, we clarified that human mitochondrial transcription factor A (TFAM) is required for equal distribution and symmetric segregation of mtDNA in cultured cells; however, the molecular mechanism involved is largely unknown. ClpX is an ATPase associated with various cellular activities (AAA+) proteins that localize to the mitochondrial matrix and is suggested to associate with mtDNA. In this study, we found that RNAi-mediated knockdown of ClpX in HeLa cells resulted in enlarged mtDNA nucleoids, which is very similar to that observed in TFAM-knockdown cells in several properties. The expression of TFAM protein was not significantly reduced in ClpX-knockdown cells. However, the enlarged mtDNA nucleoids caused by ClpX-knockdown were suppressed by overexpression of recombinant TFAM and the phenotype was not observed in knockdown with ClpP, a protease subunit of ClpXP. Endogenous ClpX and TFAM exist in close vicinity, and ClpX enhanced DNA-binding activity of TFAM in vitro. These results suggest that human ClpX, a novel mtDNA regulator, maintains mtDNA nucleoid distribution through TFAM function as a chaperone rather than as a protease and its involvement in mtDNA segregation. PMID:22841477

  10. Acquired Mitochondrial Abnormalities, Including Epigenetic Inhibition of Superoxide Dismutase 2, in Pulmonary Hypertension and Cancer: Therapeutic Implications.

    PubMed

    Archer, Stephen L

    2016-01-01

    There is no cure for non-small-cell lung cancer (NSCLC) or pulmonary arterial hypertension (PAH). Therapies lack efficacy and/or are toxic, reflecting a failure to target disease abnormalities that are distinct from processes vital to normal cells. NSCLC and PAH share reversible mitochondrial-metabolic abnormalities which may offer selective therapeutic targets. The following mutually reinforcing, mitochondrial abnormalities favor proliferation, impair apoptosis, and are relatively restricted to PAH and cancer cells: (1) Epigenetic silencing of superoxide dismutase-2 (SOD2) by methylation of CpG islands creates a pseudohypoxic redox environment that causes normoxic activation of hypoxia inducible factor (HIF-1α). (2) HIF-1α increases expression of pyruvate dehydrogenase kinase (PDK), which impairs oxidative metabolism and promotes a glycolytic metabolic state. (3) Mitochondrial fragmentation, partially due to mitofusin-2 downregulation, promotes proliferation. This review focuses on the recent discovery that decreased expression of SOD2, a putative tumor-suppressor gene and the major source of H2O2, results from hypermethylation of CpG islands. In cancer and PAH hypermethylation of a site in the enhancer region of intron 2 inhibits SOD2 transcription. In normal PASMC, SOD2 siRNA decreases H2O2 and activates HIF-1α. In PAH, reduced SOD2 expression decreases H2O2, reduces the cytosol and thereby activates HIF-1α. This causes a glycolytic shift in metabolism and increases the proliferation/apoptosis ratio by downregulating Kv1.5 channels, increasing cytosolic calcium, and inhibiting caspases. The DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, which restores SOD2 expression, corrects the proliferation/apoptosis imbalance in PAH and cancer cells. The specificity of PAH for lung vessels may relate to the selective upregulation of DNA methyltransferases that mediate CpG methylation in PASMC (DNA MT-1A and -3B). SOD2 augmentation inactivates HIF-1α in PAH

  11. Cause and Consequence: Mitochondrial Dysfunction Initiates and Propagates Neuronal Dysfunction, Neuronal Death and Behavioral Abnormalities in Age Associated Neurodegenerative Diseases

    PubMed Central

    Gibson, Gary E.; Starkov, Anatoly; Blass, John P.; Ratan, Rajiv R.; Beal, M. Flint

    2009-01-01

    SUMMARY Age-related neurodegenerative diseases are associated with mild impairment of oxidative metabolism and accumulation of abnormal proteins. Within the cell, the mitochondria appears to be a dominant site for initiation and propagation of disease processes. Shifts in metabolism in response to mild metabolic perturbations may decrease the threshold for irreversible injury in response to ordinarily sub lethal metabolic insults. Mild impairment of metabolism accrue from and lead to increased reactive oxygen species (ROS). Increased ROS change cell signaling via post transcriptional and transcriptional changes. The cause and consequences of mild impairment of mitochondrial metabolism is one focus of this review. Many experiments in tissues from humans support the notion that oxidative modification of the α-ketoglutarate dehydrogenase complex (KGDHC) compromises neuronal energy metabolism and enhance ROS production in Alzheimer’s Disease (AD). These data suggest that cognitive decline in AD derives from the selective tricarboxylic acid (TCA) cycle abnormalities. By contrast in Huntington’s Disease (HD), a movement disorder with cognitive features distinct form AD, complex II + III abnormalities may dominate. These distinct mitochondrial abnormalities culminate in oxidative stress, energy dysfunction, and aberrant homeostasis of cytosolic calcium. Cytosolic calcium, elevations even only transiently, leads to hyperactivity of a number of enzymes. One calcium activated enzyme with demonstrated pathophysiological import in HD and AD is transglutaminase (TGase). TGase is a cross linking enzymes that can modulate transcrption, inactivate metabolic enzymes, and cause aggregation of critical proteins. Recent data indicate that TGase can silence expression of genes involved in compensating for metabolic stress. Altogether, our results suggest that increasing KGDHC via inhibition of TGase or via a host of other strategies to be described would be effective therapeutic

  12. PMPCA mutations cause abnormal mitochondrial protein processing in patients with non-progressive cerebellar ataxia.

    PubMed

    Jobling, Rebekah K; Assoum, Mirna; Gakh, Oleksandr; Blaser, Susan; Raiman, Julian A; Mignot, Cyril; Roze, Emmanuel; Dürr, Alexandra; Brice, Alexis; Lévy, Nicolas; Prasad, Chitra; Paton, Tara; Paterson, Andrew D; Roslin, Nicole M; Marshall, Christian R; Desvignes, Jean-Pierre; Roëckel-Trevisiol, Nathalie; Scherer, Stephen W; Rouleau, Guy A; Mégarbané, André; Isaya, Grazia; Delague, Valérie; Yoon, Grace

    2015-06-01

    Non-progressive cerebellar ataxias are a rare group of disorders that comprise approximately 10% of static infantile encephalopathies. We report the identification of mutations in PMPCA in 17 patients from four families affected with cerebellar ataxia, including the large Lebanese family previously described with autosomal recessive cerebellar ataxia and short stature of Norman type and localized to chromosome 9q34 (OMIM #213200). All patients present with non-progressive cerebellar ataxia, and the majority have intellectual disability of variable severity. PMPCA encodes α-MPP, the alpha subunit of mitochondrial processing peptidase, the primary enzyme responsible for the maturation of the vast majority of nuclear-encoded mitochondrial proteins, which is necessary for life at the cellular level. Analysis of lymphoblastoid cells and fibroblasts from patients homozygous for the PMPCA p.Ala377Thr mutation and carriers demonstrate that the mutation impacts both the level of the alpha subunit encoded by PMPCA and the function of mitochondrial processing peptidase. In particular, this mutation impacts the maturation process of frataxin, the protein which is depleted in Friedreich ataxia. This study represents the first time that defects in PMPCA and mitochondrial processing peptidase have been described in association with a disease phenotype in humans. PMID:25808372

  13. PMPCA mutations cause abnormal mitochondrial protein processing in patients with non-progressive cerebellar ataxia

    PubMed Central

    Jobling, Rebekah K.; Assoum, Mirna; Gakh, Oleksandr; Blaser, Susan; Raiman, Julian A.; Mignot, Cyril; Roze, Emmanuel; Dürr, Alexandra; Brice, Alexis; Lévy, Nicolas; Prasad, Chitra; Paton, Tara; Paterson, Andrew D.; Roslin, Nicole M.; Marshall, Christian R.; Desvignes, Jean-Pierre; Roëckel-Trevisiol, Nathalie; Scherer, Stephen W.; Rouleau, Guy A.; Mégarbané, André; Isaya, Grazia

    2015-01-01

    Non-progressive cerebellar ataxias are a rare group of disorders that comprise approximately 10% of static infantile encephalopathies. We report the identification of mutations in PMPCA in 17 patients from four families affected with cerebellar ataxia, including the large Lebanese family previously described with autosomal recessive cerebellar ataxia and short stature of Norman type and localized to chromosome 9q34 (OMIM #213200). All patients present with non-progressive cerebellar ataxia, and the majority have intellectual disability of variable severity. PMPCA encodes α-MPP, the alpha subunit of mitochondrial processing peptidase, the primary enzyme responsible for the maturation of the vast majority of nuclear-encoded mitochondrial proteins, which is necessary for life at the cellular level. Analysis of lymphoblastoid cells and fibroblasts from patients homozygous for the PMPCA p.Ala377Thr mutation and carriers demonstrate that the mutation impacts both the level of the alpha subunit encoded by PMPCA and the function of mitochondrial processing peptidase. In particular, this mutation impacts the maturation process of frataxin, the protein which is depleted in Friedreich ataxia. This study represents the first time that defects in PMPCA and mitochondrial processing peptidase have been described in association with a disease phenotype in humans. PMID:25808372

  14. A mitochondrial DNA sequence is associated with abnormal pollen development in cytoplasmic male sterile bean plants.

    PubMed Central

    Johns, C; Lu, M; Lyznik, A; Mackenzie, S

    1992-01-01

    Cytoplasmic male sterility (CMS) in common bean is associated with the presence of a 3-kb unique mitochondrial sequence designated pvs. The pvs sequence encodes at least two open reading frames (297 and 720 bp in length) with portions derived from the chloroplast genome. Fertility restoration by the nuclear restorer gene Fr results in the loss of this transcriptionally active unique region. We examined the effect of CMS (pvs present) and fertility restoration by Fr (pvs absent) on the pattern of pollen development in bean. In the CMS line, pollen aborted in the tetrad stage late in microgametogenesis. Microspores maintained cytoplasmic connections throughout pollen development, indicating aberrant or incomplete cytokinesis. Pollen-specific events associated with pollen abortion and fertility restoration imply that a gametophytic factor or event may be involved in CMS. In situ hybridization experiments suggested that significant reduction or complete loss of the mitochondrial sterility-associated sequence occurred in fertile pollen of F2 populations segregating for fertility. These observations support a model of fertility restoration by the loss of a mitochondrial DNA sequence prior to or during microsporogenesis/gametogenesis. PMID:1498602

  15. Activation of a Mitochondrial ATPase Gene Induces Abnormal Seed Development in Arabidopsis

    PubMed Central

    Baek, Kon; Seo, Pil Joon; Park, Chung-Mo

    2011-01-01

    The ATPases associated with various cellular activities (AAA) proteins are widespread in living organisms. Some of the AAA-type ATPases possess metalloprotease activities. Other members constitute the 26S proteasome complexes. In recent years, a few AAA members have been implicated in vesicle-mediated secretion, membrane fusion, cellular organelle biogenesis, and hypersensitive responses (HR) in plants. However, the physiological roles and biochemical activities of plant AAA proteins have not yet been defined at the molecular level, and regulatory mechanisms underlying their functions are largely unknown. In this study, we showed that overexpression of an Arabidopsis gene encoding a mitochondrial AAA protein, ATPase-in-Seed-Development (ASD), induces morphological and anatomical defects in seed maturation. The ASD gene is expressed at a high level during the seed maturation process and in mature seeds but is repressed rapidly in germinating seeds. Transgenic plants overexpressing the ASD gene are morphologically normal. However, seed formation is severely disrupted in the transgenic plants. The ASD gene is induced by abiotic stresses, such as low temperatures and high salinity, in an abscisic acid (ABA)- dependent manner. The ASD protein possesses ATPase activity and is localized into the mitochondria. Our observations suggest that ASD may play a role in seed maturation by influencing mitochondrial function under abiotic stress. PMID:21359673

  16. Increased Mitochondrial Calcium Sensitivity and Abnormal Expression of Innate Immunity Genes Precede Dopaminergic Defects in Pink1-Deficient Mice

    PubMed Central

    Akundi, Ravi S.; Huang, Zhenyu; Eason, Joshua; Pandya, Jignesh D.; Zhi, Lianteng; Cass, Wayne A.; Sullivan, Patrick G.; Büeler, Hansruedi

    2011-01-01

    Background PTEN-induced kinase 1 (PINK1) is linked to recessive Parkinsonism (EOPD). Pink1 deletion results in impaired dopamine (DA) release and decreased mitochondrial respiration in the striatum of mice. To reveal additional mechanisms of Pink1-related dopaminergic dysfunction, we studied Ca2+ vulnerability of purified brain mitochondria, DA levels and metabolism and whether signaling pathways implicated in Parkinson's disease (PD) display altered activity in the nigrostriatal system of Pink1−/− mice. Methods and Findings Purified brain mitochondria of Pink1−/− mice showed impaired Ca2+ storage capacity, resulting in increased Ca2+ induced mitochondrial permeability transition (mPT) that was rescued by cyclosporine A. A subpopulation of neurons in the substantia nigra of Pink1−/− mice accumulated phospho-c-Jun, showing that Jun N-terminal kinase (JNK) activity is increased. Pink1−/− mice 6 months and older displayed reduced DA levels associated with increased DA turnover. Moreover, Pink1−/− mice had increased levels of IL-1β, IL-12 and IL-10 in the striatum after peripheral challenge with lipopolysaccharide (LPS), and Pink1−/− embryonic fibroblasts showed decreased basal and inflammatory cytokine-induced nuclear factor kappa-β (NF-κB) activity. Quantitative transcriptional profiling in the striatum revealed that Pink1−/− mice differentially express genes that (i) are upregulated in animals with experimentally induced dopaminergic lesions, (ii) regulate innate immune responses and/or apoptosis and (iii) promote axonal regeneration and sprouting. Conclusions Increased mitochondrial Ca2+ sensitivity and JNK activity are early defects in Pink1−/− mice that precede reduced DA levels and abnormal DA homeostasis and may contribute to neuronal dysfunction in familial PD. Differential gene expression in the nigrostriatal system of Pink1−/− mice supports early dopaminergic dysfunction and shows that Pink1 deletion causes aberrant

  17. A spontaneous mutation in the nicotinamide nucleotide transhydrogenase gene of C57BL/6J mice results in mitochondrial redox abnormalities.

    PubMed

    Ronchi, Juliana A; Figueira, Tiago R; Ravagnani, Felipe G; Oliveira, Helena C F; Vercesi, Anibal E; Castilho, Roger F

    2013-10-01

    NADPH is the reducing agent for mitochondrial H2O2 detoxification systems. Nicotinamide nucleotide transhydrogenase (NNT), an integral protein located in the inner mitochondrial membrane, contributes to an elevated mitochondrial NADPH/NADP(+) ratio. This enzyme catalyzes the reduction of NADP(+) at the expense of NADH oxidation and H(+) reentry to the mitochondrial matrix. A spontaneous Nnt mutation in C57BL/6J (B6J-Nnt(MUT)) mice arose nearly 3 decades ago but was only discovered in 2005. Here, we characterize the consequences of the Nnt mutation on the mitochondrial redox functions of B6J-Nnt(MUT) mice. Liver mitochondria were isolated both from an Nnt wild-type C57BL/6 substrain (B6JUnib-Nnt(W)) and from B6J-Nnt(MUT) mice. The functional evaluation of respiring mitochondria revealed major redox alterations in B6J-Nnt(MUT) mice, including an absence of transhydrogenation between NAD and NADP, higher rates of H2O2 release, the spontaneous oxidation of NADPH, the poor ability to metabolize organic peroxide, and a higher susceptibility to undergo Ca(2+)-induced mitochondrial permeability transition. In addition, the mitochondria of B6J-Nnt(MUT) mice exhibited increased oxidized/reduced glutathione ratios as compared to B6JUnib-Nnt(W) mice. Nonetheless, the maximal activity of NADP-dependent isocitrate dehydrogenase, which is a coexisting source of mitochondrial NADPH, was similar between both groups. Altogether, our data suggest that NNT functions as a high-capacity source of mitochondrial NADPH and that its functional loss due to the Nnt mutation results in mitochondrial redox abnormalities, most notably a poor ability to sustain NADP and glutathione in their reduced states. In light of these alterations, the potential drawbacks of using B6J-Nnt(MUT) mice in biomedical research should not be overlooked. PMID:23747984

  18. Acetyl-L-carnitine and lipoic acid improve mitochondrial abnormalities and serum levels of liver enzymes in a mouse model of nonalcoholic fatty liver disease.

    PubMed

    Kathirvel, Elango; Morgan, Kengathevy; French, Samuel W; Morgan, Timothy R

    2013-11-01

    Mitochondrial abnormalities are suggested to be associated with the development of nonalcoholic fatty liver. Liver mitochondrial content and function have been shown to improve in oral feeding of acetyl-L-carnitine (ALC) to rodents. Carnitine is involved in the transport of acyl-coenzyme A across the mitochondrial membrane to be used in mitochondrial β-oxidation. We hypothesized that oral administration ALC with the antioxidant lipoic acid (ALC + LA) would benefit nonalcoholic fatty liver. To test our hypothesis, we fed Balb/C mice a standard diet (SF) or SF with ALC + LA or high-fat diet (HF) or HF with ALC + LA for 6 months. Acetyl-L-carnitine and LA were dissolved at 0.2:0.1% (wt/vol) in drinking water, and mice were allowed free access to food and water. Along with physical parameters, insulin resistance (blood glucose, insulin, glucose tolerance), liver function (alanine transaminase [ALT], aspartate transaminase [AST]), liver histology (hematoxylin and eosin), oxidative stress (malondialdehyde), and mitochondrial abnormalities (carbamoyl phosphate synthase 1 and electron microscopy) were done. Compared with SF, HF had higher body, liver, liver-to-body weight ratio, white adipose tissue, ALT, AST, liver fat, oxidative stress, and insulin resistance. Coadministration of ALC + LA to HF animals significantly improved the mitochondrial marker carbamoyl phosphate synthase 1 and the size of the mitochondria in liver. Alanine transaminase and AST levels were decreased. In a nonalcoholic fatty liver mice model, ALC + LA combination improved liver mitochondrial content, size, serum ALT, and AST without significant changes in oxidative stress, insulin resistance, and liver fat accumulation. PMID:24176233

  19. Wide Distribution of Mitochondrial Genome Rearrangements in Wild Strains of the Cultivated Basidiomycete Agrocybe aegerita

    PubMed Central

    Barroso, G.; Blesa, S.; Labarere, J.

    1995-01-01

    We used restriction fragment length polymorphisms to examine mitochondrial genome rearrangements in 36 wild strains of the cultivated basidiomycete Agrocybe aegerita, collected from widely distributed locations in Europe. We identified two polymorphic regions within the mitochondrial DNA which varied independently: one carrying the Cox II coding sequence and the other carrying the Cox I, ATP6, and ATP8 coding sequences. Two types of mutations were responsible for the restriction fragment length polymorphisms that we observed and, accordingly, were involved in the A. aegerita mitochondrial genome evolution: (i) point mutations, which resulted in strain-specific mitochondrial markers, and (ii) length mutations due to genome rearrangements, such as deletions, insertions, or duplications. Within each polymorphic region, the length differences defined only two mitochondrial types, suggesting that these length mutations were not randomly generated but resulted from a precise rearrangement mechanism. For each of the two polymorphic regions, the two molecular types were distributed among the 36 strains without obvious correlation with their geographic origin. On the basis of these two polymorphisms, it is possible to define four mitochondrial haplotypes. The four mitochondrial haplotypes could be the result of intermolecular recombination between allelic forms present in the population long enough to reach linkage equilibrium. All of the 36 dikaryotic strains contained only a single mitochondrial type, confirming the previously described mitochondrial sorting out after cytoplasmic mixing in basidiomycetes. PMID:16534984

  20. Abnormal bone marrow distribution following unsuccessful hip replacement: a potential confusion on white cell scanning.

    PubMed

    Cunningham, D A

    1991-01-01

    A case is presented in which a grossly abnormal distribution of bone marrow following failed hip replacement would have led to the false diagnosis of osteomyelitis. The value of combining bone marrow scanning with indium white cell scanning in possible osteomyelitis is emphasised. PMID:2019282

  1. FRIENDLY Regulates Mitochondrial Distribution, Fusion, and Quality Control in Arabidopsis1[W][OPEN

    PubMed Central

    El Zawily, Amr M.; Schwarzländer, Markus; Finkemeier, Iris; Johnston, Iain G.; Benamar, Abdelilah; Cao, Yongguo; Gissot, Clémence; Meyer, Andreas J.; Wilson, Ken; Datla, Raju; Macherel, David; Jones, Nick S.; Logan, David C.

    2014-01-01

    Mitochondria are defining components of most eukaryotes. However, higher plant mitochondria differ biochemically, morphologically, and dynamically from those in other eukaryotes. FRIENDLY, a member of the CLUSTERED MITOCHONDRIA superfamily, is conserved among eukaryotes and is required for correct distribution of mitochondria within the cell. We sought to understand how disruption of FRIENDLY function in Arabidopsis (Arabidopsis thaliana) leads to mitochondrial clustering and the effects of this aberrant chondriome on cell and whole-plant physiology. We present evidence for a role of FRIENDLY in mediating intermitochondrial association, which is a necessary prelude to mitochondrial fusion. We demonstrate that disruption of mitochondrial association, motility, and chondriome structure in friendly affects mitochondrial quality control and leads to mitochondrial stress, cell death, and strong growth phenotypes. PMID:25165398

  2. The formation and functional consequences of heterogeneous mitochondrial distributions in skeletal muscle.

    PubMed

    Pathi, B; Kinsey, S T; Howdeshell, M E; Priester, C; McNeill, R S; Locke, B R

    2012-06-01

    Diffusion plays a prominent role in governing both rates of aerobic metabolic fluxes and mitochondrial organization in muscle fibers. However, there is no mechanism to explain how the non-homogeneous mitochondrial distributions that are prevalent in skeletal muscle arise. We propose that spatially variable degradation with dependence on O(2) concentration, and spatially uniform signals for biogenesis, can account for observed distributions of mitochondria in a diversity of skeletal muscle. We used light and transmission electron microscopy and stereology to examine fiber size, capillarity and mitochondrial distribution in fish red and white muscle, fish white muscle that undergoes extreme hypertrophic growth, and four fiber types in mouse muscle. The observed distributions were compared with those generated using a coupled reaction-diffusion/cellular automata (CA) mathematical model of mitochondrial function. Reaction-diffusion analysis of metabolites such as oxygen, ATP, ADP and PCr involved in energy metabolism and mitochondrial function were considered. Coupled to the reaction-diffusion approach was a CA approach governing mitochondrial life cycles in response to the metabolic state of the fiber. The model results were consistent with the experimental observations and showed higher mitochondrial densities near the capillaries because of the sometimes steep gradients in oxygen. The present study found that selective removal of mitochondria in the presence of low prevailing local oxygen concentrations is likely the primary factor dictating the spatial heterogeneity of mitochondria in a diversity of fibers. The model results also suggest decreased diffusional constraints corresponding to the heterogeneous mitochondrial distribution assessed using the effectiveness factor, defined as the ratio of the reaction rate in the system with finite rates of diffusion to that in the absence of any diffusion limitation. Thus, the non-uniform distribution benefits the muscle

  3. HUMMR, a hypoxia- and HIF-1α–inducible protein, alters mitochondrial distribution and transport

    PubMed Central

    Li, Yan; Lim, Seung; Hoffman, David; Aspenstrom, Pontus; Federoff, Howard J.

    2009-01-01

    Mitochondrial transport is critical for maintenance of normal neuronal function. Here, we identify a novel mitochondria protein, hypoxia up-regulated mitochondrial movement regulator (HUMMR), which is expressed in neurons and is markedly induced by hypoxia-inducible factor 1 α (HIF-1α). Interestingly, HUMMR interacts with Miro-1 and Miro-2, mitochondrial proteins that are critical for mediating mitochondrial transport. Interestingly, knockdown of HUMMR or HIF-1 function in neurons exposed to hypoxia markedly reduces mitochondrial content in axons. Because mitochondrial transport and distribution are inextricably linked, the impact of reduced HUMMR function on the direction of mitochondrial transport was also explored. Loss of HUMMR function in hypoxia diminished the percentage of motile mitochondria moving in the anterograde direction and enhanced the percentage moving in the retrograde direction. Thus, HUMMR, a novel mitochondrial protein induced by HIF-1 and hypoxia, biases mitochondria transport in the anterograde direction. These findings have broad implications for maintenance of neuronal viability and function during physiological and pathological states. PMID:19528298

  4. Screen for abnormal mitochondrial phenotypes in mouse embryonic stem cells identifies a model for succinyl-CoA ligase deficiency and mtDNA depletion

    PubMed Central

    Donti, Taraka R.; Stromberger, Carmen; Ge, Ming; Eldin, Karen W.; Craigen, William J.; Graham, Brett H.

    2014-01-01

    ABSTRACT Mutations in subunits of succinyl-CoA synthetase/ligase (SCS), a component of the citric acid cycle, are associated with mitochondrial encephalomyopathy, elevation of methylmalonic acid (MMA), and mitochondrial DNA (mtDNA) depletion. A FACS-based retroviral-mediated gene trap mutagenesis screen in mouse embryonic stem (ES) cells for abnormal mitochondrial phenotypes identified a gene trap allele of Sucla2 (Sucla2SAβgeo), which was used to generate transgenic mice. Sucla2 encodes the ADP-specific β-subunit isoform of SCS. Sucla2SAβgeo homozygotes exhibited recessive lethality, with most mutants dying late in gestation (e18.5). Mutant placenta and embryonic (e17.5) brain, heart and muscle showed varying degrees of mtDNA depletion (20–60%). However, there was no mtDNA depletion in mutant liver, where the gene is not normally expressed. Elevated levels of MMA were observed in embryonic brain. SCS-deficient mouse embryonic fibroblasts (MEFs) demonstrated a 50% reduction in mtDNA content compared with wild-type MEFs. The mtDNA depletion resulted in reduced steady state levels of mtDNA encoded proteins and multiple respiratory chain deficiencies. mtDNA content could be restored by reintroduction of Sucla2. This mouse model of SCS deficiency and mtDNA depletion promises to provide insights into the pathogenesis of mitochondrial diseases with mtDNA depletion and into the biology of mtDNA maintenance. In addition, this report demonstrates the power of a genetic screen that combines gene trap mutagenesis and FACS analysis in mouse ES cells to identify mitochondrial phenotypes and to develop animal models of mitochondrial dysfunction. PMID:24271779

  5. Heat distribution over normal and abnormal joints: thermal pattern and quantification.

    PubMed Central

    Salisbury, R S; Parr, G; De Silva, M; Hazleman, B L; Page-Thomas, D P

    1983-01-01

    We have identified regular thermal patterns over normal knee, ankle, and elbow joints and demonstrate how synovitis affecting these joints may be identified by alteration or loss of the thermal pattern. Sixty healthy volunteers were thermographed on a total of 190 occasions, and 614 out of 618 joints conformed to the normal thermal pattern. Eighty-five patients with synovitis of at least one of the specified joints were thermographed on a total of 339 occasions, and 322 out of 1362 thermograms were abnormal. No joint with clinical evidence of synovitis had a normal thermal pattern. As temperature-based parameters have been found to show marked diurnal variation and relative frequency distributions do not have this drawback, we suggest that quantification of synovitis by thermography should in future be based on abnormalities of thermal pattern rather than absolute skin temperature values. PMID:6684900

  6. A review of research trends in physiological abnormalities in autism spectrum disorders: immune dysregulation, inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures

    PubMed Central

    Rossignol, D A; Frye, R E

    2012-01-01

    Recent studies have implicated physiological and metabolic abnormalities in autism spectrum disorders (ASD) and other psychiatric disorders, particularly immune dysregulation or inflammation, oxidative stress, mitochondrial dysfunction and environmental toxicant exposures (‘four major areas'). The aim of this study was to determine trends in the literature on these topics with respect to ASD. A comprehensive literature search from 1971 to 2010 was performed in these four major areas in ASD with three objectives. First, publications were divided by several criteria, including whether or not they implicated an association between the physiological abnormality and ASD. A large percentage of publications implicated an association between ASD and immune dysregulation/inflammation (416 out of 437 publications, 95%), oxidative stress (all 115), mitochondrial dysfunction (145 of 153, 95%) and toxicant exposures (170 of 190, 89%). Second, the strength of evidence for publications in each area was computed using a validated scale. The strongest evidence was for immune dysregulation/inflammation and oxidative stress, followed by toxicant exposures and mitochondrial dysfunction. In all areas, at least 45% of the publications were rated as providing strong evidence for an association between the physiological abnormalities and ASD. Third, the time trends in the four major areas were compared with trends in neuroimaging, neuropathology, theory of mind and genetics (‘four comparison areas'). The number of publications per 5-year block in all eight areas was calculated in order to identify significant changes in trends. Prior to 1986, only 12 publications were identified in the four major areas and 51 in the four comparison areas (42 for genetics). For each 5-year period, the total number of publications in the eight combined areas increased progressively. Most publications (552 of 895, 62%) in the four major areas were published in the last 5 years (2006–2010). Evaluation

  7. Order within a mosaic distribution of mitochondrial c-type cytochrome biogenesis systems?

    PubMed

    Allen, James W A; Jackson, Andrew P; Rigden, Daniel J; Willis, Antony C; Ferguson, Stuart J; Ginger, Michael L

    2008-05-01

    Mitochondrial cytochromes c and c(1) are present in all eukaryotes that use oxygen as the terminal electron acceptor in the respiratory chain. Maturation of c-type cytochromes requires covalent attachment of the heme cofactor to the protein, and there are at least five distinct biogenesis systems that catalyze this post-translational modification in different organisms and organelles. In this study, we use biochemical data, comparative genomic and structural bioinformatics investigations to provide a holistic view of mitochondrial c-type cytochrome biogenesis and its evolution. There are three pathways for mitochondrial c-type cytochrome maturation, only one of which is present in prokaryotes. We analyze the evolutionary distribution of these biogenesis systems, which include the Ccm system (System I) and the enzyme heme lyase (System III). We conclude that heme lyase evolved once and, in many lineages, replaced the multicomponent Ccm system (present in the proto-mitochondrial endosymbiont), probably as a consequence of lateral gene transfer. We find no evidence of a System III precursor in prokaryotes, and argue that System III is incompatible with multi-heme cytochromes common to bacteria, but absent from eukaryotes. The evolution of the eukaryotic-specific protein heme lyase is strikingly unusual, given that this protein provides a function (thioether bond formation) that is also ubiquitous in prokaryotes. The absence of any known c-type cytochrome biogenesis system from the sequenced genomes of various trypanosome species indicates the presence of a third distinct mitochondrial pathway. Interestingly, this system attaches heme to mitochondrial cytochromes c that contain only one cysteine residue, rather than the usual two, within the heme-binding motif. The isolation of single-cysteine-containing mitochondrial cytochromes c from free-living kinetoplastids, Euglena and the marine flagellate Diplonema papillatum suggests that this unique form of heme attachment

  8. Metabolic abnormalities induced by mitochondrial dysfunction in skeletal muscle of the renal carcinoma Eker (TSC2+/-) rat model.

    PubMed

    Aizawa, Yumi; Shirai, Tomomi; Kobayashi, Toshiyuki; Hino, Okio; Tsujii, Yoshimasa; Inoue, Hirofumi; Kazami, Machiko; Tadokoro, Tadahiro; Suzuki, Tsukasa; Kobayashi, Ken-Ichi; Yamamoto, Yuji

    2016-08-01

    Tuberous sclerosis complex 2 (TSC2) is a mediator of insulin signal transduction, and a loss of function in TSC2 induces hyperactivation of mTORC1 pathway, which leads to tumorigenesis. We have previously demonstrated that Eker rat model, which is heterozygous for a TSC2 mutation, exhibits hyperglycemia and hyperketonemia. The present study was to investigate whether these changes also can affect metabolism in skeletal muscle of the Eker rat. Wild-type (TSC2+/+) and Eker (TSC2+/-) rats underwent an oral glucose tolerance test, and the latter showed decrease in whole-body glucose utilization. Additionally, reductions in the expression of glycolysis-, lipolysis-, and ketone body-related genes in skeletal muscle were observed in Eker rats. Furthermore, ATP content and mitochondrial DNA copy number were lower in skeletal muscle of Eker rats. These data demonstrate that heterozygous to mutation TSC2 not only affects the liver metabolism, but also skeletal muscle metabolism, via mitochondrial dysfunction. PMID:27031579

  9. Mitochondria-targeted ROS scavenger improves post-ischemic recovery of cardiac function and attenuates mitochondrial abnormalities in aged rats

    PubMed Central

    Escobales, Nelson; Nuñez, Rebeca E.; Jang, Sehwan; Parodi-Rullan, Rebecca; Ayala-Peña, Sylvette; Sacher, Joshua R.; Skoda, Erin M.; Wipf, Peter; Frontera, Walter; Javadov, Sabzali

    2014-01-01

    Mitochondria-generated reactive oxygen species (ROS) play a crucial role in the pathogenesis of aging and age-associated diseases. In this study, we evaluated the effects of XJB-5-131 (XJB), a mitochondria-targeted ROS and electron scavenger, on cardiac resistance to ischemia-reperfusion (IR)-induced oxidative stress in aged rats. Male adult (5-month old, n=17) and aged (29-month old, n=19) Fischer Brown Norway (F344/BN) rats were randomly assigned to the following groups: adult (A), adult+XJB (AX), aged (O), and aged+XJB (OX). XJB was administered 3 times per week (3 mg/kg body weight, IP) for four weeks. At the end of the treatment period, cardiac function was continuously monitored in excised hearts using the Langendorff technique for 30 min, followed by 20-min of global ischemia, and 60-min reperfusion. XJB improved post-ischemic recovery of aged hearts, as evidenced by greater left ventricular developed-pressures and rate-pressure products than the untreated, aged-matched group. The state 3 respiration rates at complexes I, II and IV of mitochondria isolated from XJB-treated aged hearts were 57% (P<0.05), 25% (P<0.05) and 28% (P<0.05), respectively, higher than controls. Ca2+-induced swelling, an indicator of permeability transition pore opening, was reduced in mitochondria of XJB-treated aged rats. In addition, XJB significantly attenuated the H2O2-induced depolarization of the mitochondrial inner membrane as well as total and mitochondrial ROS levels in cultured cardiomyocytes. This study underlines the importance of mitochondrial ROS in aging-induced cardiac dysfunction and suggests that targeting mitochondrial ROS may be an effective therapeutic approach to protect the aged heart against IR injury. PMID:25451170

  10. Mitochondria-targeted ROS scavenger improves post-ischemic recovery of cardiac function and attenuates mitochondrial abnormalities in aged rats.

    PubMed

    Escobales, Nelson; Nuñez, Rebeca E; Jang, Sehwan; Parodi-Rullan, Rebecca; Ayala-Peña, Sylvette; Sacher, Joshua R; Skoda, Erin M; Wipf, Peter; Frontera, Walter; Javadov, Sabzali

    2014-12-01

    Mitochondria-generated reactive oxygen species (ROS) play a crucial role in the pathogenesis of aging and age-associated diseases. In this study, we evaluated the effects of XJB-5-131 (XJB), a mitochondria-targeted ROS and electron scavenger, on cardiac resistance to ischemia-reperfusion (IR)-induced oxidative stress in aged rats. Male adult (5-month old, n=17) and aged (29-month old, n=19) Fischer Brown Norway (F344/BN) rats were randomly assigned to the following groups: adult (A), adult+XJB (AX), aged (O), and aged+XJB (OX). XJB was administered 3 times per week (3mg/kg body weight, IP) for four weeks. At the end of the treatment period, cardiac function was continuously monitored in excised hearts using the Langendorff technique for 30 min, followed by 20 min of global ischemia, and 60-min reperfusion. XJB improved post-ischemic recovery of aged hearts, as evidenced by greater left ventricular developed-pressures and rate-pressure products than the untreated, aged-matched group. The state 3 respiration rates at complexes I, II and IV of mitochondria isolated from XJB-treated aged hearts were 57% (P<0.05), 25% (P<0.05) and 28% (P<0.05), respectively, higher than controls. Ca(2+)-induced swelling, an indicator of permeability transition pore opening, was reduced in the mitochondria of XJB-treated aged rats. In addition, XJB significantly attenuated the H2O2-induced depolarization of the mitochondrial inner membrane as well as the total and mitochondrial ROS levels in cultured cardiomyocytes. This study underlines the importance of mitochondrial ROS in aging-induced cardiac dysfunction and suggests that targeting mitochondrial ROS may be an effective therapeutic approach to protect the aged heart against IR injury. PMID:25451170

  11. Hypertension and abnormal fat distribution but not insulin resistance in mice with P465L PPARγ

    PubMed Central

    Tsai, Yau-Sheng; Kim, Hyo-Jeong; Takahashi, Nobuyuki; Kim, Hyung-Suk; Hagaman, John R.; Kim, Jason K.; Maeda, Nobuyo

    2004-01-01

    Peroxisome proliferator–activated receptor γ (PPARγ), the molecular target of a class of insulin sensitizers, regulates adipocyte differentiation and lipid metabolism. A dominant negative P467L mutation in the ligand-binding domain of PPARγ in humans is associated with severe insulin resistance and hypertension. Homozygous mice with the equivalent P465L mutation die in utero. Heterozygous mice grow normally and have normal total adipose tissue weight. However, they have reduced interscapular brown adipose tissue and intra-abdominal fat mass, and increased extra-abdominal subcutaneous fat, compared with wild-type mice. They have normal plasma glucose levels and insulin sensitivity, and increased glucose tolerance. However, during high-fat feeding, their plasma insulin levels are mildly elevated in association with a significant increase in pancreatic islet mass. They are hypertensive, and expression of the angiotensinogen gene is increased in their subcutaneous adipose tissues. The effects of P465L on blood pressure, fat distribution, and insulin sensitivity are the same in both male and female mice regardless of diet and age. Thus the P465L mutation alone is sufficient to cause abnormal fat distribution and hypertension but not insulin resistance in mice. These results provide genetic evidence for a critical role for PPARγ in blood pressure regulation that is not dependent on altered insulin sensitivity. PMID:15254591

  12. The Prevalence and Distribution of Vitreoretinal Interface Abnormalities among Urban Community Population in China

    PubMed Central

    Liu, Lei; Yue, Song; Wu, Jingyang; Zhang, Jiahua; Lian, Jie; Huang, Desheng; Teng, Weiping; Chen, Lei

    2015-01-01

    The aim of this research was to identify the prevalence and distribution of vitreoretinal interface abnormalities (VIAs) among urban community population in Shenyang, China. According to the WHO criteria, a cross-sectional study was carried out among 304 Type 2 diabetes (T2D) patients and 304 people without diabetes as control over 45 years old. The presence of VIAs was determined by standardized grading of macular optical coherence tomography (Optovue OCT; Optovue, Inc., Fremont, CA) scans and two-field fundus photographs in at least one eye. For both men and women, high prevalence of VIAs (70.79%) was observed among over 65-years-old T2D patients. Prevalence of VIAs was observed to be high among T2D patients in all age groups compared to normal subjects. Prevalence of VIAs increased with age in all subjects. Prevalence of components of VIAs was epiretinal membrane (ERM) 11.43%, posterior vitreous detachment (PVD) 17.76%, vitreomacular traction syndrome (VMT) 5.67%, macular cysts/macular edema (MC/ME) 4.61%, full-thickness macular hole (FTMH) 0.82%, and partial thickness macular hole (PTMH) 0.74% in any eye, respectively. ERM and MC/ME were more prevalent in T2D in both males and females. The results highlight the need for early detection using OCT and approaches for the prevention of VIAs of diabetes in urban community. PMID:26759726

  13. Hypobaric Hypoxia Imbalances Mitochondrial Dynamics in Rat Brain Hippocampus

    PubMed Central

    Jain, Khushbu; Prasad, Dipti; Singh, Shashi Bala; Kohli, Ekta

    2015-01-01

    Brain is predominantly susceptible to oxidative stress and mitochondrial dysfunction during hypobaric hypoxia, and therefore undergoes neurodegeneration due to energy crisis. Evidences illustrate a high degree of association for mitochondrial fusion/fission imbalance and mitochondrial dysfunction. Mitochondrial fusion/fission is a recently reported dynamic mechanism which frequently occurs among cellular mitochondrial network. Hence, the study investigated the temporal alteration and involvement of abnormal mitochondrial dynamics (fusion/fission) along with disturbed mitochondrial functionality during chronic exposure to hypobaric hypoxia (HH). The Sprague-Dawley rats were exposed to simulated high altitude equivalent to 25000 ft for 3, 7, 14, 21, and 28 days. Mitochondrial morphology, distribution within neurons, enzyme activity of respiratory complexes, Δψm, ADP: ATP, and expression of fission/fusion key proteins were determined. Results demonstrated HH induced alteration in mitochondrial morphology by damaged, small mitochondria observed in neurons with disturbance of mitochondrial functionality and reduced mitochondrial density in neuronal processes manifested by excessive mitochondrial fragmentation (fission) and decreased mitochondrial fusion as compared to unexposed rat brain hippocampus. The study suggested that imbalance in mitochondrial dynamics is one of the noteworthy mechanisms occurring in hippocampal neurons during HH insult. PMID:26236504

  14. Distribution of nuclear mitochondrial pseudogenes in three pollinator fig wasps associated with Ficus pumila

    NASA Astrophysics Data System (ADS)

    Chen, Yan; Liu, Min; Compton, Stephen G.; Chen, Xiao-Yong

    2014-05-01

    Nuclear mitochondrial pseudogenes (NUMTs) are nuclear sequences transferred from mitochondrial genomes. Although widespread, their distribution patterns among populations or closely related species are rarely documented. We amplified and sequenced the mitochondrial cytochrome b (Cytb) gene to check for NUMTs in three fig wasp species that pollinate Ficus pumila (Wiebesia sp. 1, 2 and 3) in Southeastern China using direct and cloned sequencing. Unambiguous sequences (332) of 487 bp in length belonging to 33 haplotypes were found by direct sequencing. Their distribution was highly concordant with those of cytochrome c oxidase subunit I (COI). Obvious signs of co-amplification of NUMTs were indicated by their uneven distribution. NUMTs were observed in all individuals of 12 populations of Wiebesia sp. 3, and 13 individuals of three northern populations of Wiebesia sp. 1. Sequencing clones of potential co-amplification products confirmed that they were NUMTs. These NUMTs either clustered as NUMT clades basal to mtDNA Cytb clades (basal NUMTs), or together with Cytb haplotypes. Basal NUMTs had either stop codons or frame-shifting mutations resulting from deletion of a 106 bp fragment. In addition, no third codon or synonymous substitutions were detected within each NUMT clade. The phylogenetic tree indicated that basal NUMTs had been inserted into nuclei before divergence of the three species. No significant pairwise differences were detected in their ratios of third codon substitutions, suggesting that these NUMTs originated from one transfer event, with duplication in the nuclear genome resulting in the coexistence of the 381 bp copy. No significant substitution differences were detected between Cytb haplotypes and NUMTs that clustered with Cytb haplotypes. However, these NUMTs coexisted with Cytb haplotypes in multiple populations, suggesting that these NUMT haplotypes were recently inserted into the nuclear genome. Both basal and recently inserted NUMTs were rare

  15. Mitochondrial encephalomyopathies.

    PubMed

    Lombes, A; Bonilla, E; Dimauro, S

    1989-01-01

    Increasingly numerous studies are being devoted to mitochondrial diseases, notably those which involve the neuromuscular system. Our knowledge and understanding of these diseases is progressing rapidly. We owe to Luft et al. (1962) the first description of this type of diseases. Their patient, a woman, presented with clinical symptoms suggestive of mitochondrial dysfunction, major histological abnormalities of skeletal muscle mitochondria and defective oxidative phosphorylation coupling clearly demonstrated in mitochondria isolated from muscle. This clinical, histological and biochemical triad led to the definition of mitochondrial myopathies. Subsequently, the triad was seldom encountered, and most mitochondrial myopathies were primarily defined by the presence of morphological abnormalities of muscle mitochondria. This review deals with the morphological, clinical, biochemical and genetic aspects of mitochondrial encephalomyopathies. The various morphological abnormalities of mitochondria are described. These are not specific of any particular disease. They may be present in some non-mitochondrial diseases and may be lacking in diseases due to specific defects of mitochondrial enzymes (e.g. carnitine palmityl-transferase or pyruvate dehydrogenase). The clinical classification of mitochondrial encephalomyopathies is discussed. There are two main schools of thought: the "lumpers" do not recognize specific syndromes within the spectrum of mitochondrial "cytopathies", the "splitters" try to identify specific syndromes while recognizing the existence of borderline cases. The following syndromes are described: chronic progressive external ophthalmoplegia (CPEO), Kearns-Sayre syndrome (KSS), MERRF syndrome (myoclonic epilepsy with ragged-red fibers), MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) and Leigh and Alpers syndromes. The biochemical classification comprises five types of abnormalities: defects of transport

  16. Mitochondrial Diversity and Distribution of African Green Monkeys (Chlorocebus Gray, 1870)

    PubMed Central

    Haus, Tanja; Akom, Emmanuel; Agwanda, Bernard; Hofreiter, Michael; Roos, Christian; Zinner, Dietmar

    2013-01-01

    African green monkeys (Chlorocebus) represent a widely distributed and morphologically diverse primate genus in sub-Saharan Africa. Little attention has been paid to their genetic diversity and phylogeny. Based on morphological data, six species are currently recognized, but their taxonomy remains disputed. Here, we aim to characterize the mitochondrial (mt) DNA diversity, biogeography and phylogeny of African green monkeys. We analyzed the complete mitochondrial cytochrome b gene of 126 samples using feces from wild individuals and material from zoo and museum specimens with clear geographical provenance, including several type specimens. We found evidence for nine major mtDNA clades that reflect geographic distributions rather than taxa, implying that the mtDNA diversity of African green monkeys does not conform to existing taxonomic classifications. Phylogenetic relationships among clades could not be resolved suggesting a rapid early divergence of lineages. Several discordances between mtDNA and phenotype indicate that hybridization may have occurred in contact zones among species, including the threatened Bale monkey (Chlorocebus djamdjamensis). Our results provide both valuable data on African green monkeys’ genetic diversity and evolution and a basis for further molecular studies on this genus. Am. J. Primatol. 75:350-360, 2013. © 2013 Wiley Periodicals, Inc. PMID:23307319

  17. Application of a Random Walk Model to Geographic Distributions of Animal Mitochondrial DNA Variation

    PubMed Central

    Neigel, J. E.; Avise, J. C.

    1993-01-01

    In rapidly evolving molecules, such as animal mitochondrial DNA, mutations that delineate specific lineages may not be dispersed at sufficient rates to attain an equilibrium between genetic drift and gene flow. Here we predict conditions that lead to nonequilibrium geographic distributions of mtDNA lineages, test the robustness of these predictions and examine mtDNA data sets for consistency with our model. Under a simple isolation by distance model, the variance of an mtDNA lineage's geographic distribution is expected be proportional to its age. Simulation results indicated that this relationship is fairly robust. Analysis of mtDNA data from natural populations revealed three qualitative distributional patterns: (1) significant departure of lineage structure from equilibrium geographic distributions, a pattern exhibited in three rodent species with limited dispersal; (2) nonsignificant departure from equilibrium expectations, exhibited by two avian and two marine fish species with potentials for relatively long-distance dispersal; and (3) a progression from nonequilibrium distributions for younger lineages to equilibrium distributions for older lineages, a condition displayed by one surveyed avian species. These results demonstrate the advantages of considering mutation and genealogy in the interpretation of mtDNA geographic variation. PMID:8307331

  18. Tracing glacial refugia of Triturus newts based on mitochondrial DNA phylogeography and species distribution modeling

    PubMed Central

    2013-01-01

    Introduction The major climatic oscillations during the Quaternary Ice Age heavily influenced the distribution of species and left their mark on intraspecific genetic diversity. Past range shifts can be reconstructed with the aid of species distribution modeling and phylogeographical analyses. We test the responses of the different members of the genus Triturus (i.e. the marbled and crested newts) as the climate shifted from the previous glacial period (the Last Glacial Maximum, ~21 Ka) to the current interglacial. Results We present the results of a dense mitochondrial DNA phylogeography (visualizing genetic diversity within and divergence among populations) and species distribution modeling (using two different climate simulations) for the nine Triturus species on composite maps. Conclusions The combined use of species distribution modeling and mitochondrial phylogeography provides insight in the glacial contraction and postglacial expansion of Triturus. The combined use of the two independent techniques yields a more complete understanding of the historical biogeography of Triturus than both approaches would on their own. Triturus newts generally conform to the ‘southern richness and northern purity’ paradigm, but we also find more intricate patterns, such as the absence of genetic variation and suitable area at the Last Glacial Maximum (T. dobrogicus), an ‘extra-Mediterranean’ refugium in the Carpathian Basin (T. cristatus), and areas where species displaced one another postglacially (e.g. T. macedonicus and western T. karelinii). We provide a biogeographical scenario for Triturus, showing the positions of glacial refugia, the regions that were postglacially colonized and the areas where species displaced one another as they shifted their ranges. PMID:23514662

  19. Stimulation of adenosine A2A receptors reduces intracellular cholesterol accumulation and rescues mitochondrial abnormalities in human neural cell models of Niemann-Pick C1.

    PubMed

    Ferrante, A; De Nuccio, C; Pepponi, R; Visentin, S; Martire, A; Bernardo, A; Minghetti, L; Popoli, P

    2016-04-01

    Niemann Pick C 1 (NPC1) disease is an incurable, devastating lysosomal-lipid storage disorder characterized by hepatosplenomegaly, progressive neurological impairment and early death. Current treatments are very limited and the research of new therapeutic targets is thus mandatory. We recently showed that the stimulation of adenosine A2A receptors (A2ARs) rescues the abnormal phenotype of fibroblasts from NPC1 patients suggesting that A2AR agonists could represent a therapeutic option for this disease. However, since all NPC1 patients develop severe neurological symptoms which can be ascribed to the complex pathology occurring in both neurons and oligodendrocytes, in the present paper we tested the effects of the A2AR agonist CGS21680 in human neuronal and oligodendroglial NPC1 cell lines (i.e. neuroblastoma SH-SY5Y and oligodendroglial MO3.13 transiently transfected with NPC1 small interfering RNA). The down-regulation of the NPC1 protein effectively resulted in intracellular cholesterol accumulation and altered mitochondrial membrane potential. Both effects were significantly attenuated by CGS21680 (500 nM). The protective effects of CGS were prevented by the selective A2AR antagonist ZM241385 (500 nM). The involvement of calcium modulation was demonstrated by the ability of Bapta-AM (5-7 μM) in reverting the effect of CGS. The A2A-dependent activity was prevented by the PKA-inhibitor KT5720, thus showing the involvement of the cAMP/PKA signaling. These findings provide a clear in vitro proof of concept that A2AR agonists are promising potential drugs for NPC disease. PMID:26631535

  20. Nanoscale distribution of mitochondrial import receptor Tom20 is adjusted to cellular conditions and exhibits an inner-cellular gradient.

    PubMed

    Wurm, Christian A; Neumann, Daniel; Lauterbach, Marcel A; Harke, Benjamin; Egner, Alexander; Hell, Stefan W; Jakobs, Stefan

    2011-08-16

    The translocase of the mitochondrial outer membrane (TOM) complex is the main import pore for nuclear-encoded proteins into mitochondria, yet little is known about its spatial distribution within the outer membrane. Super-resolution stimulated emission depletion microscopy was used to determine quantitatively the nanoscale distribution of Tom20, a subunit of the TOM complex, in more than 1,000 cells. We demonstrate that Tom20 is located in clusters whose nanoscale distribution is finely adjusted to the cellular growth conditions as well as to the specific position of a cell within a microcolony. The density of the clusters correlates to the mitochondrial membrane potential. The distributions of clusters of Tom20 and of Tom22 follow an inner-cellular gradient from the perinuclear to the peripheral mitochondria. We conclude that the nanoscale distribution of the TOM complex is finely adjusted to the cellular conditions, resulting in distribution gradients both within single cells and between adjacent cells. PMID:21799113

  1. Mitochondrial evidence for panmixia despite perceived barriers to gene flow in a widely distributed waterbird.

    PubMed

    Oomen, Rebekah A; Reudink, Matthew W; Nocera, Joseph J; Somers, Christopher M; Green, M Clay; Kyle, Christopher J

    2011-01-01

    We examined the mitochondrial genetic structure of American white pelicans (Pelecanus erythrorhynchos) to: 1) verify or refute whether American white pelicans are panmictic and 2) understand if any lack of genetic structure is the result of contemporary processes or historical phenomena. Sequence analysis of mitochondrial DNA control region haplotypes of 367 individuals from 19 colonies located across their North American range revealed a lack of population genetic or phylogeographic structure. This lack of structure was unexpected because: 1) Major geographic barriers such as the North American Continental Divide are thought to limit dispersal; 2) Differences in migratory behavior are expected to promote population differentiation; and 3) Many widespread North American migratory bird species show historic patterns of differentiation resulting from having inhabited multiple glacial refugia. Further, high haplotype diversity and many rare haplotypes are maintained across the species' distribution, despite frequent local extinctions and recolonizations that are expected to decrease diversity. Our findings suggest that American white pelicans have a high effective population size and low natal philopatry. We suggest that the rangewide panmixia we observed in American white pelicans is due to high historical and contemporary gene flow, enabled by high mobility and a lack of effective physical or behavioral barriers. PMID:21705489

  2. Widespread geographical distribution of mitochondrial haplotypes in rock-dwelling cichlid fishes from Lake Tanganyika.

    PubMed

    Meyer, A; Knowles, L L; Verheyen, E

    1996-06-01

    The spectacularly diverse cichlid fish species flocks of the East African Rift Lakes have elicited much debate on the potential evolutionary mechanisms responsible for the origin of these adaptive radiations. An historical perspective on population structure may offer insights into the processes driving population differentiation and possibly speciation. Here, we examine mitochondrial DNA (mtDNA) sequence variation in two endemic species of rock-dwelling cichlids, Simochromis babaulti and S. diagramma, from Lake Tanganyika. Phylogeographic analyses were used to infer what factors might have been important in the genetic structuring of Simochromis populations. Patterns of mtDNA differentiation in Simochromis were compared to those of other rock-dwelling cichlids to distinguish between competing hypotheses concerning the processes underlying their evolution. In striking contrast to previous findings, populations of Simochromis, even those separated by up to 300 km, were found to share mitochondrial DNA haplotypes. There is no correspondence between mtDNA genealogies and the geographical distribution of populations. Only S. babaulti, but not S. diagramma was found to have a significant association between genetic and geographic distance. These phylogeographic patterns suggest that the evolutionary effects of abiotic and biotic factors shaping population genetic structure may differ substantially even among closely related species of rock-dwelling cichlids. Physical events and barriers to gene flow that are believed to have had a major impact on the geographical distribution and intralacustrine speciation of Tropheus do not seem to have equally strongly affected its close relative Simochromis. These findings emphasize that no single mechanism can be responsible for the formation of population structure, speciation, and the adaptive radiation of all cichlid fishes. PMID:8688956

  3. A Genetic Discontinuity in a Continuously Distributed Species: Mitochondrial DNA in the American Oyster, Crassostrea Virginica

    PubMed Central

    Reeb, C. A.; Avise, J. C.

    1990-01-01

    Restriction site variation in mitochondrial DNA (mtDNA) of the American oyster (Crassostrea virginica) was surveyed in continuously distributed populations sampled from the Gulf of St. Lawrence, Canada, to Brownsville, Texas. mtDNA clonal diversity was high, with 82 different haplotypes revealed among 212 oysters with 13 endonucleases. The mtDNA clones grouped into two distinct genetic arrays (estimated to differ by about 2.6% in nucleotide sequence) that characterized oysters collected north vs. south of a region on the Atlantic mid-coast of Florida. The population genetic ``break'' in mtDNA contrasts with previous reports of near uniformity of nuclear (allozyme) allele frequencies throughout the range of the species, but agrees closely with the magnitude and pattern of mtDNA differentiation reported in other estuarine species in the southeastern United States. This concordance of mtDNA phylogenetic pattern across independently evolving species provides strong evidence for vicariant biogeographic processes in initiating intraspecific population structure. The post-Miocene ecological history of the region suggests that reduced precipitation levels in an enlarged Floridian peninsula may have created discontinuities in suitable estuarine habitat for oysters during glacial periods, and that today such population separations are maintained by the combined influence of ecological gradients and oceanic currents on larval dispersal. The results are consistent with the hypothesis that historical vicariant events, in conjunction with contemporary environmental influences on gene flow, can result in genetic discontinuities in continuously distributed species with high dispersal capability. PMID:1968412

  4. The Spectrum of Mitochondrial Ultrastructural Defects in Mitochondrial Myopathy

    PubMed Central

    Vincent, Amy E.; Ng, Yi Shiau; White, Kathryn; Davey, Tracey; Mannella, Carmen; Falkous, Gavin; Feeney, Catherine; Schaefer, Andrew M.; McFarland, Robert; Gorman, Grainne S.; Taylor, Robert W.; Turnbull, Doug M.; Picard, Martin

    2016-01-01

    Mitochondrial functions are intrinsically linked to their morphology and membrane ultrastructure. Characterizing abnormal mitochondrial structural features may thus provide insight into the underlying pathogenesis of inherited and acquired mitochondrial diseases. Following a systematic literature review on ultrastructural defects in mitochondrial myopathy, we investigated skeletal muscle biopsies from seven subjects with genetically defined mtDNA mutations. Mitochondrial ultrastructure and morphology were characterized using two complimentary approaches: transmission electron microscopy (TEM) and serial block face scanning EM (SBF-SEM) with 3D reconstruction. Six ultrastructural abnormalities were identified including i) paracrystalline inclusions, ii) linearization of cristae and abnormal angular features, iii) concentric layering of cristae membranes, iv) matrix compartmentalization, v) nanotunelling, and vi) donut-shaped mitochondria. In light of recent molecular advances in mitochondrial biology, these findings reveal novel aspects of mitochondrial ultrastructure and morphology in human tissues with implications for understanding the mechanisms linking mitochondrial dysfunction to disease. PMID:27506553

  5. The Spectrum of Mitochondrial Ultrastructural Defects in Mitochondrial Myopathy.

    PubMed

    Vincent, Amy E; Ng, Yi Shiau; White, Kathryn; Davey, Tracey; Mannella, Carmen; Falkous, Gavin; Feeney, Catherine; Schaefer, Andrew M; McFarland, Robert; Gorman, Grainne S; Taylor, Robert W; Turnbull, Doug M; Picard, Martin

    2016-01-01

    Mitochondrial functions are intrinsically linked to their morphology and membrane ultrastructure. Characterizing abnormal mitochondrial structural features may thus provide insight into the underlying pathogenesis of inherited and acquired mitochondrial diseases. Following a systematic literature review on ultrastructural defects in mitochondrial myopathy, we investigated skeletal muscle biopsies from seven subjects with genetically defined mtDNA mutations. Mitochondrial ultrastructure and morphology were characterized using two complimentary approaches: transmission electron microscopy (TEM) and serial block face scanning EM (SBF-SEM) with 3D reconstruction. Six ultrastructural abnormalities were identified including i) paracrystalline inclusions, ii) linearization of cristae and abnormal angular features, iii) concentric layering of cristae membranes, iv) matrix compartmentalization, v) nanotunelling, and vi) donut-shaped mitochondria. In light of recent molecular advances in mitochondrial biology, these findings reveal novel aspects of mitochondrial ultrastructure and morphology in human tissues with implications for understanding the mechanisms linking mitochondrial dysfunction to disease. PMID:27506553

  6. The Protective Effect of Icariin on Mitochondrial Transport and Distribution in Primary Hippocampal Neurons from 3× Tg-AD Mice

    PubMed Central

    Chen, Yijing; Han, Shuangxue; Huang, Xiuxian; Ni, Jiazuan; He, Xiaoyang

    2016-01-01

    Icariin, a pharmacologically active component isolated from the Chinese herb Epimedium, has been shown to improve spatial learning and memory abilities in Alzheimer’s disease (AD) rats through inhibition of Aβ production and tau protein hyperphosphorylation. However, the potential mechanism of icariin-induced protective effects against mitochondrial dysfunctions in AD still remains unclear. In the present study, we investigated the effect of icariin on the modulation of mitochondrial transport and distribution in primary hippocampal cultures from triple-transgenic (3× Tg) AD mice. The results showed that icariin enhanced mitochondrial motility and increased mitochondrial index and mitochondrial length and size in the diseased neurons. Additionally, the expression of the key mitochondrial enzyme, pyruvate dehydrogenase-E1α (PDHE1α), and the post synaptic density protein 95 (PSD95), was preserved in AD neurons after icariin treatment, accompanied by a downregulation of Aβ and phosphorylated tau expression in the corresponding areas. Further study showed that icariin treatment resulted in a decrease in mitochondrial fission protein dynamin-related protein 1 (Drp1) and an increase in fusion protein Mitofusin 2 (Mfn2). These data indicate that icariin can promote mitochondrial transport, protect mitochondria against fragmentation and preserve the expression of mitochondrial and synaptic functional proteins in AD neurons. Thus, icariin may be a potential therapeutic complement for AD and other mitochondrial malfunction-related neuronal degenerative diseases. PMID:26828481

  7. Mitochondrial dynamics and quality control in Huntington's disease.

    PubMed

    Guedes-Dias, Pedro; Pinho, Brígida R; Soares, Tânia R; de Proença, João; Duchen, Michael R; Oliveira, Jorge M A

    2016-06-01

    Huntington's disease (HD) is an inherited neurodegenerative disorder caused by polyglutamine expansion mutations in the huntingtin protein. Despite its ubiquitous distribution, expression of mutant huntingtin (mHtt) is particularly detrimental to medium spiny neurons within the striatum. Mitochondrial dysfunction has been associated with HD pathogenesis. Here we review the current evidence for mHtt-induced abnormalities in mitochondrial dynamics and quality control, with a particular focus on brain and neuronal data pertaining to striatal vulnerability. We address mHtt effects on mitochondrial biogenesis, protein import, complex assembly, fission and fusion, mitochondrial transport, and on the degradation of damaged mitochondria via autophagy (mitophagy). For an integrated perspective on potentially converging pathogenic mechanisms, we also address impaired autophagosomal transport and abnormal mHtt proteostasis in HD. PMID:26388396

  8. Spatial Intensity Distribution Analysis Reveals Abnormal Oligomerization of Proteins in Single Cells.

    PubMed

    Godin, Antoine G; Rappaz, Benjamin; Potvin-Trottier, Laurent; Kennedy, Timothy E; De Koninck, Yves; Wiseman, Paul W

    2015-08-18

    Knowledge of membrane receptor organization is essential for understanding the initial steps in cell signaling and trafficking mechanisms, but quantitative analysis of receptor interactions at the single-cell level and in different cellular compartments has remained highly challenging. To achieve this, we apply a quantitative image analysis technique-spatial intensity distribution analysis (SpIDA)-that can measure fluorescent particle concentrations and oligomerization states within different subcellular compartments in live cells. An important technical challenge faced by fluorescence microscopy-based measurement of oligomerization is the fidelity of receptor labeling. In practice, imperfect labeling biases the distribution of oligomeric states measured within an aggregated system. We extend SpIDA to enable analysis of high-order oligomers from fluorescence microscopy images, by including a probability weighted correction algorithm for nonemitting labels. We demonstrated that this fraction of nonemitting probes could be estimated in single cells using SpIDA measurements on model systems with known oligomerization state. Previously, this artifact was measured using single-step photobleaching. This approach was validated using computer-simulated data and the imperfect labeling was quantified in cells with ion channels of known oligomer subunit count. It was then applied to quantify the oligomerization states in different cell compartments of the proteolipid protein (PLP) expressed in COS-7 cells. Expression of a mutant PLP linked to impaired trafficking resulted in the detection of PLP tetramers that persist in the endoplasmic reticulum, while no difference was measured at the membrane between the distributions of wild-type and mutated PLPs. Our results demonstrate that SpIDA allows measurement of protein oligomerization in different compartments of intact cells, even when fractional mislabeling occurs as well as photobleaching during the imaging process, and

  9. Mitochondrial Dynamics and Mitochondrial Dysfunction in Diabetes.

    PubMed

    Wada, Jun; Nakatsuka, Atsuko

    2016-06-01

    The mitochondria are involved in active and dynamic processes, such as mitochondrial biogenesis, fission, fusion and mitophagy to maintain mitochondrial and cellular functions. In obesity and type 2 diabetes, impaired oxidation, reduced mitochondrial contents, lowered rates of oxidative phosphorylation and excessive reactive oxygen species (ROS) production have been reported. Mitochondrial biogenesis is regulated by various transcription factors such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), peroxisome proliferator-activated receptors (PPARs), estrogen-related receptors (ERRs), and nuclear respiratory factors (NRFs). Mitochondrial fusion is promoted by mitofusin 1 (MFN1), mitofusin 2 (MFN2) and optic atrophy 1 (OPA1), while fission is governed by the recruitment of dynamin-related protein 1 (DRP1) by adaptor proteins such as mitochondrial fission factor (MFF), mitochondrial dynamics proteins of 49 and 51 kDa (MiD49 and MiD51), and fission 1 (FIS1). Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and PARKIN promote DRP1-dependent mitochondrial fission, and the outer mitochondrial adaptor MiD51 is required in DRP1 recruitment and PARKIN-dependent mitophagy. This review describes the molecular mechanism of mitochondrial dynamics, its abnormality in diabetes and obesity, and pharmaceuticals targeting mitochondrial biogenesis, fission, fusion and mitophagy. PMID:27339203

  10. S-Nitrosylation of Drp1 links excessive mitochondrial fission to neuronal injury in neurodegeneration

    PubMed Central

    Nakamura, Tomohiro; Cieplak, Piotr; Cho, Dong-Hyung; Godzik, Adam; Lipton, Stuart A.

    2010-01-01

    Neurons are known to use large amounts of energy for their normal function and activity. In order to meet this demand, mitochondrial fission, fusion, and movement events (mitochondrial dynamics) control mitochondrial morphology, facilitating biogenesis and proper distribution of mitochondria within neurons. In contrast, dysfunction in mitochondrial dynamics results in reduced cell bioenergetics and thus contributes to neuronal injury and death in many neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease, and Huntington’s disease. We recently reported that amyloid-β peptide, thought to be a key mediator of AD pathogenesis, engenders S-nitrosylation and thus hyperactivation of the mitochondrial fission protein Drp1. This activation leads to excessive mitochondrial fragmentation, bioenergetic compromise, and synaptic damage in models of AD. Here, we provide an extended commentary on our findings of nitric oxide-mediated abnormal mitochondrial dynamics. PMID:20447471

  11. S-nitrosylation of Drp1 links excessive mitochondrial fission to neuronal injury in neurodegeneration.

    PubMed

    Nakamura, Tomohiro; Cieplak, Piotr; Cho, Dong-Hyung; Godzik, Adam; Lipton, Stuart A

    2010-08-01

    Neurons are known to use large amounts of energy for their normal function and activity. In order to meet this demand, mitochondrial fission, fusion, and movement events (mitochondrial dynamics) control mitochondrial morphology, facilitating biogenesis and proper distribution of mitochondria within neurons. In contrast, dysfunction in mitochondrial dynamics results in reduced cell bioenergetics and thus contributes to neuronal injury and death in many neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease. We recently reported that amyloid-beta peptide, thought to be a key mediator of AD pathogenesis, engenders S-nitrosylation and thus hyperactivation of the mitochondrial fission protein Drp1. This activation leads to excessive mitochondrial fragmentation, bioenergetic compromise, and synaptic damage in models of AD. Here, we provide an extended commentary on our findings of nitric oxide-mediated abnormal mitochondrial dynamics. PMID:20447471

  12. Abnormal distribution of microhardness in tungsten inert gas arc butt-welded AZ61 magnesium alloy plates

    SciTech Connect

    Xu Nan; Shen Jun; Xie Weidong; Wang Linzhi; Wang Dan; Min Dong

    2010-07-15

    In this study, the effects of heat input on the distribution of microhardness of tungsten inert gas (TIG) arc welded hot-extruded AZ61 magnesium alloy joints were investigated. The results show that with an increase of heat input, the distributions of microhardness at the top and bottom of the welded joints are different because they are determined by both the effect of grain coarsening and the effect of dispersion strengthening. With an increase of the heat input, the microhardness of the heat-affected zone (HAZ) at the top and bottom of welded joints and the fusion zone (FZ) at the bottom of welded joints decreased gradually, while the microhardness of the FZ at the top of welded joints decreased initially and then increased sharply. The reason for the abnormal distribution of microhardness of the FZ at the top of the welded joints is that this area is close to the heat source during welding and then large numbers of hard {beta}-Mg{sub 17}(Al,Zn){sub 12} particles are precipitated. Hence, in this case, the effect of dispersion strengthening dominated the microhardness.

  13. Transmural Distribution of Metabolic Abnormalities and Glycolytic Activity during Dobutamine Induced Demand Ischemia

    PubMed Central

    Jameel, Mohammad N; Wang, Xiaohong; Eijgelshoven, Marcel H.J.; Mansoor, Abdul; Zhang, Jianyi

    2008-01-01

    The heterogeneity across the LV wall is characterized by higher rates of oxygen consumption, systolic thickening fraction, myocardial perfusion and lower energetic state in the subendocardial layers (ENDO). During dobutamine stimulation induced demand ischemia, the transmural distribution of energy demand and metabolic markers of ischemia are not known. In this study, hemodynamics, transmural high energy phosphate (HEP) and 2-deoxyglucose-6-phosphate (2DGP) levels and myocardial blood flow (MBF) were determined under basal conditions (B), during dobutamine infusion (DOB: 20 μg/kg/min iv.), and during coronary stenosis+DOB+2-deoxy-glucose (2DG) infusion. DOB increased rate pressure products (RPP) and MBF significantly without affecting subendocardial to subepicardial blood flow ratio (ENDO/EPI) or HEP levels. During coronary stenosis+DOB+2-deoxy-glucose (2DG) infusion RPP, ischemic zone (IZ) MBF and ENDO/EPI decreased significantly. IZ PCr/ATP decreased significantly (2.30 +/- 0.14, 2.06 +/- 0.13 and 2.04 +/- 0.11 to 1.77 +/- 0.12, 1.70 +/- 0.11 and 1.72 +/- 0.12; EPI, MID and ENDO, respectively) and 2DG6P accumulated in all layers as evidenced by the 2DG6P/PCr (0.55 +/- 0.12, 0.52 +/- 0.10 and 0.37 +/- 0.08; EPI, MID and ENDO respectively; p<0.05, EPI>ENDO). In the IZ the wet weight/dry weight ratio was significantly increased as compared to the normal zone (5.9 +/- 0.5 vs. 4.4 +/- 0.4; p<0.05). Thus, in stenotic perfused bed, during dobutamine induced high cardiac workstate, despite higher blood flow the subepicardial layers showed the greater metabolic changes that characterized by a shift toward higher carbohydrate metabolism suggesting a homeostatic responses to high cardiac workstate is characterized by more glucose utilization in energy metabolism. PMID:18424629

  14. Transmural distribution of metabolic abnormalities and glycolytic activity during dobutamine-induced demand ischemia.

    PubMed

    Jameel, Mohammad N; Wang, Xiaohong; Eijgelshoven, Marcel H J; Mansoor, Abdul; Zhang, Jianyi

    2008-06-01

    The heterogeneity across the left ventricular wall is characterized by higher rates of oxygen consumption, systolic thickening fraction, myocardial perfusion, and lower energetic state in the subendocardial layers (ENDO). During dobutamine stimulation-induced demand ischemia, the transmural distribution of energy demand and metabolic markers of ischemia are not known. In this study, hemodynamics, transmural high-energy phosphate (HEP), 2-deoxyglucose-6-phosphate (2-DGP) levels, and myocardial blood flow (MBF) were determined under basal conditions, during dobutamine infusion (DOB: 20 microg x kg(-1) x min(-1) iv), and during coronary stenosis + DOB + 2-deoxyglucose (2-DG) infusion. DOB increased rate pressure products (RPP) and MBF significantly without affecting the subendocardial-to-subepicardial blood flow ratio (ENDO/EPI) or HEP levels. During coronary stenosis + DOB + 2-DG infusion, RPP, ischemic zone (IZ) MBF, and ENDO/EPI decreased significantly. The IZ ratio of creatine phosphate-to-ATP decreased significantly [2.30 +/- 0.14, 2.06 +/- 0.13, and 2.04 +/- 0.11 to 1.77 +/- 0.12, 1.70 +/- 0.11, and 1.72 +/- 0.12 for EPI, midmyocardial (MID), and ENDO, respectively], and 2-DGP accumulated in all layers, as evidenced by the 2-DGP/PCr (0.55 +/- 0.12, 0.52 +/- 0.10, and 0.37 +/- 0.08 for EPI, MID, and ENDO, respectively; P < 0.05, EPI > ENDO). In the IZ the wet weight-to-dry weight ratio was significantly increased compared with the normal zone (5.9 +/- 0.5 vs. 4.4 +/- 0.4; P < 0.05). Thus, in the stenotic perfused bed, during dobutamine-induced high cardiac work state, despite higher blood flow, the subepicardial layers showed the greater metabolic changes characterized by a shift toward higher carbohydrate metabolism, suggesting that a homeostatic response to high-cardiac work state is characterized by more glucose utilization in energy metabolism. PMID:18424629

  15. RE-EVALUATION OF THE GEOGRAPHIC DISTRIBUTION AND PHYLOGEOGRAPHY OF THE SIGMODON HISPIDUS COMPLEX BASED ON MITOCHONDRIAL DNA SEQUENCES

    PubMed Central

    Bradley, Robert D.; Henson, Dallas D.; Durish, Nevin D.

    2010-01-01

    Geographic distribution among members of the Sigmodon hispidus complex (Sigmodon hirsutus, S. hispidus, and S. toltecus) were examined using DNA sequences from the mitochondrial cytochrome-b gene. Geographic distribution of each taxon was defined based on DNA sequences obtained from 69 samples (19 newly obtained and 50 from previous studies) collected from North, Central, and South America. These data indicated that S. hispidus is restricted to the southern one-half of the United States and northeastern Mexico (Nuevo León and Tamaulipas), S. toltecus occupies the eastern one-third of Mexico (central Tamaulipas) to northern Honduras, and S. hirsutus is distributed from central Chiapas and southeastern Oaxaca to northern South America (Venezuela). The newly collected data extend distributions of S. hispidus from the southern United States southward into northeastern Mexico and that of S. toltecus from Chiapas, Mexico, southward to Honduras. Genetic divergence and patterns of phylogeography were examined within each taxon. PMID:20613884

  16. [Distribution of a deletion-insertion polymorphism in intergenic region V of mitochondrial DNA among the aboriginal population of Tuva].

    PubMed

    Golubenko, M V; Puzyrev, V P; Saliukov, V B; Kucher, A N; Sanchat, N O

    2000-03-01

    Mitochondrial DNA region V deletion-insertion polymorphism was examined in three Tuvinian populations inhabiting western, northeastern, and southeastern parts of the republic. The 9-bp deletion was characterized by nonrandom distribution across the Tuva territory: its frequency in the western population (13.37%) was statistically significantly higher than that in the northeastern (4.62%), and southeastern populations, as well as in Mongols, who are territorially and ethnically close to Tuvinians. The insertion mutation in the region V was detected with a frequency of about 3% in two out of the three populations tested. PMID:10779913

  17. Regulation of mitochondrial ceramide distribution by members of the BCL-2 family[S

    PubMed Central

    Zhang, Tejia; Barclay, Lauren; Walensky, Loren D.; Saghatelian, Alan

    2015-01-01

    Apoptosis is an intricately regulated cellular process that proceeds through different cell type- and signal-dependent pathways. In the mitochondrial apoptotic program, mitochondrial outer membrane permeabilization by BCL-2 proteins leads to the release of apoptogenic factors, caspase activation, and cell death. In addition to protein components of the mitochondrial apoptotic machinery, an interesting role for lipids and lipid metabolism in BCL-2 family-regulated apoptosis is also emerging. We used a comparative lipidomics approach to uncover alterations in lipid profile in the absence of the proapoptotic proteins BAX and BAK in mouse embryonic fibroblasts (MEFs). We detected over 1,000 ions in these experiments and found changes in an ion with an m/z of 534.49. Structural elucidation of this ion through tandem mass spectrometry revealed that this molecule is a ceramide with a 16-carbon N-acyl chain and sphingadiene backbone (d18:2/16:0 ceramide). Targeted LC/MS analysis revealed elevated levels of additional sphingadiene-containing ceramides (d18:2-Cers) in BAX, BAK-double knockout MEFs. Elevated d18:2-Cers are also found in immortalized baby mouse kidney epithelial cells lacking BAX and BAK. These results support the existence of a distinct biochemical pathway for regulating ceramides with different backbone structures and suggest that sphingadiene-containing ceramides may have functions that are distinct from the more common sphingosine-containing species. PMID:26059977

  18. Glacial history of the European marine mussels Mytilus, inferred from distribution of mitochondrial DNA lineages.

    PubMed

    Smietanka, B; Burzyński, A; Hummel, H; Wenne, R

    2014-09-01

    Mussels of the genus Mytilus have been used to assess the circumglacial phylogeography of the intertidal zone. These mussels are representative components of the intertidal zone and have rapidly evolving mitochondrial DNA, suitable for high resolution phylogeographic analyses. In Europe, the three Mytilus species currently share mitochondrial haplotypes, owing to the cases of extensive genetic introgression. Genetic diversity of Mytilus edulis, Mytilus trossulus and Mytilus galloprovincialis was studied using a 900-bp long part of the most variable fragment of the control region from one of their two mitochondrial genomes. To this end, 985 specimens were sampled along the European coasts, at sites ranging from the Black Sea to the White Sea. The relevant DNA fragments were amplified, sequenced and analyzed. Contrary to the earlier findings, our coalescence and nested cladistics results show that only a single M. edulis glacial refugium existed in the Atlantic. Despite that, the species survived the glaciation retaining much of its diversity. Unsurprisingly, M. galloprovincialis survived in the Mediterranean Sea. In a relatively short time period, around the climatic optimum at 10 ky ago, the species underwent rapid expansion coupled with population differentiation. Following the expansion, further contemporary gene flow between populations was limited. PMID:24619178

  19. Glacial history of the European marine mussels Mytilus, inferred from distribution of mitochondrial DNA lineages

    PubMed Central

    Śmietanka, B; Burzyński, A; Hummel, H; Wenne, R

    2014-01-01

    Mussels of the genus Mytilus have been used to assess the circumglacial phylogeography of the intertidal zone. These mussels are representative components of the intertidal zone and have rapidly evolving mitochondrial DNA, suitable for high resolution phylogeographic analyses. In Europe, the three Mytilus species currently share mitochondrial haplotypes, owing to the cases of extensive genetic introgression. Genetic diversity of Mytilus edulis, Mytilus trossulus and Mytilus galloprovincialis was studied using a 900-bp long part of the most variable fragment of the control region from one of their two mitochondrial genomes. To this end, 985 specimens were sampled along the European coasts, at sites ranging from the Black Sea to the White Sea. The relevant DNA fragments were amplified, sequenced and analyzed. Contrary to the earlier findings, our coalescence and nested cladistics results show that only a single M. edulis glacial refugium existed in the Atlantic. Despite that, the species survived the glaciation retaining much of its diversity. Unsurprisingly, M. galloprovincialis survived in the Mediterranean Sea. In a relatively short time period, around the climatic optimum at 10 ky ago, the species underwent rapid expansion coupled with population differentiation. Following the expansion, further contemporary gene flow between populations was limited. PMID:24619178

  20. Dynamin-related protein 1 and mitochondrial fragmentation in neurodegenerative diseases.

    PubMed

    Reddy, P Hemachandra; Reddy, Tejaswini P; Manczak, Maria; Calkins, Marcus J; Shirendeb, Ulziibat; Mao, Peizhong

    2011-06-24

    The purpose of this article is to review the recent developments of abnormal mitochondrial dynamics, mitochondrial fragmentation, and neuronal damage in neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis. The GTPase family of proteins, including fission proteins, dynamin related protein 1 (Drp1), mitochondrial fission 1 (Fis1), and fusion proteins (Mfn1, Mfn2 and Opa1) are essential to maintain mitochondrial fission and fusion balance, and to provide necessary adenosine triphosphate to neurons. Among these, Drp1 is involved in several important aspects of mitochondria, including shape, size, distribution, remodeling, and maintenance of mitochondria in mammalian cells. In addition, recent advancements in molecular, cellular, electron microscopy, and confocal imaging studies revealed that Drp1 is associated with several cellular functions, including mitochondrial and peroxisomal fragmentation, phosphorylation, SUMOylation, ubiquitination, and cell death. In the last two decades, tremendous progress has been made in researching mitochondrial dynamics, in yeast, worms, and mammalian cells; and this research has provided evidence linking Drp1 to neurodegenerative diseases. Researchers in the neurodegenerative disease field are beginning to recognize the possible involvement of Drp1 in causing mitochondrial fragmentation and abnormal mitochondrial dynamics in neurodegenerative diseases. This article summarizes research findings relating Drp1 to mitochondrial fission and fusion, in yeast, worms, and mammals. Based on findings from the Reddy laboratory and others', we propose that mutant proteins of neurodegenerative diseases, including AD, PD, HD, and ALS, interact with Drp1, activate mitochondrial fission machinery, fragment mitochondria excessively, and impair mitochondrial transport and mitochondrial dynamics, ultimately causing mitochondrial dysfunction and neuronal damage. PMID:21145355

  1. Optical Cryoimaging Reveals a Heterogeneous Distribution of Mitochondrial Redox State in ex vivo Guinea Pig Hearts and Its Alteration During Ischemia and Reperfusion

    PubMed Central

    Motlagh, Mohammad Masoudi; Salehpour, Fahimeh; Sepehr, Reyhaneh; Heisner, James S.; Dash, Ranjan K.; Camara, Amadou K. S.

    2016-01-01

    Oxidation of substrates to generate ATP in mitochondria is mediated by redox reactions of NADH and FADH2. Cardiac ischemia and reperfusion (IR) injury compromises mitochondrial oxidative phosphorylation. We hypothesize that IR alters the metabolic heterogeneity of mitochondrial redox state of the heart that is only evident in the 3-D optical cryoimaging of the perfused heart before, during, and after IR. The study involved four groups of hearts: time control (TC: heart perfusion without IR), global ischemia (Isch), global ischemia followed by reperfusion (IR) and TC with PCP (a mitochondrial uncoupler) perfusion. Mitochondrial NADH and FAD autofluorescence signals were recorded spectrofluorometrically online in guinea pig ex vivo-perfused hearts in the Langendorff mode. At the end of each specified protocol, hearts were rapidly removed and snap frozen in liquid N2 for later 3-D optical cryoimaging of the mitochondrial NADH, FAD, and NADH/FAD redox ratio (RR). The TC hearts revealed a heterogeneous spatial distribution of NADH, FAD, and RR. Ischemia and IR altered the spatial distribution and caused an overall increase and decrease in the RR by 55% and 64%, respectively. Uncoupling with PCP resulted in the lowest level of the RR (73% oxidation) compared with TC. The 3-D optical cryoimaging of the heart provides novel insights into the heterogeneous distribution of mitochondrial NADH, FAD, RR, and metabolism from the base to the apex during ischemia and IR. This 3-D information of the mitochondrial redox state in the normal and ischemic heart was not apparent in the dynamic spectrofluorometric data. PMID:27574574

  2. Optical Cryoimaging Reveals a Heterogeneous Distribution of Mitochondrial Redox State in ex vivo Guinea Pig Hearts and Its Alteration During Ischemia and Reperfusion.

    PubMed

    Ranji, Mahsa; Motlagh, Mohammad Masoudi; Salehpour, Fahimeh; Sepehr, Reyhaneh; Heisner, James S; Dash, Ranjan K; Camara, Amadou K S

    2016-01-01

    Oxidation of substrates to generate ATP in mitochondria is mediated by redox reactions of NADH and FADH2. Cardiac ischemia and reperfusion (IR) injury compromises mitochondrial oxidative phosphorylation. We hypothesize that IR alters the metabolic heterogeneity of mitochondrial redox state of the heart that is only evident in the 3-D optical cryoimaging of the perfused heart before, during, and after IR. The study involved four groups of hearts: time control (TC: heart perfusion without IR), global ischemia (Isch), global ischemia followed by reperfusion (IR) and TC with PCP (a mitochondrial uncoupler) perfusion. Mitochondrial NADH and FAD autofluorescence signals were recorded spectrofluorometrically online in guinea pig ex vivo-perfused hearts in the Langendorff mode. At the end of each specified protocol, hearts were rapidly removed and snap frozen in liquid N2 for later 3-D optical cryoimaging of the mitochondrial NADH, FAD, and NADH/FAD redox ratio (RR). The TC hearts revealed a heterogeneous spatial distribution of NADH, FAD, and RR. Ischemia and IR altered the spatial distribution and caused an overall increase and decrease in the RR by 55% and 64%, respectively. Uncoupling with PCP resulted in the lowest level of the RR (73% oxidation) compared with TC. The 3-D optical cryoimaging of the heart provides novel insights into the heterogeneous distribution of mitochondrial NADH, FAD, RR, and metabolism from the base to the apex during ischemia and IR. This 3-D information of the mitochondrial redox state in the normal and ischemic heart was not apparent in the dynamic spectrofluorometric data. PMID:27574574

  3. Molecular Identification of Paramecium bursaria Syngens and Studies on Geographic Distribution using Mitochondrial Cytochrome C Oxidase Subunit I (COI).

    PubMed

    Zagata, Patrycja; Greczek-Stachura, Magdalena; Tarcz, Sebastian; Rautian, Maria

    2015-01-01

    Paramecium bursaria is composed of five syngens that are morphologically indistinguishable but sexually isolated. The aim of the present study was to confirm by molecular methods (analyses of mitochondrial COI) the identification of P. bursaria syngens originating from different geographical locations. Phylograms constructed using both the neighbor-joining and maximum-likelihood methods based on a comparison of 34 sequences of P. bursaria strains and P. multimicronucleatum, P. caudatum and P.calkinsi strains used as outgroups revealed five clusters which correspond to results obtained previously by mating reaction. Our analysis shows the existence of 24 haplotypes for the COI gene sequence in the studied strains. The interspecies haplotype diversity was Hd = 0.967. We confirmed genetic differentiation between strains of P. bursaria and the occurrence of a correlation between geographical distribution and the correspondent syngen. PMID:26103689

  4. Meiotic abnormalities

    SciTech Connect

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  5. Restriction enzyme analysis of the mitochondrial genome in mitochondrial myopathy.

    PubMed Central

    Poulton, J; Turnbull, D M; Mehta, A B; Wilson, J; Gardiner, R M

    1988-01-01

    The mitochondrial myopathies are a heterogeneous group of disorders some of which may be caused by mutations in the mitochondrial genome. Mitochondrial DNA from 10 patients with mitochondrial myopathy and their mothers was analysed using five restriction enzymes and 11 mitochondrial probes in bacteriophage M13. No abnormalities were found in seven out of the 10 patients. Polymorphisms which have not previously been reported were detected in three patients and two of their mothers. These results exclude the presence of deletions or insertions of greater than 60 bp in the region of the mitochondrial genome examined. Any causative mitochondrial DNA mutations in these disorders are therefore likely to be point mutations or small structural rearrangements. Images PMID:2903249

  6. Disjunct distribution of highly diverged mitochondrial lineage clade and population subdivision in a marine bivalve with pelagic larval dispersal.

    PubMed

    Luttikhuizen, P C; Drent, J; Baker, A J

    2003-08-01

    Mitochondrial DNA sequence data for 295 individuals of the marine bivalve Macoma balthica (L.) were collected from 10 sites across the European distribution, and from Alaska. The data were used to infer population subdivision history and estimate current levels of gene flow. Inferred historical biogeography was expected to be congruent with colonization of the Atlantic Ocean from the Pacific Ocean after the opening of the Bering Strait 3.5 Ma. In addition, the last glacial maximum, about 18000 years ago, was expected to have been responsible for most of the present-day distribution of molecular variation within Europe, because the area must have been recolonized after confinement to France and the south of the British Isles during the last glacial maximum. Current gene flow was hypothesized to be high, because the larvae of M. balthica spend 2-5 weeks drifting in the water column. The geographical distribution of one highly diverged haplotype clade was found to be disjunct and was encountered exclusively in samples from the Baltic Sea and Alaska. A molecular clock calibration for marine bivalve cytochrome-c-oxidase I dates this clade as having split off from the other haplotypes 9.8-39 Ma. Multiple colonizations of the Atlantic Ocean from the Pacific by M. balthica may explain the strong differences found between Baltic Sea and other European populations of this species. The sympatric occurrence of the highly diverged mitochondrial lineages in western parts of the Baltic Sea points to secondary admixture. With the use of coalescent analysis, population divergence times for French vs. other non-Baltic European populations ('Atlantic population assemblage') were estimated at a minimum of about 110000 years ago, well before the last glacial maximum 18000 years ago. Signatures of population divergence of M. balthica that appear to have originated during the Pleistocene have thus survived the last glacial maximum. Some of the populations within the Atlantic assemblage

  7. Congenital Abnormalities

    MedlinePlus

    ... serious health problems (e.g. Down syndrome ). Single-Gene Abnormalities Sometimes the chromosomes are normal in number, ... blood flow to the fetus impair fetal growth. Alcohol consumption and certain drugs during pregnancy significantly increase ...

  8. Craniofacial Abnormalities

    MedlinePlus

    ... of the skull and face. Craniofacial abnormalities are birth defects of the face or head. Some, like cleft ... palate, are among the most common of all birth defects. Others are very rare. Most of them affect ...

  9. Walking abnormalities

    MedlinePlus

    ... include: Arthritis of the leg or foot joints Conversion disorder (a psychological disorder) Foot problems (such as a ... injuries. For an abnormal gait that occurs with conversion disorder, counseling and support from family members are strongly ...

  10. Chromosome Abnormalities

    MedlinePlus

    ... decade, newer techniques have been developed that allow scientists and doctors to screen for chromosomal abnormalities without using a microscope. These newer methods compare the patient's DNA to a normal DNA ...

  11. Nail abnormalities

    MedlinePlus

    Nail abnormalities are problems with the color, shape, texture, or thickness of the fingernails or toenails. ... Fungus or yeast cause changes in the color, texture, and shape of the nails. Bacterial infection may ...

  12. MELAS syndrome and cardiomyopathy: linking mitochondrial function to heart failure pathogenesis.

    PubMed

    Hsu, Ying-Han R; Yogasundaram, Haran; Parajuli, Nirmal; Valtuille, Lucas; Sergi, Consolato; Oudit, Gavin Y

    2016-01-01

    Heart failure remains an important clinical burden, and mitochondrial dysfunction plays a key role in its pathogenesis. The heart has a high metabolic demand, and mitochondrial function is a key determinant of myocardial performance. In mitochondrial disorders, hypertrophic remodeling is the early pattern of cardiomyopathy with progression to dilated cardiomyopathy, conduction defects and ventricular pre-excitation occurring in a significant proportion of patients. Cardiac dysfunction occurs in approximately a third of patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, a stereotypical example of a mitochondrial disorder leading to a cardiomyopathy. We performed unique comparative ultrastructural and gene expression in a MELAS heart compared with non-failing controls. Our results showed a remarkable increase in mitochondrial inclusions and increased abnormal mitochondria in MELAS cardiomyopathy coupled with variable sarcomere thickening, heterogeneous distribution of affected cardiomyocytes and a greater elevation in the expression of disease markers. Investigation and management of patients with mitochondrial cardiomyopathy should follow the well-described contemporary heart failure clinical practice guidelines and include an important role of medical and device therapies. Directed metabolic therapy is lacking, but current research strategies are dedicated toward improving mitochondrial function in patients with mitochondrial disorders. PMID:26712328

  13. Mitochondrial Genome Sequencing in Mesolithic North East Europe Unearths a New Sub-Clade within the Broadly Distributed Human Haplogroup C1

    PubMed Central

    Der Sarkissian, Clio; Brotherton, Paul; Balanovsky, Oleg; Templeton, Jennifer E. L.; Llamas, Bastien; Soubrier, Julien; Moiseyev, Vyacheslav; Khartanovich, Valery; Cooper, Alan; Haak, Wolfgang

    2014-01-01

    The human mitochondrial haplogroup C1 has a broad global distribution but is extremely rare in Europe today. Recent ancient DNA evidence has demonstrated its presence in European Mesolithic individuals. Three individuals from the 7,500 year old Mesolithic site of Yuzhnyy Oleni Ostrov, Western Russia, could be assigned to haplogroup C1 based on mitochondrial hypervariable region I sequences. However, hypervariable region I data alone could not provide enough resolution to establish the phylogenetic relationship of these Mesolithic haplotypes with haplogroup C1 mitochondrial DNA sequences found today in populations of Europe, Asia and the Americas. In order to obtain high-resolution data and shed light on the origin of this European Mesolithic C1 haplotype, we target-enriched and sequenced the complete mitochondrial genome of one Yuzhnyy Oleni Ostrov C1 individual. The updated phylogeny of C1 haplogroups indicated that the Yuzhnyy Oleni Ostrov haplotype represents a new distinct clade, provisionally coined “C1f”. We show that all three C1 carriers of Yuzhnyy Oleni Ostrov belong to this clade. No haplotype closely related to the C1f sequence could be found in the large current database of ancient and present-day mitochondrial genomes. Hence, we have discovered past human mitochondrial diversity that has not been observed in modern-day populations so far. The lack of positive matches in modern populations may be explained by under-sampling of rare modern C1 carriers or by demographic processes, population extinction or replacement, that may have impacted on populations of Northeast Europe since prehistoric times. PMID:24503968

  14. Glacial history of the North Atlantic marine snail, Littorina saxatilis, inferred from distribution of mitochondrial DNA lineages.

    PubMed

    Panova, Marina; Blakeslee, April M H; Miller, A Whitman; Mäkinen, Tuuli; Ruiz, Gregory M; Johannesson, Kerstin; André, Carl

    2011-01-01

    The North Atlantic intertidal gastropod, Littorina saxatilis (Olivi, 1792), exhibits extreme morphological variation between and within geographic regions and has become a model for studies of local adaptation; yet a comprehensive analysis of the species' phylogeography is lacking. Here, we examine phylogeographic patterns of the species' populations in the North Atlantic and one remote Mediterranean population using sequence variation in a fragment of the mitochondrial cytochrome b gene (607 bp). We found that, as opposed to many other rocky intertidal species, L. saxatilis has likely had a long and continuous history in the Northwest Atlantic, including survival during the last glacial maximum (LGM), possibly in two refugia. In the Northeast Atlantic, several areas likely harboured refugial populations that recolonized different parts of this region after glacial retreat, resulting in strong population structure. However, the outlying monomorphic Venetian population is likely a recent anthropogenic introduction from northern Europe and not a remnant of an earlier wider distribution in the Mediterranean Sea. Overall, our detailed phylogeography of L. saxatilis adds an important piece to the understanding of Pleistocene history in North Atlantic marine biota as well as being the first study to describe the species' evolutionary history in its natural range. The latter contribution is noteworthy because the snail has recently become an important model species for understanding evolutionary processes of speciation; thus our work provides integral information for such endeavours. PMID:21412417

  15. 76 FR 7238 - Pipeline Safety: Dangers of Abnormal Snow and Ice Build-Up on Gas Distribution Systems

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-09

    ... distribution system facilities appear to have been related to either the stress of snow and ice or the... distribution system facilities that appear to have been related to either the stress of snow and ice or... greatest risk. Damage may result from the stresses imposed by the additional loading of the snow or...

  16. 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

  17. Distribution of introns in the mitochondrial gene nad1 in land plants: phylogenetic and molecular evolutionary implications.

    PubMed

    Dombrovska, Olena; Qiu, Yin-Long

    2004-07-01

    Forty-six species of diverse land plants were investigated by sequencing for their intron content in the mitochondrial gene nad1. A total of seven introns, all belonging to group II, were found, and two were newly discovered in this study. All 13 liverworts examined contain no intron, the same condition as in green algae. Mosses and hornworts, however, share one intron by themselves and another one with vascular plants. These intron distribution patterns are consistent with the hypothesis that liverworts represent the basal-most land plants and that the two introns were gained in the common ancestor of mosses-hornworts-vascular plants after liverworts had diverged. Hornworts also possess a unique intron of their own. A fourth intron was found only in Equisetum L., Marattiaceae, Ophioglossum L., Osmunda L., Asplenium L., and Adiantum L., and was likely acquired in their common ancestor, which supports the monophyly of moniliformopses. Three introns that were previously characterized in angiosperms and a few pteridophytes are now all extended to lycopods, and were likely gained in the common ancestor of vascular plants. Phylogenetic analyses of the intron sequences recovered topologies mirroring those of the plants, suggesting that the introns have all been vertically inherited. All seven nad1 group II introns show broad phylogenetic distribution patterns, with the narrowest being in moniliformopses and hornworts, lineages that date back to at least the Devonian (345 million years ago) and Silurian (435 million years ago), respectively. Hence, these introns must have invaded the genes via ancient transpositional events during the early stage of land plant evolution. Potentially heavy RNA editing was observed in nad1 of Haplomitrium Dedecek, Takakia Hatt. & Inoue, hornworts, Isoetes L., Ophioglossum, and Asplenium. A new nomenclature is proposed for group II introns. PMID:15186811

  18. Microangiopathy in the cerebellum of patients with mitochondrial DNA disease

    PubMed Central

    Lax, Nichola Z.; Pienaar, Ilse S.; Reeve, Amy K.; Hepplewhite, Philippa D.; Jaros, Evelyn; Taylor, Robert W.; Kalaria, Raj N.

    2012-01-01

    Neuropathological findings in mitochondrial DNA disease vary and are often dependent on the type of mitochondrial DNA defect. Many reports document neuronal cell loss, demyelination, gliosis and necrotic lesions in post-mortem material. However, previous studies highlight vascular abnormalities in patients harbouring mitochondrial DNA defects, particularly in those with the m.3243A>G mutation in whom stroke-like events are part of the mitochondrial encephalopathy lactic acidosis and stroke-like episodes syndrome. We investigated microangiopathic changes in the cerebellum of 16 genetically and clinically well-defined patients. Respiratory chain deficiency, high levels of mutated mitochondrial DNA and increased mitochondrial mass were present within the smooth muscle cells and endothelial cells comprising the vessel wall in patients. These changes were not limited to those harbouring the m.3243A>G mutation frequently associated with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes, but were documented in patients harbouring m.8344A>G and autosomal recessive polymerase (DNA directed), gamma (POLG) mutations. In 8 of the 16 patients, multiple ischaemic-like lesions occurred in the cerebellar cortex suggestive of vascular smooth muscle cell dysfunction. Indeed, changes in vascular smooth muscle and endothelium distribution and cell size are indicative of vascular cell loss. We found evidence of blood–brain barrier breakdown characterized by plasma protein extravasation following fibrinogen and IgG immunohistochemistry. Reduced immunofluorescence was also observed using markers for endothelial tight junctions providing further evidence in support of blood–brain barrier breakdown. Understanding the structural and functional changes occurring in central nervous system microvessels in patients harbouring mitochondrial DNA defects will provide an important insight into mechanisms of neurodegeneration in mitochondrial DNA disease. Since therapeutic

  19. Female genetic distribution bias in mitochondrial genome observed in Parkinson’s Disease patients in northern China

    PubMed Central

    Chu, Qiaohong; Luo, Xiaoguang; Zhan, Xiaoni; Ren, Yan; Pang, Hao

    2015-01-01

    Genetic polymorphisms associated with susceptibility to Parkinson’s disease (PD) have been described in mitochondrial DNA (mtDNA). To explore the potential contribution of mtDNA mutations to the risk of PD in a Chinese population, we examined the linkage relationship between several single nucleotide polymorphisms (SNPs) and haplotypes in mtDNA and PD. We genotyped 5 SNPs located on coding genes using PCR-RFLP analysis. A specific allele 10398G demonstrated an increased risk of PD (OR 1.30; 95% CI 0.95–1.76; P = 0.013). After stratification by gender, the increased risk appeared to be more significant in females (OR 1.91; 95% CI 1.16–3.16; P = 0.001). But the significance only appeared in females under Bonferroni correction. No significant differences were detected for other SNPs (T4336C, G5460A, G9055A, and G13708A). Individual haplotype composed of 4336T-5460G-9055G-10398A-13708G was found to be associated with protective effect regarding PD (P = 0.0025). The haplotypes 4336T-5460G-9055G-10398G-13708G and 4336T-5460G-9055G-10398A-13708G were more significantly associated in females (P = 0.0036 for risk and P = 0.0006 for protective effects). These data suggest that the A10398G and two haplotypes coupled with 10398A or 10398G are closely associated with susceptibility to PD in a northern Chinese population. This association demonstrated a female genetic distribution bias. PMID:26602989

  20. A revised molecular phylogeny of the globally distributed hawkmoth genus Hyles (Lepidoptera: Sphingidae), based on mitochondrial and nuclear DNA sequences.

    PubMed

    Hundsdoerfer, Anna K; Rubinoff, Daniel; Attié, Marc; Wink, Michael; Kitching, Ian J

    2009-09-01

    The hawkmoth genus Hyles comprises some 29 species with a global distribution. In this study, we augment the previous taxon sampling with more species and add sequences from a nuclear gene to produce a refined phylogenetic hypothesis. A total evidence reconstruction based on Bayesian analysis of the combined mitochondrial (COI, t-RNA-Leu, COII; 2284 bp) and nuclear (EF1alpha; 773 bp) sequences is discussed and compared with the results from separate analyses of the two genes. The total evidence phylogeny corroborates many of the phylogenetic relationships previously postulated within the genus. In addition, the hitherto unsampled enigmatic species Hyles biguttata from Madagascar appears as sister group to Hyles livornicoides from Australia, although support for the relationship is relatively weak. The high level of differentiation of Hyles perkinsi from H. calida (both Hawaii), and the status of these two as sister species, is corroborated by both sources of sequence data. However, their phylogenetic position when mt DNA sequences alone are considered differs markedly from that under total evidence. The previously postulated relationships within the Hyles euphorbiae complex (HEC) s.s. are largely corroborated, but H. dahlii is now more closely related and the HEC s.l. is redefined to include H. zygophylli and H. stroehlei (two species that had not been studied previously using molecular data) and to exclude H. siehei and H. hippophaes. The nuclear sequences alone are insufficiently variable to fully resolve all lineages and the phylogeny suggests that nuclear gene swapping and incomplete lineage sorting have occurred implying recent divergence. The results from the total evidence analysis provide a phylogenetic hypothesis that both corroborates and complements the previous biogeographic scenario, and provides new insights into the origins of several of the included taxa. PMID:19482093

  1. Novel Logistic Regression Model of Chest CT Attenuation Coefficient Distributions for the Automated Detection of Abnormal (Emphysema or ILD) versus Normal Lung

    PubMed Central

    Chan, Kung-Sik; Jiao, Feiran; Mikulski, Marek A.; Gerke, Alicia; Guo, Junfeng; Newell, John D; Hoffman, Eric A.; Thompson, Brad; Lee, Chang Hyun; Fuortes, Laurence J.

    2015-01-01

    Rationale and Objectives We evaluated the role of automated quantitative computed tomography (CT) scan interpretation algorithm in detecting Interstitial Lung Disease (ILD) and/or emphysema in a sample of elderly subjects with mild lung disease.ypothesized that the quantification and distributions of CT attenuation values on lung CT, over a subset of Hounsfield Units (HU) range [−1000 HU, 0 HU], can differentiate early or mild disease from normal lung. Materials and Methods We compared results of quantitative spiral rapid end-exhalation (functional residual capacity; FRC) and end-inhalation (total lung capacity; TLC) CT scan analyses in 52 subjects with radiographic evidence of mild fibrotic lung disease to 17 normal subjects. Several CT value distributions were explored, including (i) that from the peripheral lung taken at TLC (with peels at 15 or 65mm), (ii) the ratio of (i) to that from the core of lung, and (iii) the ratio of (ii) to its FRC counterpart. We developed a fused-lasso logistic regression model that can automatically identify sub-intervals of [−1000 HU, 0 HU] over which a CT value distribution provides optimal discrimination between abnormal and normal scans. Results The fused-lasso logistic regression model based on (ii) with 15 mm peel identified the relative frequency of CT values over [−1000, −900] and that over [−450,−200] HU as a means of discriminating abnormal versus normal, resulting in a zero out-sample false positive rate and 15%false negative rate of that was lowered to 12% by pooling information. Conclusions We demonstrated the potential usefulness of this novel quantitative imaging analysis method in discriminating ILD and/or emphysema from normal lungs. PMID:26776294

  2. Leishmania major Telomerase TERT Protein Has a Nuclear/Mitochondrial Eclipsed Distribution That Is Affected by Oxidative Stress

    PubMed Central

    Campelo, Riward; Díaz Lozano, Isabel; Figarella, Katherine; Osuna, Antonio

    2014-01-01

    In its canonical role the reverse transcriptase telomerase recovers the telomeric repeats that are lost during DNA replication. Other locations and activities have been recently described for the telomerase protein subunit TERT in mammalian cells. In the present work, using biochemistry, molecular biology, and electron microscopy techniques, we found that in the human parasite Leishmania major, TERT (and telomerase activity) shared locations between the nuclear, mitochondrial, and cytoplasmic compartments. Also, some telomerase activity and TERT protein could be found in ∼100-nm nanovesicles. In the mitochondrial compartment, TERT appears to be mainly associated with the kinetoplast DNA. When Leishmania cells were exposed to H2O2, TERT changed its relative abundance and activity between the nuclear and mitochondrial compartments, with the majority of activity residing in the mitochondrion. Finally, overexpression of TERT in Leishmania transfected cells not only increased the parasitic cell growth rate but also increased their resistance to oxidative stress. PMID:25312950

  3. Mitochondrial dynamics and cell death in heart failure.

    PubMed

    Marín-García, José; Akhmedov, Alexander T

    2016-03-01

    The highly regulated processes of mitochondrial fusion (joining), fission (division) and trafficking, collectively called mitochondrial dynamics, determine cell-type specific morphology, intracellular distribution and activity of these critical organelles. Mitochondria are critical for cardiac function, while their structural and functional abnormalities contribute to several common cardiovascular diseases, including heart failure (HF). The tightly balanced mitochondrial fusion and fission determine number, morphology and activity of these multifunctional organelles. Although the intracellular architecture of mature cardiomyocytes greatly restricts mitochondrial dynamics, this process occurs in the adult human heart. Fusion and fission modulate multiple mitochondrial functions, ranging from energy and reactive oxygen species production to Ca(2+) homeostasis and cell death, allowing the heart to respond properly to body demands. Tightly controlled balance between fusion and fission is of utmost importance in the high energy-demanding cardiomyocytes. A shift toward fission leads to mitochondrial fragmentation, while a shift toward fusion results in the formation of enlarged mitochondria and in the fusion of damaged mitochondria with healthy organelles. Mfn1, Mfn2 and OPA1 constitute the core machinery promoting mitochondrial fusion, whereas Drp1, Fis1, Mff and MiD49/51 are the core components of fission machinery. Growing evidence suggests that fusion/fission factors in adult cardiomyocytes play essential noncanonical roles in cardiac development, Ca(2+) signaling, mitochondrial quality control and cell death. Impairment of this complex circuit causes cardiomyocyte dysfunction and death contributing to heart injury culminating in HF. Pharmacological targeting of components of this intricate network may be a novel therapeutic modality for HF treatment. PMID:26872674

  4. Human mitochondrial transcription factor A is required for the segregation of mitochondrial DNA in cultured cells.

    PubMed

    Kasashima, Katsumi; Sumitani, Megumi; Endo, Hitoshi

    2011-01-15

    The segregation and transmission of the mitochondrial genome in humans are complicated processes but are particularly important for understanding the inheritance and clinical abnormalities of mitochondrial disorders. However, the molecular mechanism of the segregation of mitochondrial DNA (mtDNA) is largely unclear. In this study, we demonstrated that human mitochondrial transcription factor A (TFAM) is required for the segregation of mtDNA in cultured cells. RNAi-mediated knockdown of TFAM in HeLa cells resulted in the enlarged mtDNA, as indicated by the assembly of fluorescent signals stained with PicoGreen. Fluorescent in situ hybridization confirmed the enlarged mtDNA and further showed the existence of increased numbers of mitochondria lacking mtDNA signals in TFAM knockdown cells. By complementation analysis, the C-terminal tail of TFAM, which enhances its affinity with DNA, was found to be required for the appropriate distribution of mtDNA. Furthermore, we found that TFAM knockdown induced asymmetric segregation of mtDNA between dividing daughter cells. These results suggest an essential role for human TFAM in symmetric segregation of mtDNA. PMID:20955698

  5. Identification of the human mitochondrial S-adenosylmethionine transporter: bacterial expression, reconstitution, functional characterization and tissue distribution.

    PubMed Central

    Agrimi, G; Di Noia, M A; Marobbio, C M T; Fiermonte, G; Lasorsa, F M; Palmieri, F

    2004-01-01

    The mitochondrial carriers are a family of transport proteins that, with a few exceptions, are found in the inner membranes of mitochondria. They shuttle metabolites and cofactors through this membrane, and connect cytoplasmic functions with others in the matrix. SAM (S-adenosylmethionine) has to be transported into the mitochondria where it is converted into S-adenosylhomocysteine in methylation reactions of DNA, RNA and proteins. The transport of SAM has been investigated in rat liver mitochondria, but no protein has ever been associated with this activity. By using information derived from the phylogenetically distant yeast mitochondrial carrier for SAM and from related human expressed sequence tags, a human cDNA sequence was completed. This sequence was overexpressed in bacteria, and its product was purified, reconstituted into phospholipid vesicles and identified from its transport properties as the human mitochondrial SAM carrier (SAMC). Unlike the yeast orthologue, SAMC catalysed virtually only countertransport, exhibited a higher transport affinity for SAM and was strongly inhibited by tannic acid and Bromocresol Purple. SAMC was found to be expressed in all human tissues examined and was localized to the mitochondria. The physiological role of SAMC is probably to exchange cytosolic SAM for mitochondrial S-adenosylhomocysteine. This is the first report describing the identification and characterization of the human SAMC and its gene. PMID:14674884

  6. Haem degradation in abnormal haemoglobins.

    PubMed Central

    Brown, S B; Docherty, J C

    1978-01-01

    The coupled oxidation of certain abnormal haemoglobins leads to different bile-pigment isomer distributions from that of normal haemoglobin. The isomer pattern may be correlated with the structure of the abnormal haemoglobin in the neighbourhood of the haem pocket. This is support for haem degradation by an intramolecular reaction. PMID:708385

  7. The Use of Neuroimaging in the Diagnosis of Mitochondrial Disease

    ERIC Educational Resources Information Center

    Friedman, Seth D.; Shaw, Dennis W. W.; Ishak, Gisele; Gropman, Andrea L.; Saneto, Russell P.

    2010-01-01

    Mutations in nuclear and mitochondrial DNA impacting mitochondrial function result in disease manifestations ranging from early death to abnormalities in all major organ systems and to symptoms that can be largely confined to muscle fatigue. The definitive diagnosis of a mitochondrial disorder can be difficult to establish. When the constellation…

  8. Investigating complex I deficiency in Purkinje cells and synapses in patients with mitochondrial disease

    PubMed Central

    Chrysostomou, Alexia; Grady, John P.; Laude, Alex; Taylor, Robert W.; Turnbull, Doug M.

    2015-01-01

    Aims Cerebellar ataxia is common in patients with mitochondrial disease, and despite previous neuropathological investigations demonstrating vulnerability of the olivocerebellar pathway in patients with mitochondrial disease, the exact neurodegenerative mechanisms are still not clear. We use quantitative quadruple immunofluorescence to enable precise quantification of mitochondrial respiratory chain protein expression in Purkinje cell bodies and their synaptic terminals in the dentate nucleus. Methods We investigated NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 protein expression in 12 clinically and genetically defined patients with mitochondrial disease and ataxia and 10 age‐matched controls. Molecular genetic analysis was performed to determine heteroplasmy levels of mutated mitochondrial DNA in Purkinje cell bodies and inhibitory synapses. Results Our data reveal that complex I deficiency is present in both Purkinje cell bodies and their inhibitory synapses which surround dentate nucleus neurons. Inhibitory synapses are fewer and enlarged in patients which could represent a compensatory mechanism. Mitochondrial DNA heteroplasmy demonstrated similarly high levels of mutated mitochondrial DNA in cell bodies and synapses. Conclusions This is the first study to use a validated quantitative immunofluorescence technique to determine complex I expression in neurons and presynaptic terminals, evaluating the distribution of respiratory chain deficiencies and assessing the degree of morphological abnormalities affecting synapses. Respiratory chain deficiencies detected in Purkinje cell bodies and their synapses and structural synaptic changes are likely to contribute to altered cerebellar circuitry and progression of ataxia. PMID:26337858

  9. The genetics of mitochondrial disease.

    PubMed

    Davis, Ryan L; Sue, Carolyn M

    2011-11-01

    The discovery that defects in mitochondria and mitochondrial DNA could cause human disease has led to the development of a rapidly expanding group of disorders known as mitochondrial disease. Mitochondrial disease is so named because of the common feature of impaired mitochondrial function. The main function of the mitochondrion is to produce energy for the cell in the form of ATP. ATP is generated by the respiratory chain, a series of complex proteins that are located in the mitochondrial membrane, and are encoded for by both the mitochondrial and nuclear genomes. Consequently, mitochondrial disease can be caused by mutations in either mitochondrial or nuclear DNA. Given the distribution of mitochondria throughout the body, the specific properties of mitochondrial DNA, and the mitochondrion's dependence on nuclear genes for its normal function, the clinical presentation of mitochondrial disease can be highly variable. Thus, familiarity with typical clinical presentations and knowledge of the genes that contribute to mitochondrial function will aid the clinician in the recognition, diagnosis, and management of patients with this group of diverse disorders. PMID:22266889

  10. Compensatory elevation of voluntary activity in mouse mutants with impaired mitochondrial energy metabolism

    PubMed Central

    Lapointe, Jérôme; G. Hughes, Bryan; Bigras, Eve; Hekimi, Siegfried

    2014-01-01

    Abstract Mitochondria play a crucial role in determining whole‐body metabolism and exercise capacity. Genetic mouse models of mild mitochondrial dysfunction provide an opportunity to understand how mitochondrial function affects these parameters. MCLK1 (a.k.a. Coq7) is an enzyme implicated in the biosynthesis of ubiquinone (UQ; Coenzyme Q). Low levels of MCLK1 in Mclk1+/− heterozygous mutants lead to abnormal sub‐mitochondrial distribution of UQ, impaired mitochondrial function, elevated mitochondrial oxidative stress, and increased lifespan. Here, we report that young Mclk1+/− males, but not females, show a significant decrease in whole‐body metabolic rate as measured by indirect calorimetry. Such a sex‐specific effect of mitochondrial dysfunction on energy metabolism has also been reported for heterozygous mice carrying a mutation for the gene encoding the “Rieske” protein of mitochondrial complex III (RISP+/P224S). We find that both Mclk1+/− and RISP+/P224S males are capable of restoring their defective metabolic rates by making significantly more voluntary use of a running wheel compared to wild type. However, this increase in voluntary activity does not reflect their exercise capacity, which we found to be impaired as revealed by a shorter treadmill distance run before exhaustion. In contrast to what is observed in Mclk1+/− and RISP+/P224S mutants, Sod2+/− mice with elevated oxidative stress and major mitochondrial dysfunction did not increase voluntary activity. Our study reveals a sex‐specific effect on how impaired mitochondrial function impacts whole‐body energy metabolism and locomotory behavior, and contributes to the understanding of the metabolic and behavioral consequences of mitochondrial disorders. PMID:25413331

  11. Organelle-cytoskeletal interactions: actin mutations inhibit meiosis-dependent mitochondrial rearrangement in the budding yeast Saccharomyces cerevisiae.

    PubMed Central

    Smith, M G; Simon, V R; O'Sullivan, H; Pon, L A

    1995-01-01

    During early stages of meiosis I, yeast mitochondria fuse to form a single continuous thread. Thereafter, portions of the mitochondrial thread are equally distributed to daughter cells. Using time-lapse fluorescence microscopy and a membrane potential sensing dye, mitochondria are resolved as small particles at the cell periphery in pre-meiotic, living yeast. These organelles display low levels of movement. During meiosis I, we observed a threefold increase in mitochondrial motility. Mitochondrial movements were linear, occurred at a maximum velocity of 25 +/- 6.7 nm/s, and resulted in organelle collision and fusion to form elongated tubular structures. Mitochondria do not co-localize with microtubules. Destabilization of microtubules by nocodazole treatment has no significant effect on the rate and extent of thread formation. In contrast, yeast bearing temperature-sensitive mutations in the actin-encoding ACT1 gene (act1-3 and act1-133) exhibit abnormal mitochondrial aggregation, fragmentation, and enlargement as well as loss of mitochondrial motility. In act1-3 cells, mitochondrial defects and actin delocalization occur only at restrictive temperatures. The act1-133 mutation, which perturbs the myosin-binding site of actin without significantly affecting actin cytoskeletal structure in meiotic yeast, results in mitochondrial morphology and motility defects at restrictive and permissive temperatures. These studies support a role for the actin cytoskeleton in the control of mitochondrial position and movements in meiotic yeast. Images PMID:8573793

  12. Associations of postural knowledge and basic motor skill with dyspraxia in autism: implication for abnormalities in distributed connectivity and motor learning.

    PubMed

    Dowell, Lauren R; Mahone, E Mark; Mostofsky, Stewart H

    2009-09-01

    Children with autism often have difficulty performing skilled movements. Praxis performance requires basic motor skill, knowledge of representations of the movement (mediated by parietal regions), and transcoding of these representations into movement plans (mediated by premotor circuits). The goals of this study were (a) to determine whether dyspraxia in autism is associated with impaired representational ("postural") knowledge and (b) to examine the contributions of postural knowledge and basic motor skill to dyspraxia in autism. Thirty-seven children with autism spectrum disorder (ASD) and 50 typically developing (TD) children, ages 8-13, completed (a) an examination of basic motor skills, (b) a postural knowledge test assessing praxis discrimination, and (c) a praxis examination. Children with ASD showed worse basic motor skill and postural knowledge than did controls. The ASD group continued to show significantly poorer praxis than did controls after accounting for age, IQ, basic motor skill, and postural knowledge. Dyspraxia in autism appears to be associated with impaired formation of spatial representations, as well as transcoding and execution. Distributed abnormality across parietal, premotor, and motor circuitry, as well as anomalous connectivity, may be implicated. PMID:19702410

  13. Associations of Postural Knowledge and Basic Motor Skill with Dyspraxia in Autism: Implication for Abnormalities in Distributed Connectivity and Motor Learning

    PubMed Central

    Dowell, Lauren R.; Mahone, E. Mark; Mostofsky, Stewart H.

    2009-01-01

    Children with autism often have difficulty performing skilled movements. Praxis performance requires basic motor skill, knowledge of representations of the movement (mediated by parietal regions), and transcoding of these representations into movement plans (mediated by premotor circuits). The goals of this study were: (a) to determine whether dyspraxia in autism is associated with impaired representational (“postural”) knowledge, and (b) to examine the contributions of postural knowledge and basic motor skill to dyspraxia in autism. Thirty-seven children with autism spectrum disorder (ASD) and 50 typically developing (TD) children, ages 8–13, completed: (a) an examination of basic motor skills, (b) a postural knowledge test assessing praxis discrimination, and (c) a praxis examination. Children with ASD showed worse basic motor skill and postural knowledge than controls. The ASD group continued to show significantly poorer praxis than controls after accounting for age, IQ, basic motor skill, and postural knowledge. Dyspraxia in autism appears to be associated with impaired formation of spatial representations, as well as transcoding and execution. Distributed abnormality across parietal, premotor, and motor circuitry, as well as anomalous connectivity may be implicated. PMID:19702410

  14. Integrated analysis of the involvement of nitric oxide synthesis in mitochondrial proliferation, mitochondrial deficiency and apoptosis in skeletal muscle fibres

    PubMed Central

    Rodrigues, Gabriela Silva; Godinho, Rosely Oliveira; Kiyomoto, Beatriz Hitomi; Gamba, Juliana; Oliveira, Acary Souza Bulle; Schmidt, Beny; Tengan, Célia Harumi

    2016-01-01

    Nitric oxide (NO) is an important signaling messenger involved in different mitochondrial processes but only few studies explored the participation of NO in mitochondrial abnormalities found in patients with genetic mitochondrial deficiencies. In this study we verified whether NO synthase (NOS) activity was altered in different types of mitochondrial abnormalities and whether changes in mitochondrial function and NOS activity could be associated with the induction of apoptosis. We performed a quantitative and integrated analysis of NOS activity in individual muscle fibres of patients with mitochondrial diseases, considering mitochondrial function (cytochrome-c-oxidase activity), mitochondrial content, mitochondrial DNA mutation and presence of apoptotic nuclei. Our results indicated that sarcolemmal NOS activity was increased in muscle fibres with mitochondrial proliferation, supporting the relevance of neuronal NOS in the mitochondrial biogenesis process. Sarcoplasmic NOS activity was reduced in cytochrome-c-oxidase deficient fibres, probably as a consequence of the involvement of NO in the regulation of the respiratory chain. Alterations in NOS activity or mitochondrial abnormalities were not predisposing factors to apoptotic nuclei. Taken together, our results show that NO can be considered a potential molecular target for strategies to increase mitochondrial content and indicate that this approach may not be associated with increased apoptotic events. PMID:26856437

  15. Mitochondrial Cardiomyopathies

    PubMed Central

    El-Hattab, Ayman W.; Scaglia, Fernando

    2016-01-01

    Mitochondria are found in all nucleated human cells and perform various essential functions, including the generation of cellular energy. Mitochondria are under dual genome control. Only a small fraction of their proteins are encoded by mitochondrial DNA (mtDNA), whereas more than 99% of them are encoded by nuclear DNA (nDNA). Mutations in mtDNA or mitochondria-related nDNA genes result in mitochondrial dysfunction leading to insufficient energy production required to meet the needs for various organs, particularly those with high energy requirements, including the central nervous system, skeletal and cardiac muscles, kidneys, liver, and endocrine system. Because cardiac muscles are one of the high energy demanding tissues, cardiac involvement occurs in mitochondrial diseases with cardiomyopathies being one of the most frequent cardiac manifestations found in these disorders. Cardiomyopathy is estimated to occur in 20–40% of children with mitochondrial diseases. Mitochondrial cardiomyopathies can vary in severity from asymptomatic status to severe manifestations including heart failure, arrhythmias, and sudden cardiac death. Hypertrophic cardiomyopathy is the most common type; however, mitochondrial cardiomyopathies might also present as dilated, restrictive, left ventricular non-compaction, and histiocytoid cardiomyopathies. Cardiomyopathies are frequent manifestations of mitochondrial diseases associated with defects in electron transport chain complexes subunits and their assembly factors, mitochondrial transfer RNAs, ribosomal RNAs, ribosomal proteins, translation factors, mtDNA maintenance, and coenzyme Q10 synthesis. Other mitochondrial diseases with cardiomyopathies include Barth syndrome, Sengers syndrome, TMEM70-related mitochondrial complex V deficiency, and Friedreich ataxia. PMID:27504452

  16. Mitochondrial vasculopathy.

    PubMed

    Finsterer, Josef; Zarrouk-Mahjoub, Sinda

    2016-05-26

    Mitochondrial disorders (MIDs) are usually multisystem disorders (mitochondrial multiorgan disorder syndrome) either on from onset or starting at a point during the disease course. Most frequently affected tissues are those with a high oxygen demand such as the central nervous system, the muscle, endocrine glands, or the myocardium. Recently, it has been shown that rarely also the arteries may be affected (mitochondrial arteriopathy). This review focuses on the type, diagnosis, and treatment of mitochondrial vasculopathy in MID patients. A literature search using appropriate search terms was carried out. Mitochondrial vasculopathy manifests as either microangiopathy or macroangiopathy. Clinical manifestations of mitochondrial microangiopathy include leukoencephalopathy, migraine-like headache, stroke-like episodes, or peripheral retinopathy. Mitochondrial macroangiopathy manifests as atherosclerosis, ectasia of arteries, aneurysm formation, dissection, or spontaneous rupture of arteries. The diagnosis relies on the documentation and confirmation of the mitochondrial metabolic defect or the genetic cause after exclusion of non-MID causes. Treatment is not at variance compared to treatment of vasculopathy due to non-MID causes. Mitochondrial vasculopathy exists and manifests as micro- or macroangiopathy. Diagnosing mitochondrial vasculopathy is crucial since appropriate treatment may prevent from severe complications. PMID:27231520

  17. Mitochondrial vasculopathy

    PubMed Central

    Finsterer, Josef; Zarrouk-Mahjoub, Sinda

    2016-01-01

    Mitochondrial disorders (MIDs) are usually multisystem disorders (mitochondrial multiorgan disorder syndrome) either on from onset or starting at a point during the disease course. Most frequently affected tissues are those with a high oxygen demand such as the central nervous system, the muscle, endocrine glands, or the myocardium. Recently, it has been shown that rarely also the arteries may be affected (mitochondrial arteriopathy). This review focuses on the type, diagnosis, and treatment of mitochondrial vasculopathy in MID patients. A literature search using appropriate search terms was carried out. Mitochondrial vasculopathy manifests as either microangiopathy or macroangiopathy. Clinical manifestations of mitochondrial microangiopathy include leukoencephalopathy, migraine-like headache, stroke-like episodes, or peripheral retinopathy. Mitochondrial macroangiopathy manifests as atherosclerosis, ectasia of arteries, aneurysm formation, dissection, or spontaneous rupture of arteries. The diagnosis relies on the documentation and confirmation of the mitochondrial metabolic defect or the genetic cause after exclusion of non-MID causes. Treatment is not at variance compared to treatment of vasculopathy due to non-MID causes. Mitochondrial vasculopathy exists and manifests as micro- or macroangiopathy. Diagnosing mitochondrial vasculopathy is crucial since appropriate treatment may prevent from severe complications. PMID:27231520

  18. Mitochondrial Cardiomyopathies.

    PubMed

    El-Hattab, Ayman W; Scaglia, Fernando

    2016-01-01

    Mitochondria are found in all nucleated human cells and perform various essential functions, including the generation of cellular energy. Mitochondria are under dual genome control. Only a small fraction of their proteins are encoded by mitochondrial DNA (mtDNA), whereas more than 99% of them are encoded by nuclear DNA (nDNA). Mutations in mtDNA or mitochondria-related nDNA genes result in mitochondrial dysfunction leading to insufficient energy production required to meet the needs for various organs, particularly those with high energy requirements, including the central nervous system, skeletal and cardiac muscles, kidneys, liver, and endocrine system. Because cardiac muscles are one of the high energy demanding tissues, cardiac involvement occurs in mitochondrial diseases with cardiomyopathies being one of the most frequent cardiac manifestations found in these disorders. Cardiomyopathy is estimated to occur in 20-40% of children with mitochondrial diseases. Mitochondrial cardiomyopathies can vary in severity from asymptomatic status to severe manifestations including heart failure, arrhythmias, and sudden cardiac death. Hypertrophic cardiomyopathy is the most common type; however, mitochondrial cardiomyopathies might also present as dilated, restrictive, left ventricular non-compaction, and histiocytoid cardiomyopathies. Cardiomyopathies are frequent manifestations of mitochondrial diseases associated with defects in electron transport chain complexes subunits and their assembly factors, mitochondrial transfer RNAs, ribosomal RNAs, ribosomal proteins, translation factors, mtDNA maintenance, and coenzyme Q10 synthesis. Other mitochondrial diseases with cardiomyopathies include Barth syndrome, Sengers syndrome, TMEM70-related mitochondrial complex V deficiency, and Friedreich ataxia. PMID:27504452

  19. Distribution of the PBC-specific- (M2) and the naturally-occurring mitochondrial antigen- (NOMAg) systems in plants.

    PubMed Central

    Lang, P; Klein, R; Becker, E W; Berg, P A

    1992-01-01

    In previous studies it was demonstrated that antibodies in sera from patients with primary biliary cirrhosis (PBC) and their relatives can recognize two different antigen systems in the ATPase fraction prepared from beef heart mitochondria, namely the PBC-related M2- and the naturally occurring mitochondrial antigen (NOMAg)-related epitopes. Since separation of these two antigen systems could not be achieved using mammalian mitochondria, mitochondria from a wide spectrum of plants were analysed with respect to the presence of mitochondrial antigens. Mitochondria from 29 species of plants were prepared and tested by ELISA and Western blot using marker sera from patients with PBC reacting in the Western blot with M2a,b,c,d (alpha-ketoacid-dehydrogenase complex) and NOMAg-specific sera recognizing the three major epitopes epsilon, zeta, and eta at 65, 61 and 58 kD. Naturally occurring mitochondrial antibody (NOMA)-positive marker sera reacted in the ELISA with mitochondria from all plants, and the zeta/eta positive sera gave also a positive reaction at 61/58 kD in the Western blot while the epsilon epitope could not be visualized by this method. In contrast, the M2 antigen was detected preferentially in lower plants such as algae, fungi, and ferns. Analysing these data with respect to the evolution of proteins one would have to assume that the M2 antigen was lost in most higher plants or underwent some structural alterations. Furthermore, considering the fact that the M2- and the NOMAg-related epitopes could be only partially separated, i.e. there were no plant mitochondria showing only M2 but no NOMAg, one could speculate that anti-M2 antibodies are derived from the pool of naturally occurring antibodies. Images Fig. 2 PMID:1281057

  20. Mitochondrial Dynamics in Pulmonary Arterial Hypertension

    PubMed Central

    Ryan, John; Dasgupta, Asish; Huston, Jessica; Chen, Kuang-Huieh; Archer, Stephen L.

    2015-01-01

    Pulmonary arterial hypertension (PAH) is an idiopathic cardiopulmonary disease characterized by obstruction of small pulmonary arteries by excessive proliferation and apoptosis-resistance of vascular cells, as well as inflammation, thrombosis and vasoconstriction. Vascular obstruction increases the afterload faced by the right ventricle (RV), leading to RV failure. The proliferative, obstructive vasculopathy of PAH shares several mitochondrial abnormalities with cancer, notably a shift to aerobic glycolysis and mitochondrial fragmentation. Mitochondria in the pulmonary artery smooth muscle cell (PASMC) normally serve as oxygen sensors. In PAH, acquired mitochondrial abnormalities, including epigenetic silencing of superoxide dismutase (SOD2), disrupt oxygen sensing creating a pseudo-hypoxic environment characterized by normoxic activation of Hypoxia-Inducible Factor-1α (HIF-1α). The resulting metabolic shift to aerobic glycolysis (the Warburg phenomenon) reflects inhibition of pyruvate dehydrogenase by pyruvate dehydrogenase kinases. In addition, altered mitochondrial dynamics result in mitochondrial fragmentation. The molecular basis of this structural change includes upregulation and activation of fission mediators, notably dynamin-related protein 1 (DRP-1), and downregulation of fusion mediators, especially mitofusin-2 (MFN2). These pathogenic mitochondrial abnormalities offer new therapeutic targets. Inhibition of mitotic fission or enhancement of fusion in PAH PASMC slows cell proliferation, causes cell cycle arrest, and induces apoptosis. DRP-1 inhibition or MFN2 gene therapy can regress PAH in experimental models of PAH. This review focuses on the etiology of mitochondrial fragmentation in PAH and explores the therapeutic implications of mitochondrial dynamics in the pulmonary vasculature and RV. PMID:25672499

  1. Inherited mitochondrial neuropathies.

    PubMed

    Finsterer, Josef

    2011-05-15

    Mitochondrial disorders (MIDs) occasionally manifest as polyneuropathy either as the dominant feature or as one of many other manifestations (inherited mitochondrial neuropathy). MIDs in which polyneuropathy is the dominant feature, include NARP syndrome due to the transition m.8993T>, CMT2A due to MFN2 mutations, CMT2K and CMT4A due to GDAP1 mutations, and axonal/demyelinating neuropathy with external ophthalmoplegia due to POLG1 mutations. MIDs in which polyneuropathy is an inconstant feature among others is the MELAS syndrome, MERRF syndrome, LHON, Mendelian PEO, KSS, Leigh syndrome, MNGIE, SANDO; MIRAS, MEMSA, AHS, MDS (hepato-cerebral form), IOSCA, and ADOA syndrome. In the majority of the cases polyneuropathy presents in a multiplex neuropathy distribution. Nerve conduction studies may reveal either axonal or demyelinated or mixed types of neuropathies. If a hereditary neuropathy is due to mitochondrial dysfunction, the management of these patients is at variance from non-mitochondrial hereditary neuropathies. Patients with mitochondrial hereditary neuropathy need to be carefully investigated for clinical or subclinical involvement of other organs or systems. Supportive treatment with co-factors, antioxidants, alternative energy sources, or lactate lowering agents can be tried. Involvement of other organs may require specific treatment. Mitochondrial neuropathies should be included in the differential diagnosis of hereditary neuropathies. PMID:21402391

  2. Lipid metabolism in mitochondrial membranes.

    PubMed

    Mayr, Johannes A

    2015-01-01

    Mitochondrial membranes have a unique lipid composition necessary for proper shape and function of the organelle. Mitochondrial lipid metabolism involves biosynthesis of the phospholipids phosphatidylethanolamine, cardiolipin and phosphatidylglycerol, the latter is a precursor of the late endosomal lipid bis(monoacylglycero)phosphate. It also includes mitochondrial fatty acid synthesis necessary for the formation of the lipid cofactor lipoic acid. Furthermore the synthesis of coenzyme Q takes place in mitochondria as well as essential parts of the steroid and vitamin D metabolism. Lipid transport and remodelling, which are necessary for tailoring and maintaining specific membrane properties, are just partially unravelled. Mitochondrial lipids are involved in organelle maintenance, fission and fusion, mitophagy and cytochrome c-mediated apoptosis. Mutations in TAZ, SERAC1 and AGK affect mitochondrial phospholipid metabolism and cause Barth syndrome, MEGDEL and Sengers syndrome, respectively. In these disorders an abnormal mitochondrial energy metabolism was found, which seems to be due to disturbed protein-lipid interactions, affecting especially enzymes of the oxidative phosphorylation. Since a growing number of enzymes and transport processes are recognised as parts of the mitochondrial lipid metabolism, a further increase of lipid-related disorders can be expected. PMID:25082432

  3. Mitochondrial Diseases

    PubMed Central

    Lee, Young-Mock

    2012-01-01

    Mitochondria contain the respiratory chain enzyme complexes that carry out oxidative phosphorylation and produce the main part of cellular energy in the form of ATP. Although several proteins related with signalling, assembling, transporting, and enzymatic function can be impaired in mitochondrial diseases, most frequently the activity of the respiratory chain protein complexes is primarily or secondarily affected, leading to impaired oxygen utilization and reduced energy production. Mitochondrial diseases usually show a chronic, slowly progressive course and present with multiorgan involvement with varying onset between birth and late adulthood. Neuromuscular system is frequently affected in mitochondrial diseases. Although there is actually no specific therapy and cure for mitochondrial diseases, the understanding of the pathophysiology may further facilitate the diagnostic approach and open perspectives to future in mitochondrial diseases. PMID:24649452

  4. Mitochondrial cytopathies.

    PubMed

    El-Hattab, Ayman W; Scaglia, Fernando

    2016-09-01

    Mitochondria are found in all nucleated human cells and perform a variety of essential functions, including the generation of cellular energy. Most of mitochondrial proteins are encoded by the nuclear DNA (nDNA) whereas a very small fraction is encoded by the mitochondrial DNA (mtDNA). Mutations in mtDNA or mitochondria-related nDNA genes can result in mitochondrial dysfunction which leads to a wide range of cellular perturbations including aberrant calcium homeostasis, excessive reactive oxygen species production, dysregulated apoptosis, and insufficient energy generation to meet the needs of various organs, particularly those with high energy demand. Impaired mitochondrial function in various tissues and organs results in the multi-organ manifestations of mitochondrial diseases including epilepsy, intellectual disability, skeletal and cardiac myopathies, hepatopathies, endocrinopathies, and nephropathies. Defects in nDNA genes can be inherited in an autosomal or X-linked manners, whereas, mtDNA is maternally inherited. Mitochondrial diseases can result from mutations of nDNA genes encoding subunits of the electron transport chain complexes or their assembly factors, proteins associated with the mitochondrial import or networking, mitochondrial translation factors, or proteins involved in mtDNA maintenance. MtDNA defects can be either point mutations or rearrangements. The diagnosis of mitochondrial disorders can be challenging in many cases and is based on clinical recognition, biochemical screening, histopathological studies, functional studies, and molecular genetic testing. Currently, there are no satisfactory therapies available for mitochondrial disorders that significantly alter the course of the disease. Therapeutic options include symptomatic treatment, cofactor supplementation, and exercise. PMID:26996063

  5. Weight Loss by Ppc-1, a Novel Small Molecule Mitochondrial Uncoupler Derived from Slime Mold

    PubMed Central

    Suzuki, Toshiyuki; Kikuchi, Haruhisa; Ogura, Masato; Homma, Miwako K.; Oshima, Yoshiteru; Homma, Yoshimi

    2015-01-01

    Mitochondria play a key role in diverse processes including ATP synthesis and apoptosis. Mitochondrial function can be studied using inhibitors of respiration, and new agents are valuable for discovering novel mechanisms involved in mitochondrial regulation. Here, we screened small molecules derived from slime molds and other microorganisms for their effects on mitochondrial oxygen consumption. We identified Ppc-1 as a novel molecule which stimulates oxygen consumption without adverse effects on ATP production. The kinetic behavior of Ppc-1 suggests its function as a mitochondrial uncoupler. Serial administration of Ppc-1 into mice suppressed weight gain with no abnormal effects on liver or kidney tissues, and no evidence of tumor formation. Serum fatty acid levels were significantly elevated in mice treated with Ppc-1, while body fat content remained low. After a single administration, Ppc-1 distributes into various tissues of individual animals at low levels. Ppc-1 stimulates adipocytes in culture to release fatty acids, which might explain the elevated serum fatty acids in Ppc-1-treated mice. The results suggest that Ppc-1 is a unique mitochondrial regulator which will be a valuable tool for mitochondrial research as well as the development of new drugs to treat obesity. PMID:25668511

  6. Weight loss by Ppc-1, a novel small molecule mitochondrial uncoupler derived from slime mold.

    PubMed

    Suzuki, Toshiyuki; Kikuchi, Haruhisa; Ogura, Masato; Homma, Miwako K; Oshima, Yoshiteru; Homma, Yoshimi

    2015-01-01

    Mitochondria play a key role in diverse processes including ATP synthesis and apoptosis. Mitochondrial function can be studied using inhibitors of respiration, and new agents are valuable for discovering novel mechanisms involved in mitochondrial regulation. Here, we screened small molecules derived from slime molds and other microorganisms for their effects on mitochondrial oxygen consumption. We identified Ppc-1 as a novel molecule which stimulates oxygen consumption without adverse effects on ATP production. The kinetic behavior of Ppc-1 suggests its function as a mitochondrial uncoupler. Serial administration of Ppc-1 into mice suppressed weight gain with no abnormal effects on liver or kidney tissues, and no evidence of tumor formation. Serum fatty acid levels were significantly elevated in mice treated with Ppc-1, while body fat content remained low. After a single administration, Ppc-1 distributes into various tissues of individual animals at low levels. Ppc-1 stimulates adipocytes in culture to release fatty acids, which might explain the elevated serum fatty acids in Ppc-1-treated mice. The results suggest that Ppc-1 is a unique mitochondrial regulator which will be a valuable tool for mitochondrial research as well as the development of new drugs to treat obesity. PMID:25668511

  7. Self-similar mitochondrial DNA.

    PubMed

    Oiwa, Nestor N; Glazier, James A

    2004-01-01

    We show that repeated sequences, like palindromes (local repetitions) and homologies between two different nucleotide sequences (motifs along the genome), compose a self-similar (fractal) pattern in mitochondrial DNA. This self-similarity comes from the looplike structures distributed along the genome. The looplike structures generate scaling laws in a pseudorandom DNA walk constructed from the sequence, called a Lévy flight. We measure the scaling laws from the generalized fractal dimension and singularity spectrum for mitochondrial DNA walks for 35 different species. In particular, we report characteristic loop distributions for mammal mitochondrial genomes. PMID:15371639

  8. Chromosomal abnormalities in human sperm

    SciTech Connect

    Martin, R.H.

    1985-01-01

    The ability to analyze human sperm chromosome complements after penetration of zona pellucida-free hamster eggs provides the first opportunity to study the frequency and type of chromosomal abnormalities in human gametes. Two large-scale studies have provided information on normal men. We have studied 1,426 sperm complements from 45 normal men and found an abnormality rate of 8.9%. Brandriff et al. (5) found 8.1% abnormal complements in 909 sperm from 4 men. The distribution of numerical and structural abnormalities was markedly dissimilar in the 2 studies. The frequency of aneuploidy was 5% in our sample and only 1.6% in Brandriff's, perhaps reflecting individual variability among donors. The frequency of 24,YY sperm was low: 0/1,426 and 1/909. This suggests that the estimates of nondisjunction based on fluorescent Y body data (1% to 5%) are not accurate. We have also studied men at increased risk of sperm chromosomal abnormalities. The frequency of chromosomally unbalanced sperm in 6 men heterozygous for structural abnormalities varied dramatically: 77% for t11;22, 32% for t6;14, 19% for t5;18, 13% for t14;21, and 0% for inv 3 and 7. We have also studied 13 cancer patients before and after radiotherapy and demonstrated a significant dose-dependent increase of sperm chromosome abnormalities (numerical and structural) 36 months after radiation treatment.

  9. Analysis of mitochondrial haplogroups associated with TTR Val30Ala familial amyloidotic polyneuropathy in Chinese patients.

    PubMed

    Liu, Jing-Yao; Jiang, Xin-Mei; Zhang, Min; Guo, Ying-Jie

    2012-12-01

    Extracellular deposition of abnormal transthyretin (TTR) amyloid fibrils leads to familial amyloidotic polyneuropathy (FAP), an inherited autsomal dominant disease. A large number of protein variants, each caused by a different point mutation in the TTR gene have been identified, including TTR Val30Ala. Since the age of onset, organ involvement, and disease progression are highly variable in FAP, even among individuals with the same TTR genetic variation. it is likely that other genetic and environmental factors influence FAP disease phenotype. One study has found a relationship between mitochondrial haplogroups and age of onset of FAP. In this study, we wondered whether certain mitochondrial haplogroups were associated with the cases of TTR Val30Ala FAP in a Chinese population. Mitochondrial haplogroup analysis was performed on a group of patients and their relatives and on a group of healthy controls. All FAP probands were unrelated in their maternal lineages. The chi-squared test for independence found no difference in mitochondrial haplogroup distribution between FAP and control groups. This is the first study reporting frequency and distribution of different haplogroups in FAP in a Chinese population. Although the study group was small, TTR Val30Ala FAP in China seems unrelated to mitochondrial haplogroup. PMID:22784244

  10. Mitochondrial DNA.

    ERIC Educational Resources Information Center

    Wright, Russell G.; Bottino, Paul J.

    1986-01-01

    Provides background information for teachers on mitochondrial DNA, pointing out that it may have once been a free-living organism. Includes a ready-to-duplicate exercise titled "Using Microchondrial DNA to Measure Evolutionary Distance." (JN)

  11. Mitochondrial Myopathies

    MedlinePlus

    ... line and are therefore called the electron transport chain, and complex V actually churns out ATP, so ... coQ10 , is a component of the electron transport chain, which uses oxygen to manufacture ATP. Some mitochondrial ...

  12. Mitochondrial Diseases

    MedlinePlus

    ... in your body tissues. If you have a metabolic disorder, something goes wrong with this process. Mitochondrial diseases are a group of metabolic disorders. Mitochondria are small structures that produce energy in ...

  13. Mitochondrial Myopathy

    MedlinePlus

    ... with ragged-red fibers, and mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes. The symptoms of ... riboflavin, coenzyme Q, and carnitine (a specialized amino acid) may provide subjective improvement in fatigue and energy ...

  14. Mitochondrial genetics

    PubMed Central

    Chinnery, Patrick Francis; Hudson, Gavin

    2013-01-01

    Introduction In the last 10 years the field of mitochondrial genetics has widened, shifting the focus from rare sporadic, metabolic disease to the effects of mitochondrial DNA (mtDNA) variation in a growing spectrum of human disease. The aim of this review is to guide the reader through some key concepts regarding mitochondria before introducing both classic and emerging mitochondrial disorders. Sources of data In this article, a review of the current mitochondrial genetics literature was conducted using PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). In addition, this review makes use of a growing number of publically available databases including MITOMAP, a human mitochondrial genome database (www.mitomap.org), the Human DNA polymerase Gamma Mutation Database (http://tools.niehs.nih.gov/polg/) and PhyloTree.org (www.phylotree.org), a repository of global mtDNA variation. Areas of agreement The disruption in cellular energy, resulting from defects in mtDNA or defects in the nuclear-encoded genes responsible for mitochondrial maintenance, manifests in a growing number of human diseases. Areas of controversy The exact mechanisms which govern the inheritance of mtDNA are hotly debated. Growing points Although still in the early stages, the development of in vitro genetic manipulation could see an end to the inheritance of the most severe mtDNA disease. PMID:23704099

  15. Adenine nucleotide translocator isoforms 1 and 2 are differently distributed in the mitochondrial inner membrane and have distinct affinities to cyclophilin D.

    PubMed Central

    Vyssokikh, M Y; Katz, A; Rueck, A; Wuensch, C; Dörner, A; Zorov, D B; Brdiczka, D

    2001-01-01

    Different isoforms of the adenine nucleotide translocase (ANT) are expressed in a tissue-specific manner. It was assumed that ANT-1 and ANT-2 co-exist in every single mitochondrion and might be differently distributed within the membrane structures that constitute the peripheral inner membrane or the crista membrane. To discriminate between ANT originating from peripheral or from cristal inner membranes we made use of the fact that complexes between porin, the outer-membrane pore protein, and the ANT can be generated. Such complexes between porin and the ANT in the peripheral inner membrane were induced in rat heart mitochondria and isolated from rat brain and kidney. Using ANT-isotype-specific antibodies and sequence analysis of the N-terminal end, it was discovered that the peripheral inner membrane contained ANT-1 and ANT-2, whereas the cristal membrane contained exclusively ANT-2. Cyclophilin was co-purified with the porin-ANT complexes, whereas it was absent in the crista-derived ANT. This suggested that ANT-1 might have a higher affinity for cyclophilin. This specific intra-mitochondrial distribution of the two ANT isotypes and cyclophilin D suggests specific functions of the peripheral and crista-forming parts of the inner membrane and the two ANT isotypes therein. PMID:11513733

  16. Sleep Disorders Associated with Primary Mitochondrial Diseases

    PubMed Central

    Ramezani, Ryan J.; Stacpoole, Peter W.

    2014-01-01

    Study Objectives: Primary mitochondrial diseases are caused by heritable or spontaneous mutations in nuclear DNA or mitochondrial DNA. Such pathological mutations are relatively common in humans and may lead to neurological and neuromuscular complication that could compromise normal sleep behavior. To gain insight into the potential impact of primary mitochondrial disease and sleep pathology, we reviewed the relevant English language literature in which abnormal sleep was reported in association with a mitochondrial disease. Design: We examined publications reported in Web of Science and PubMed from February 1976 through January 2014, and identified 54 patients with a proven or suspected primary mitochondrial disorder who were evaluated for sleep disturbances. Measurements and Results: Both nuclear DNA and mitochondrial DNA mutations were associated with abnormal sleep patterns. Most subjects who underwent polysomnography had central sleep apnea, and only 5 patients had obstructive sleep apnea. Twenty-four patients showed decreased ventilatory drive in response to hypoxia and/or hypercapnia that was not considered due to weakness of the intrinsic muscles of respiration. Conclusions: Sleep pathology may be an underreported complication of primary mitochondrial diseases. The probable underlying mechanism is cellular energy failure causing both central neurological and peripheral neuromuscular degenerative changes that commonly present as central sleep apnea and poor ventilatory response to hypercapnia. Increased recognition of the genetics and clinical manifestations of mitochondrial diseases by sleep researchers and clinicians is important in the evaluation and treatment of all patients with sleep disturbances. Prospective population-based studies are required to determine the true prevalence of mitochondrial energy failure in subjects with sleep disorders, and conversely, of individuals with primary mitochondrial diseases and sleep pathology. Citation: Ramezani RJ

  17. Infantile mitochondrial disorder associated with subclinical hypothyroidism is caused by a rare mitochondrial DNA 8691A>G mutation: a case report.

    PubMed

    Hao, Xiaosheng; Liu, Songyan; Wu, Xuemei; Hao, Yunpeng; Chen, Yinbo

    2015-07-01

    Mitochondrial diseases, ~15% of cases, are because of mitochondrial DNA mutations. This study reported a case of an 11-month-old male infant with mitochondrial disease characteristics and subclinical hypothyroidism (a high thyrotropin level). Laboratory tests were all normal and the enzymatic activities of mitochondrial respiratory chain enzyme complexes I-IV were normal. However, thyroid tests showed abnormal results, and complex V showed a deficiency activity of 52.8% of the low limit of healthy individuals (normal activity is >60.7%). The patient experienced convulsions, and the 24-h ambulatory electroencephalography results showed abnormalities, but the electromyography results were normal. Axial brain MRI showed abnormal dysplasia over the white matter myelination in the bilateral horn of the lateral ventricle. Furthermore, DNA sequencing data showed a novel mutation at 8691A>G of the mitochondrial ATPase 6 gene. This case adds to the growing literature of mitochondrial disorders caused by mitochondrial ATPase 6 mutations. PMID:26053701

  18. Genotype Distribution of Human Papillomavirus among Women with Cervical Cytological Abnormalities or Invasive Squamous Cell Carcinoma in a High-Incidence Area of Esophageal Carcinoma in China

    PubMed Central

    Wang, Yuanyuan; Wang, Shaohong; Shen, Jinhui; Peng, Yanyan; Chen, Lechuan; Mai, Ruiqin

    2016-01-01

    Data of HPV genotype including 16 high-risk HPV (HR-HPV) and 4 low-risk HPV from 38,397 women with normal cytology, 1341 women with cervical cytology abnormalities, and 223 women with ISCC were retrospectively evaluated by a hospital-based study. The prevalence of high-risk HPV (HR-HPV) was 6.51%, 41.83%, and 96.86% in women with normal cytology, cervical cytology abnormalities, and ISCC, respectively. The three most common HPV types were HPV-52 (1.76%), HPV-16 (1.28%), and HPV-58 (0.97%) in women with normal cytology, whereas the most prevalent HPV type was HPV-16 (16.85%), followed by HPV-52 (9.55%) and HPV-58 (7.83%) in women with cervical cytology abnormalities. Specifically, HPV-16 had the highest frequency in ASC-H (24.16%, 36/149) and HSIL (35.71%, 110/308), while HPV-52 was the most common type in ASC-US (8.28%, 53/640) and LSIL (16.80%, 41/244). HPV-16 (75.78%), HPV18 (10.31%), and HPV58 (9.87%) were the most common types in women with ISCC. These data might contribute to increasing the knowledge of HPV epidemiology and providing the guide for vaccine selection for women in Shantou. PMID:27610364

  19. Genotype Distribution of Human Papillomavirus among Women with Cervical Cytological Abnormalities or Invasive Squamous Cell Carcinoma in a High-Incidence Area of Esophageal Carcinoma in China.

    PubMed

    Wang, Yuanyuan; Wang, Shaohong; Shen, Jinhui; Peng, Yanyan; Chen, Lechuan; Mai, Ruiqin; Zhang, Guohong

    2016-01-01

    Data of HPV genotype including 16 high-risk HPV (HR-HPV) and 4 low-risk HPV from 38,397 women with normal cytology, 1341 women with cervical cytology abnormalities, and 223 women with ISCC were retrospectively evaluated by a hospital-based study. The prevalence of high-risk HPV (HR-HPV) was 6.51%, 41.83%, and 96.86% in women with normal cytology, cervical cytology abnormalities, and ISCC, respectively. The three most common HPV types were HPV-52 (1.76%), HPV-16 (1.28%), and HPV-58 (0.97%) in women with normal cytology, whereas the most prevalent HPV type was HPV-16 (16.85%), followed by HPV-52 (9.55%) and HPV-58 (7.83%) in women with cervical cytology abnormalities. Specifically, HPV-16 had the highest frequency in ASC-H (24.16%, 36/149) and HSIL (35.71%, 110/308), while HPV-52 was the most common type in ASC-US (8.28%, 53/640) and LSIL (16.80%, 41/244). HPV-16 (75.78%), HPV18 (10.31%), and HPV58 (9.87%) were the most common types in women with ISCC. These data might contribute to increasing the knowledge of HPV epidemiology and providing the guide for vaccine selection for women in Shantou. PMID:27610364

  20. Mitochondrial Division and Fusion in Metabolism

    PubMed Central

    Roy, Madhuparna; Reddy, P. Hemachandra; Iijima, Miho; Sesaki, Hiromi

    2015-01-01

    Mitochondria govern many metabolic processes. In addition, mitochondria sense the status of metabolism and change their functions to regulate energy production, cell death, and thermogenesis. Recent studies have revealed that mitochondrial structural remodeling through division and fusion is critical to the organelle’s function. It has also become clear that abnormalities in mitochondrial division and fusion are linked to the pathophysiology of metabolic diseases such as diabetes and obesity. Here, we discuss the current understanding of the mechanisms of mitochondrial dynamics and their role in cellular and organismal metabolism. PMID:25703628

  1. Mitochondrial Evolution

    PubMed Central

    Gray, Michael W.

    2012-01-01

    Viewed through the lens of the genome it contains, the mitochondrion is of unquestioned bacterial ancestry, originating from within the bacterial phylum α-Proteobacteria (Alphaproteobacteria). Accordingly, the endosymbiont hypothesis—the idea that the mitochondrion evolved from a bacterial progenitor via symbiosis within an essentially eukaryotic host cell—has assumed the status of a theory. Yet mitochondrial genome evolution has taken radically different pathways in diverse eukaryotic lineages, and the organelle itself is increasingly viewed as a genetic and functional mosaic, with the bulk of the mitochondrial proteome having an evolutionary origin outside Alphaproteobacteria. New data continue to reshape our views regarding mitochondrial evolution, particularly raising the question of whether the mitochondrion originated after the eukaryotic cell arose, as assumed in the classical endosymbiont hypothesis, or whether this organelle had its beginning at the same time as the cell containing it. PMID:22952398

  2. Mitochondrial dysfunction in ataxia-telangiectasia.

    PubMed

    Valentin-Vega, Yasmine A; Maclean, Kirsteen H; Tait-Mulder, Jacqueline; Milasta, Sandra; Steeves, Meredith; Dorsey, Frank C; Cleveland, John L; Green, Douglas R; Kastan, Michael B

    2012-02-01

    Ataxia-telangiectasia mutated (ATM) plays a central role in DNA damage responses, and its loss leads to development of T-cell malignancies. Here, we show that ATM loss also leads to intrinsic mitochondrial abnormalities in thymocytes, including elevated reactive oxygen species, increased aberrant mitochondria, high cellular respiratory capacity, and decreased mitophagy. A fraction of ATM protein is localized in mitochondria, and it is rapidly activated by mitochondrial dysfunction. Unexpectedly, allelic loss of the autophagy regulator Beclin-1 significantly delayed tumor development in ATM-null mice. This effect was not associated with rescue of DNA damage signaling but rather with a significant reversal of the mitochondrial abnormalities. These data support a model in which ATM plays direct roles in modulating mitochondrial homeostasis and suggest that mitochondrial dysfunction and associated increases in mitochondrial reactive oxygen species contribute to the cancer-prone phenotype observed in organisms lacking ATM. Thus, ataxia-telangiectasia should be considered, at least in part, as a mitochondrial disease. PMID:22144182

  3. Biochemical abnormalities in Pearson syndrome.

    PubMed

    Crippa, Beatrice Letizia; Leon, Eyby; Calhoun, Amy; Lowichik, Amy; Pasquali, Marzia; Longo, Nicola

    2015-03-01

    Pearson marrow-pancreas syndrome is a multisystem mitochondrial disorder characterized by bone marrow failure and pancreatic insufficiency. Children who survive the severe bone marrow dysfunction in childhood develop Kearns-Sayre syndrome later in life. Here we report on four new cases with this condition and define their biochemical abnormalities. Three out of four patients presented with failure to thrive, with most of them having normal development and head size. All patients had evidence of bone marrow involvement that spontaneously improved in three out of four patients. Unique findings in our patients were acute pancreatitis (one out of four), renal Fanconi syndrome (present in all patients, but symptomatic only in one), and an unusual organic aciduria with 3-hydroxyisobutyric aciduria in one patient. Biochemical analysis indicated low levels of plasma citrulline and arginine, despite low-normal ammonia levels. Regression analysis indicated a significant correlation between each intermediate of the urea cycle and the next, except between ornithine and citrulline. This suggested that the reaction catalyzed by ornithine transcarbamylase (that converts ornithine to citrulline) might not be very efficient in patients with Pearson syndrome. In view of low-normal ammonia levels, we hypothesize that ammonia and carbamylphosphate could be diverted from the urea cycle to the synthesis of nucleotides in patients with Pearson syndrome and possibly other mitochondrial disorders. PMID:25691415

  4. Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue.

    PubMed

    Winter, Lilli; Wittig, Ilka; Peeva, Viktoriya; Eggers, Britta; Heidler, Juliana; Chevessier, Frederic; Kley, Rudolf A; Barkovits, Katalin; Strecker, Valentina; Berwanger, Carolin; Herrmann, Harald; Marcus, Katrin; Kornblum, Cornelia; Kunz, Wolfram S; Schröder, Rolf; Clemen, Christoph S

    2016-09-01

    Secondary mitochondrial dysfunction is a feature in a wide variety of human protein aggregate diseases caused by mutations in different proteins, both in the central nervous system and in striated muscle. The functional relationship between the expression of a mutated protein and mitochondrial dysfunction is largely unknown. In particular, the mechanism how this dysfunction drives the disease process is still elusive. To address this issue for protein aggregate myopathies, we performed a comprehensive, multi-level analysis of mitochondrial pathology in skeletal muscles of human patients with mutations in the intermediate filament protein desmin and in muscles of hetero- and homozygous knock-in mice carrying the R349P desmin mutation. We demonstrate that the expression of mutant desmin causes disruption of the extrasarcomeric desmin cytoskeleton and extensive mitochondrial abnormalities regarding subcellular distribution, number and shape. At the molecular level, we uncovered changes in the abundancy and assembly of the respiratory chain complexes and supercomplexes. In addition, we revealed a marked reduction of mtDNA- and nuclear DNA-encoded mitochondrial proteins in parallel with large-scale deletions in mtDNA and reduced mtDNA copy numbers. Hence, our data demonstrate that the expression of mutant desmin causes multi-level damage of mitochondria already in early stages of desminopathies. PMID:27393313

  5. Abnormal Head Position

    MedlinePlus

    ... cause. Can a longstanding head turn lead to any permanent problems? Yes, a significant abnormal head posture could cause permanent ... occipitocervical synostosis and unilateral hearing loss. Are there any ... postures? Yes. Abnormal head postures can usually be improved depending ...

  6. Urine - abnormal color

    MedlinePlus

    ... straw-yellow. Abnormally colored urine may be cloudy, dark, or blood-colored. Causes Abnormal urine color may ... red blood cells, or mucus in the urine. Dark brown but clear urine is a sign of ...

  7. Mitochondrial impairment induced by 3-nitropropionic acid is enhanced by endogenous metalloprotease activity inhibition in cultured rat striatal neurons.

    PubMed

    de Oca Balderas, Pavel Montes; Ospina, Gabriel Gutiérrez; Del Ángel, Abel Santamaría

    2013-06-24

    Metalloproteases from the metzincin family mediate molecule processing at the cell membrane termed ectodomain shedding (ES). This mechanism enables the generation of intracellular and extracellular fragments from cell membrane molecules that exert additional functions involved in cell processes including cell death, beyond those of full length molecules. Micotoxin 3-nitropropionic acid (3-NP) induces striatal neuronal degeneration in vivo and in vitro through mitochondrial complex II inhibition. In this study, we hypothesized that metalloproteases regulate mitochondrial activity in cultured rat striatal neurons undergoing degeneration. To test this idea, striatal neuronal cultures characterized by NeuN and GAD-67 expression were treated with 3-NP together with the metalloprotease inhibitor GM6001 and their mitochondrial activity was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Our results showed that metalloprotease inhibition potentiated mitochondrial activity impairment induced by 3-NP whereas the inhibitor alone had no effect. These results indicate that metalloproteases regulate and promote mitochondrial functionality in striatal neurons undergoing degeneration induced by 3-NP. Since NMDA receptor is involved in the excitotoxic neuronal death triggered by 3-NP and is known to undergo ES, we analyzed NMDAR subunit NR1 phenotypic distribution by immunofluorescence. 3-NP and GM6001 induced abnormal perinuclear NR1 accumulation that was not observed with 3-NP or GM6001 alone. This observation suggests that metalloproteases are involved in NR1 cellular reorganization induced by 3-NP, and that their inhibition results in abnormal NR1 distribution. Together results indicate that endogenous metalloproteases are activated during striatal neurodegeneration induced by 3-NP eliciting an adaptative or compensatory response that protects mitochondrial functionality. PMID:23643981

  8. GABA receptor subunit distribution and FMRP-mGluR5 signaling abnormalities in the cerebellum of subjects with schizophrenia, mood disorders, and autism.

    PubMed

    Fatemi, S Hossein; Folsom, Timothy D

    2015-09-01

    Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. GABAergic receptor abnormalities have been documented in several major psychiatric disorders including schizophrenia, mood disorders, and autism. Abnormal expression of mRNA and protein for multiple GABA receptors has also been observed in multiple brain regions leading to alterations in the balance between excitatory/inhibitory signaling in the brain with potential profound consequences for normal cognition and maintenance of mood and perception. Altered expression of GABAA receptor subunits has been documented in fragile X mental retardation 1 (FMR1) knockout mice, suggesting that loss of its protein product, fragile X mental retardation protein (FMRP), impacts GABAA subunit expression. Recent postmortem studies from our laboratory have shown reduced expression of FMRP in the brains of subjects with schizophrenia, bipolar disorder, major depression, and autism. FMRP acts as a translational repressor and, under normal conditions, inhibits metabotropic glutamate receptor 5 (mGluR5)-mediated signaling. In fragile X syndrome (FXS), the absence of FMRP is hypothesized to lead to unregulated mGluR5 signaling, ultimately resulting in the behavioral and intellectual impairments associated with this disorder. Our laboratory has identified changes in mGluR5 expression in autism, schizophrenia, and mood disorders. In the current review article, we discuss our postmortem data on GABA receptors, FMRP, and mGluR5 levels and compare our results with other laboratories. Finally, we discuss the interactions between these molecules and the potential for new therapeutic interventions that target these interconnected signaling systems. PMID:25432637

  9. Mitochondrial Disorders of DNA Polymerase γ Dysfunction

    PubMed Central

    Zhang, Linsheng; Chan, Sherine S. L.; Wolff, Daynna J.

    2011-01-01

    Context Primary mitochondrial dysfunction is one of the most common causes of inherited disorders predominantly involving the neuromuscular system. Advances in the molecular study of mitochondrial DNA have changed our vision and our approach to primary mitochondrial disorders. Many of the mitochondrial disorders are caused by mutations in nuclear genes and are inherited in an autosomal recessive pattern. Among the autosomal inherited mitochondrial disorders, those related to DNA polymerase γ dysfunction are the most common and the best studied. Understanding the molecular mechanisms and being familiar with the recent advances in laboratory diagnosis of this group of mitochondrial disorders are essential for pathologists to interpret abnormal histopathology and laboratory results and to suggest further studies for a definitive diagnosis. Objectives To help pathologists better understand the common clinical syndromes originating from mutations in DNA polymerase γ and its associated proteins and use the stepwise approach of clinical, laboratory, and pathologic diagnosis of these syndromes. Data Sources Review of pertinent published literature and relevant Internet databases. Conclusions Mitochondrial disorders are now better recognized with the development of molecular tests for clinical diagnosis. A cooperative effort among primary physicians, diagnostic pathologists, geneticists, and molecular biologists with expertise in mitochondrial disorders is required to reach a definitive diagnosis. PMID:21732785

  10. The Neuro-Ophthalmology of Mitochondrial Disease

    PubMed Central

    Fraser, J. Alexander; Biousse, Valérie; Newman, Nancy J.

    2010-01-01

    Mitochondrial diseases frequently manifest neuro-ophthalmologic symptoms and signs. Because of the predilection of mitochondrial disorders to involve the optic nerves, extraocular muscles, retina, and even the retrochiasmal visual pathways, the ophthalmologist is often the first physician to be consulted. Disorders caused by mitochondrial dysfunction can result from abnormalities in either the mitochondrial DNA or in nuclear genes which encode mitochondrial proteins. Inheritance of these mutations will follow patterns specific to their somatic or mitochondrial genetics. Genotype-phenotype correlations are inconstant, and considerable overlap may occur among these syndromes. The diagnostic approach to the patient with suspected mitochondrial disease entails a detailed personal and family history, careful ophthalmic, neurologic, and systemic examination, directed investigations, and attention to potentially life-threatening sequelae. Although curative treatments for mitochondrial disorders are currently lacking, exciting research advances are being made, particularly in the area of gene therapy. Leber hereditary optic neuropathy, with its window of opportunity for timely intervention and its accessibility to directed therapy, offers a unique model to study future therapeutic interventions. Most patients and their relatives benefit from informed genetic counseling. PMID:20471050

  11. Mitochondrial dysfunction: a neglected component of skin diseases.

    PubMed

    Feichtinger, René G; Sperl, Wolfgang; Bauer, Johann W; Kofler, Barbara

    2014-09-01

    Aberrant mitochondrial structure and function influence tissue homeostasis and thereby contribute to multiple human disorders and ageing. Ten per cent of patients with primary mitochondrial disorders present skin manifestations that can be categorized into hair abnormalities, rashes, pigmentation abnormalities and acrocyanosis. Less attention has been paid to the fact that several disorders of the skin are linked to alterations of mitochondrial energy metabolism. This review article summarizes the contribution of mitochondrial pathology to both common and rare skin diseases. We explore the intriguing observation that a wide array of skin disorders presents with primary or secondary mitochondrial pathology and that a variety of molecular defects can cause dysfunctional mitochondria. Among them are mutations in mitochondrial- and nuclear DNA-encoded subunits and assembly factors of oxidative phosphorylation (OXPHOS) complexes; mutations in intermediate filament proteins involved in linking, moving and shaping of mitochondria; and disorders of mitochondrial DNA metabolism, fatty acid metabolism and heme synthesis. Thus, we assume that mitochondrial involvement is the rule rather than the exception in skin diseases. We conclude the article by discussing how improving mitochondrial function can be beneficial for aged skin and can be used as an adjunct therapy for certain skin disorders. Consideration of mitochondrial energy metabolism in the skin creates a new perspective for both dermatologists and experts in metabolic disease. PMID:24980550

  12. Geographic Patterns of Genetic Variation in a Broadly Distributed Marine Vertebrate: New Insights into Loggerhead Turtle Stock Structure from Expanded Mitochondrial DNA Sequences

    PubMed Central

    Shamblin, Brian M.; Bolten, Alan B.; Abreu-Grobois, F. Alberto; Bjorndal, Karen A.; Cardona, Luis; Carreras, Carlos; Clusa, Marcel; Monzón-Argüello, Catalina; Nairn, Campbell J.; Nielsen, Janne T.; Nel, Ronel; Soares, Luciano S.; Stewart, Kelly R.; Vilaça, Sibelle T.; Türkozan, Oguz; Yilmaz, Can; Dutton, Peter H.

    2014-01-01

    Previous genetic studies have demonstrated that natal homing shapes the stock structure of marine turtle nesting populations. However, widespread sharing of common haplotypes based on short segments of the mitochondrial control region often limits resolution of the demographic connectivity of populations. Recent studies employing longer control region sequences to resolve haplotype sharing have focused on regional assessments of genetic structure and phylogeography. Here we synthesize available control region sequences for loggerhead turtles from the Mediterranean Sea, Atlantic, and western Indian Ocean basins. These data represent six of the nine globally significant regional management units (RMUs) for the species and include novel sequence data from Brazil, Cape Verde, South Africa and Oman. Genetic tests of differentiation among 42 rookeries represented by short sequences (380 bp haplotypes from 3,486 samples) and 40 rookeries represented by long sequences (∼800 bp haplotypes from 3,434 samples) supported the distinction of the six RMUs analyzed as well as recognition of at least 18 demographically independent management units (MUs) with respect to female natal homing. A total of 59 haplotypes were resolved. These haplotypes belonged to two highly divergent global lineages, with haplogroup I represented primarily by CC-A1, CC-A4, and CC-A11 variants and haplogroup II represented by CC-A2 and derived variants. Geographic distribution patterns of haplogroup II haplotypes and the nested position of CC-A11.6 from Oman among the Atlantic haplotypes invoke recent colonization of the Indian Ocean from the Atlantic for both global lineages. The haplotypes we confirmed for western Indian Ocean RMUs allow reinterpretation of previous mixed stock analysis and further suggest that contemporary migratory connectivity between the Indian and Atlantic Oceans occurs on a broader scale than previously hypothesized. This study represents a valuable model for conducting

  13. Geographic patterns of genetic variation in a broadly distributed marine vertebrate: new insights into loggerhead turtle stock structure from expanded mitochondrial DNA sequences.

    PubMed

    Shamblin, Brian M; Bolten, Alan B; Abreu-Grobois, F Alberto; Bjorndal, Karen A; Cardona, Luis; Carreras, Carlos; Clusa, Marcel; Monzón-Argüello, Catalina; Nairn, Campbell J; Nielsen, Janne T; Nel, Ronel; Soares, Luciano S; Stewart, Kelly R; Vilaça, Sibelle T; Türkozan, Oguz; Yilmaz, Can; Dutton, Peter H

    2014-01-01

    Previous genetic studies have demonstrated that natal homing shapes the stock structure of marine turtle nesting populations. However, widespread sharing of common haplotypes based on short segments of the mitochondrial control region often limits resolution of the demographic connectivity of populations. Recent studies employing longer control region sequences to resolve haplotype sharing have focused on regional assessments of genetic structure and phylogeography. Here we synthesize available control region sequences for loggerhead turtles from the Mediterranean Sea, Atlantic, and western Indian Ocean basins. These data represent six of the nine globally significant regional management units (RMUs) for the species and include novel sequence data from Brazil, Cape Verde, South Africa and Oman. Genetic tests of differentiation among 42 rookeries represented by short sequences (380 bp haplotypes from 3,486 samples) and 40 rookeries represented by long sequences (∼800 bp haplotypes from 3,434 samples) supported the distinction of the six RMUs analyzed as well as recognition of at least 18 demographically independent management units (MUs) with respect to female natal homing. A total of 59 haplotypes were resolved. These haplotypes belonged to two highly divergent global lineages, with haplogroup I represented primarily by CC-A1, CC-A4, and CC-A11 variants and haplogroup II represented by CC-A2 and derived variants. Geographic distribution patterns of haplogroup II haplotypes and the nested position of CC-A11.6 from Oman among the Atlantic haplotypes invoke recent colonization of the Indian Ocean from the Atlantic for both global lineages. The haplotypes we confirmed for western Indian Ocean RMUs allow reinterpretation of previous mixed stock analysis and further suggest that contemporary migratory connectivity between the Indian and Atlantic Oceans occurs on a broader scale than previously hypothesized. This study represents a valuable model for conducting

  14. [Peripheral neuropathies due to mitochondrial disorders].

    PubMed

    Funalot, B

    2009-12-01

    Involvement of peripheral nerves is frequent in mitochondrial disorders but with variable severity. Mitochondrial diseases causing peripheral neuropathies (PN) may be due to mutations of mitochondrial DNA (mtDNA), as is the case in MERRF and MELAS syndromes, or to mutations of nuclear genes. Secondary abnormalities of mtDNA (such as multiple deletions of muscle mtDNA) may result from mitochondrial disorders due to mutations in nuclear genes involved in mtDNA maintenance. This is the case in several syndromes caused by impaired mtDNA maintenance, such as Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoplegia (SANDO) due to recessive mutations in the POLG gene, which encodes the catalytic subunit of mtDNA polymerase (DNA polymerase gamma), or Mitochondrial Neuro-Gastro-Intestinal Encephalomyopathy (MNGIE), due to recessive mutations in the TYMP gene, which encodes thymidine phosphorylase. Genetically-determined PN due to mutations of mitofusin 2, a GTPase involved in the fusion of external mitochondrial membranes, were identified during the last few years. Characteristic ultrastructural lesions (abnormalities of axonal mitochondria) are observed on longitudinal sections of nerve biopsies in patients with PN due to mitofusin 2 mutations. PMID:19942242

  15. Extraocular mitochondrial myopathies and their differential diagnoses.

    PubMed

    Schoser, Benedikt G H; Pongratz, Dieter

    2006-06-01

    The diagnosis of mitochondrial myopathy depends upon a constellation of findings, family history, type of muscle involvement, specific laboratory abnormalities, and the results of histological, pathobiochemical and genetic analysis. In the present paper, the authors describe the diagnostic approach to mitochondrial myopathies manifesting as extraocular muscle disease. The most common ocular manifestation of mitochondrial myopathy is progressive external ophthalmoplegia (PEO). To exclude myasthenia gravis, ocular myositis, thyroid associated orbitopathy, oculopharyngeal muscular dystrophy, and congenital fibrosis of the extraocular muscles in patients with an early onset or long-lasting very slowly progressive ptosis and external ophthalmoplegia, almost without any diplopia, and normal to mildly elevated serum creatine kinase and lactate, electromyography, nerve conduction studies and MRI of the orbits should be performed. A PEO phenotype forces one to look comprehensively for other multisystemic mitochondrial features (e.g., exercise induced weakness, encephalopathy, polyneuropathy, diabetes, heart disease). Thereafter, and presently even in familiar PEO, a diagnostic muscle biopsy should be taken. Histological and ultrastructural hallmarks are mitochondrial proliferations and structural abnormalities, lipid storage, ragged-red fibers, or cytochrome-C negative myofibers. In addition, Southern blotting may reveal the common deletion, or molecular analysis may verify specific mutations of distinct mitochondrial or nuclear genes. PMID:16760117

  16. ESCI Award 2006. Mitochondrial function and endocrine diseases.

    PubMed

    Stark, R; Roden, M

    2007-04-01

    Mitochondria are fundamental for oxidative energy production and impairment of their functionality can lead to reduced ATP synthesis and contribute to initiation of apoptosis. Endocrine tissues critically rely on oxidative phosphorylation so that mitochondrial abnormalities may either be causes or consequences of diminished hormone production or action. Abnormalities typical for diseases caused by mitochondrial DNA mutations such as Kearns-Sayre syndrome or mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome are also seen in certain endocrine diseases. Lack or excess of thyroid hormones, major ubiquitous regulators of mitochondrial content and activity, cause muscular abnormalities and multisystem disorders. Mitochondria are a further prerequisite for steroidogenesis as well as insulin secretion and action. Recent studies showed that reduced mitochondrial ATP synthesis in skeletal muscle is a feature of certain hereditary and acquired forms of insulin resistance and diabetes mellitus. Finally, ageing is not only accompanied by various degrees of hormonal deficiency and insulin resistance but is also associated with a progressive decline of mitochondrial number and function. Future research is needed to examine whether mitochondrial abnormalities are the cause or consequence of ageing and frequent metabolic diseases such as obesity and type 2 diabetes mellitus, and to address mitochondria as a target for novel therapeutic regimes. PMID:17373958

  17. [Mitochondrial neurogastrointestinal encephalopathy disease].

    PubMed

    Benureau, A; Meyer, P; Maillet, O; Leboucq, N; Legras, S; Jeziorski, E; Fournier-Favre, S; Jeandel, C; Gaignard, P; Slama, A; Rivier, F; Roubertie, A; Carneiro, M

    2014-12-01

    Mitochondrial neurogastrointestinal encephalopathy disease (MNGIE) is a rare autosomal-recessive syndrome, resulting from mutations in the TYMP gene, located at 22q13. The mutation induces a thymidine phosphorylase (TP) deficit, which leads to a nucleotide pool imbalance and to instability of the mitochondrial DNA. The clinical picture regroups gastrointestinal dysmotility, cachexia, ptosis, ophthalmoplegia, peripheral neuropathy, and asymptomatic leukoencephalopathy. The prognosis is unfavorable. We present the case of a 14-year-old Caucasian female whose symptoms started in early childhood. The diagnosis was suspected after magnetic resonance imaging (MRI), performed given the atypical features of mental anorexia, which revealed white matter abnormalities. She presented chronic vomiting, postprandial abdominal pain, and problems gaining weight accompanied by cachexia. This diagnosis led to establishing proper care, in particular an enteral and parenteral nutrition program. There is no known specific effective treatment, but numerous studies are in progress. In this article, after reviewing the existing studies, we discuss the main diagnostic and therapeutic aspects of the disease. We argue for the necessity of performing a cerebral MRI given the atypical features of a patient with suspected mental anorexia (or when the clinical pattern of a patient with mental anorexia seems atypical), so that MNGIE can be ruled out. PMID:25282463

  18. Mitochondrial dynamics and the cell cycle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Nuclear-mitochondrial (NM) communication impacts many aspects of plant development including vigor, sterility and viability. Dynamic changes in mitochondrial number, shape, size, and cellular location takes place during the cell cycle possibly impacting the process itself and leading to distribution...

  19. Caveolin-3 null mice show a loss of caveolae, changes in the microdomain distribution of the dystrophin-glycoprotein complex, and t-tubule abnormalities.

    PubMed

    Galbiati, F; Engelman, J A; Volonte, D; Zhang, X L; Minetti, C; Li, M; Hou, H; Kneitz, B; Edelmann, W; Lisanti, M P

    2001-06-15

    Caveolin-3, a muscle-specific caveolin-related protein, is the principal structural protein of caveolae membrane domains in striated muscle cells. Recently, we identified a novel autosomal dominant form of limb-girdle muscular dystrophy (LGMD-1C) in humans that is due to mutations within the coding sequence of the human caveolin-3 gene (3p25). These LGMD-1C mutations lead to an approximately 95% reduction in caveolin-3 protein expression, i.e. a caveolin-3 deficiency. Here, we created a caveolin-3 null (CAV3 -/-) mouse model, using standard homologous recombination techniques, to mimic a caveolin-3 deficiency. We show that these mice lack caveolin-3 protein expression and sarcolemmal caveolae membranes. In addition, analysis of skeletal muscle tissue from these caveolin-3 null mice reveals: (i) mild myopathic changes; (ii) an exclusion of the dystrophin-glycoprotein complex from lipid raft domains; and (iii) abnormalities in the organization of the T-tubule system, with dilated and longitudinally oriented T-tubules. These results have clear mechanistic implications for understanding the pathogenesis of LGMD-1C at a molecular level. PMID:11259414

  20. United Mitochondrial Disease Foundation

    MedlinePlus

    ... Caregivers! Want to help? Enroll now in the Mitochondrial Disease Community Registry to advance the development of treatments and cures. HOME What is Mitochondrial Disease Types of Mitochondrial Disease Possible Symptoms Getting a ...

  1. What Is Mitochondrial DNA?

    MedlinePlus

    ... DNA What is mitochondrial DNA? What is mitochondrial DNA? Although most DNA is packaged in chromosomes within ... proteins. For more information about mitochondria and mitochondrial DNA: Molecular Expressions, a web site from the Florida ...

  2. Tooth - abnormal shape

    MedlinePlus

    Hutchinson incisors; Abnormal tooth shape; Peg teeth; Mulberry teeth; Conical teeth ... The appearance of normal teeth varies, especially the molars. ... conditions. Specific diseases can affect tooth shape, tooth ...

  3. Tooth - abnormal shape

    MedlinePlus

    Hutchinson incisors; Abnormal tooth shape; Peg teeth; Mulberry teeth; Conical teeth ... from many different conditions. Specific diseases can affect tooth shape, tooth color, time of appearance, or absence ...

  4. [Diagnosis and therapy of mitochondrial diseases].

    PubMed

    Pál, Endre

    2012-07-30

    Mitochondrial diseases are a significant part of neuromuscular diseases. Majority of them is multisystemic disorder. The diagnosis can be established in more and more cases. Beyond the routine neurological examination imaging methods (MRI and MR-spectroscopy) and electrophysiology (EMG, ENG, EEG, evoked potential tests) might be helpful in setting the diagnosis. Raised blood lactate level supports the diagnosis. Muscle biopsy demonstrates mitochondrial abnormalities in the majority of cases. The positivity of genetic tests is low, because the amount of mitochondrial DNA alterations is different in tissues. Therefore other tissue than blood (mainly muscle) is necessary for genetic tests. The other reason is that the respiratory chain is under double -mitochondrial and nuclear - genetic control, and testing the nuclear genes are available only in selected laboratories. The treatment is limited, mainly symptomatic. PMID:23074842

  5. Inherited mitochondrial disorders.

    PubMed

    Finsterer, Josef

    2012-01-01

    Though inherited mitochondrial disorders (MIDs) are most well known for their syndromic forms, for which widely known acronyms (MELAS, MERRF, NARP, LHON etc.) have been coined, the vast majority of inherited MIDs presents in a non-syndromic form. Since MIDs are most frequently multisystem disorders already at onset or during the disease course, a MID should be suspected if there is a combination of neurological and non-neurological abnormalities. Neurological abnormalities occurring as a part of a MID include stroke-like episodes, epilepsy, migraine-like headache, movement disorders, cerebellar ataxia, visual impairment, encephalopathy, cognitive impairment, dementia, psychosis, hypopituitarism, aneurysms, or peripheral nervous system disease, such as myopathy, neuropathy, or neuronopathy. Non-neurological manifestations concern the ears, the endocrine organs, the heart, the gastrointestinal tract, the kidneys, the bone marrow, and the skin. Whenever there is an unexplained combination of neurological and non-neurological disease in a patient or kindred, a MID should be suspected and appropriate diagnostic measures initiated. Genetic testing should be guided by the phenotype, the biopsy findings, and the biochemical results. PMID:22399423

  6. The normal and abnormal distribution of the adrenomedullary imaging agent m-(I-/sup 131/)iodobenzylguanidine (I-/sup 131/ MIBG) in man: evaluation by scintigraphy

    SciTech Connect

    Nakajo, M.; Shapiro, B.; Copp, J.; Kalff, V.; Gross, M.D.; Sisson, J.C.; Beierwaltes, W.H.

    1983-08-01

    The scintigraphic distribution of m-(/sup 131/I)iodobenzylguanidine (I-/sup 131/ MIBG), an adrenal medullary imaging agent, was studied to determine the patterns of uptake of this agent in man. The normal distribution of I-/sup 131/ MIBG includes clear portrayal of the salivary glands, liver, spleen, and urinary bladder. The heart, middle and lower lung zones, and colon were less frequently or less clearly seen. The upper lung zones and kidneys were seldom visualized. The thyroid appeared only in cases of inadequate thyroidal blockade. The ''normal'' adrenal glands were seldom seen and faintly imaged in 2% at 24 hr after injection and in 16% at 48 hr, in patients shown not to have pheochromocytomas, whereas intra-adrenal, extraadrenal, and malignant pheochromocytomas usually appeared as intense focal areas of I-/sup 131/ MIBG uptake at 24 through 72 hr.

  7. Normal and abnormal distribution of the adrenomedullary imaging agent m-(I-131)iodobenzylguanidine (I-131 MIBG) in man; evaluation by scintigraphy

    SciTech Connect

    Nakajo, M.; Shapiro, B.; Copp, J.; Kalff, V.; Gross, M.D.; Sisson, J.C.; Beierwaltes, W.H.

    1983-08-01

    The scintigraphic distribution of m-(/sup 131/I)iodobenzylguanidine (I-131 MIBG), an adrenal medullary imaging agent, was studied to determine the patterns of uptake of this agent in man. The normal distribution of I-131 MIBG includes clear portrayal of the salivary glands, liver, spleen, and urinary bladder. The heart, middle and lower lung zones, and colon were less frequently or less clearly seen. The upper lung zones and kidneys were seldom visualized. The thyroid appeared only in cases of inadequate thyroidal blockade. The normal adrenal glands were seldom seen and faintly imaged in 2% at 24 h after injection and in 16% at 48 h, in patients shown not to have pheochromocytomas, whereas intra-adrenal, extra-adrenal, and malignant pheochromocytomas usually appeared as intense focal areas of I-131 MIBG uptake at 24 through 72 h.

  8. Structurally abnormal human autosomes

    SciTech Connect

    1993-12-31

    Chapter 25, discusses structurally abnormal human autosomes. This discussion includes: structurally abnormal chromosomes, chromosomal polymorphisms, pericentric inversions, paracentric inversions, deletions or partial monosomies, cri du chat (cat cry) syndrome, ring chromosomes, insertions, duplication or pure partial trisomy and mosaicism. 71 refs., 8 figs.

  9. Mitochondrial maintenance failure in aging and role of sexual dimorphism

    PubMed Central

    Tower, John

    2014-01-01

    Gene expression changes during aging are partly conserved across species, and suggest that oxidative stress, inflammation and proteotoxicity result from mitochondrial malfunction and abnormal mitochondrial-nuclear signaling. Mitochondrial maintenance failure may result from trade-offs between mitochondrial turnover versus growth and reproduction, sexual antagonistic pleiotropy and genetic conflicts resulting from uni-parental mitochondrial transmission, as well as mitochondrial and nuclear mutations and loss of epigenetic regulation. Aging phenotypes and interventions are often sex-specific, indicating that both male and female sexual differentiation promote mitochondrial failure and aging. Studies in mammals and invertebrates implicate autophagy, apoptosis, AKT, PARP, p53 and FOXO in mediating sex-specific differences in stress resistance and aging. The data support a model where the genes Sxl in Drosophila, sdc-2 in C. elegans, and Xist in mammals regulate mitochondrial maintenance across generations and in aging. Several interventions that increase life span cause a mitochondrial unfolded protein response (UPRmt), and UPRmt is also observed during normal aging, indicating hormesis. The UPRmt may increase life span by stimulating mitochondrial turnover through autophagy, and/or by inhibiting the production of hormones and toxic metabolites. The data suggest that metazoan life span interventions may act through a common hormesis mechanism involving liver UPRmt, mitochondrial maintenance and sexual differentiation. PMID:25447815

  10. Characterization of mitochondrial transport in neurons.

    PubMed

    Zhou, Bing; Lin, Mei-Yao; Sun, Tao; Knight, Adam L; Sheng, Zu-Hang

    2014-01-01

    Mitochondria are cellular power plants that supply ATP to power various biological activities essential for neuronal growth, survival, and function. Due to extremely varied morphological features, neurons face exceptional challenges to maintain energy homeostasis. Neurons require specialized mechanisms distributing mitochondria to distal synapses where energy is in high demand. Axons and synapses undergo activity-dependent remodeling, thereby altering mitochondrial distribution. The uniform microtubule polarity has made axons particularly useful for exploring mechanisms regulating mitochondrial transport. Mitochondria alter their motility under stress conditions or when their integrity is impaired. Therefore, research into the mechanisms regulating mitochondrial motility in healthy and diseased neurons is an important emerging frontier in neurobiology. In this chapter, we discuss the current protocols in the characterization of axonal mitochondrial transport in primary neuron cultures isolated from embryonic rats and adult mice. We also briefly discuss new procedures developed in our lab in analyzing mitochondrial motility patterns at presynaptic terminals and evaluate their impact on synaptic vesicle release. PMID:25416353

  11. Grapes, galls, and geography: the distribution of nuclear and mitochondrial DNA variation across host-plant species and regions in a specialist herbivore.

    PubMed

    Downie, D A; Fisher, J R; Granett, J

    2001-07-01

    Studies of patterns of molecular variation in natural populations can provide important insights into a number of evolutionary problems. Among these, the question of whether geographic factors are more important than ecological factors in promoting population differentiation and ultimately speciation has been an important and contentious area in evolutionary biology. Systems involving herbivorous insects have played a leading role in this discussion. This study examined the distribution of molecular variation in a highly specialized gall-forming insect, grape phylloxera (Daktulosphaira vitifoliae Fitch), that is found on both sympatric and allopatric host-plant species of the genus Vitis. In addition, the relationship of insects in the introduced range in the United States to ancestral populations in the native range was examined. Evidence for differentiation along host-plant lines from both nuclear (RAPD) and mitochondrial (COI) DNA was confounded with the effect of geography. Differentiation was found where hosts were allopatric or parapatric, but no evidence was found for such differentiation on two hosts, V. vulpina and V. aestivalis, that are broadly sympatric. The question of population differentiation onto these sympatric hosts can be considered to be resolved--it has not occurred in spite of a long history of association. Evidence was equivocal, but suggestive of a period of divergence in allopatry prior to reestablishment of contact, for insects associated with another host plant species, V. cinerea, found in both sympatric and parapatric populations. A low level of diversity and placement of samples collected from the grape species V. riparia at the tip of a phylogenetic tree supports the hypothesis that this host has been recently colonized from populations from the Mississippi Valley. A polyphyletic origin for biotype B grape phylloxera was supported: Although most samples collected from vineyards in the introduced range in California had similar

  12. IgG (Gm) allotypes and multiple sclerosis in a French population: phenotype distribution and quantitative abnormalities in CSF with respect to sex, disease severity, and presence of intrathecal antibodies.

    PubMed

    Sesboüé, R; Daveau, M; Degos, J D; Martin-Mondiere, C; Goust, J M; Schuller, E; Rivat-Peran, L; Coquerel, A; Dujardin, M; Salier, J P

    1985-11-01

    The association of a given Gm allotype or phenotype with MS susceptibility, as previously described in some Caucasian populations, was not observed in a large French MS group, whether or not considering the possible influence of sex or disease severity. This result could be related to variations in geographical distribution of Gm alleles and MS susceptibility gene(s) or suggests the simultaneous involvement of Gm and other genetic system(s). In contrast, the corresponding CSFs exhibited already known MS-associated abnormalities of IgG1 (G1m) allotype contents, which therefore did not merely result from a Gm-associated MS susceptibility. These quantitative abnormalities were not sex dependent, but may fluctuate with MS severity. The G1m allotype levels in each CSF were not correlated with titers of various intrathecal antibodies but with the number of antibody specificities detected, a picture arguing for a polyclonal, non-antigen-specific activation of G1m allotype-producing B cells present in MS brain. PMID:4042430

  13. Mitochondrial dysfunction in bipolar disorder: Evidence, pathophysiology and translational implications.

    PubMed

    Scaini, Giselli; Rezin, Gislaine T; Carvalho, Andre F; Streck, Emilio L; Berk, Michael; Quevedo, João

    2016-09-01

    Bipolar disorder (BD) is a chronic psychiatric illness characterized by severe and biphasic changes in mood. Several pathophysiological mechanisms have been hypothesized to underpin the neurobiology of BD, including the presence of mitochondrial dysfunction. A confluence of evidence points to an underlying dysfunction of mitochondria, including decreases in mitochondrial respiration, high-energy phosphates and pH; changes in mitochondrial morphology; increases in mitochondrial DNA polymorphisms; and downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration. Mitochondria play a pivotal role in neuronal cell survival or death as regulators of both energy metabolism and cell survival and death pathways. Thus, in this review, we discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BD. The final part of this review discusses mitochondria as a potential target of therapeutic interventions in BD. PMID:27377693

  14. Mitochondrial DNA deletion in a patient with combined features of Leigh and Pearson syndromes

    SciTech Connect

    Blok, R.B.; Thorburn, D.R.; Danks, D.M.

    1994-09-01

    We describe a heteroplasmic 4237 bp mitochondrial DNA (mtDNA) deletion in an 11 year old girl who has suffered from progressive illness since birth. She has some features of Leigh syndrome (global developmental delay with regression, brainstem dysfunction and lactic acidosis), together with other features suggestive of Pearson syndrome (history of pancytopenia and failure to thrive). The deletion was present at a level greater than 50% in skeletal muscle, but barely detectable in skin fibroblasts following Southern blot analysis, and only observed in blood following PCR analysis. The deletion spanned nt 9498 to nt 13734, and was flanked by a 12 bp direct repeat. Genes for cytochrome c oxidase subunit III, NADH dehydrogenase subunits 3, 4L, 4 and 5, and tRNAs for glycine, arginine, histidine, serine({sup AGY}) and leucine({sup CUN}) were deleted. Southern blotting also revealed an altered Apa I restriction site which was shown by sequence analysis to be caused by G{r_arrow}A nucleotide substitution at nt 1462 in the 12S rRNA gene. This was presumed to be a polymorphism. No abnormalities of mitochondrial ultrastructure, distribution or of respiratory chain enzyme complexes I-IV in skeletal muscle were observed. Mitochondrial disorders with clinical features overlapping more than one syndrome have been reported previously. This case further demonstrates the difficulty in correlating observed clinical features with a specific mitochondrial DNA mutation.

  15. Mitochondrial Fusion Is Essential for Steroid Biosynthesis

    PubMed Central

    Cooke, Mariana; Soria, Gastón; Cornejo Maciel, Fabiana; Gottifredi, Vanesa; Podestá, Ernesto J.

    2012-01-01

    Although the contribution of mitochondrial dynamics (a balance in fusion/fission events and changes in mitochondria subcellular distribution) to key biological process has been reported, the contribution of changes in mitochondrial fusion to achieve efficient steroid production has never been explored. The mitochondria are central during steroid synthesis and different enzymes are localized between the mitochondria and the endoplasmic reticulum to produce the final steroid hormone, thus suggesting that mitochondrial fusion might be relevant for this process. In the present study, we showed that the hormonal stimulation triggers mitochondrial fusion into tubular-shaped structures and we demonstrated that mitochondrial fusion does not only correlate-with but also is an essential step of steroid production, being both events depend on PKA activity. We also demonstrated that the hormone-stimulated relocalization of ERK1/2 in the mitochondrion, a critical step during steroidogenesis, depends on mitochondrial fusion. Additionally, we showed that the SHP2 phosphatase, which is required for full steroidogenesis, simultaneously modulates mitochondrial fusion and ERK1/2 localization in the mitochondrion. Strikingly, we found that mitofusin 2 (Mfn2) expression, a central protein for mitochondrial fusion, is upregulated immediately after hormone stimulation. Moreover, Mfn2 knockdown is sufficient to impair steroid biosynthesis. Together, our findings unveil an essential role for mitochondrial fusion during steroidogenesis. These discoveries highlight the importance of organelles’ reorganization in specialized cells, prompting the exploration of the impact that organelle dynamics has on biological processes that include, but are not limited to, steroid synthesis. PMID:23029265

  16. Loss of PLA2G6 leads to elevated mitochondrial lipid peroxidation and mitochondrial dysfunction

    PubMed Central

    Castillo-Quan, Jorge Iván; Bartolome, Fernando; Angelova, Plamena R.; Li, Li; Pope, Simon; Cochemé, Helena M.; Khan, Shabana; Asghari, Shabnam; Bhatia, Kailash P.; Hardy, John; Abramov, Andrey Y.; Partridge, Linda

    2015-01-01

    The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A2 beta enzyme that selectively hydrolyses glycerophospholipids to release free fatty acids. Mutations in PLA2G6 have been associated with disorders such as infantile neuroaxonal dystrophy, neurodegeneration with brain iron accumulation type II and Karak syndrome. More recently, PLA2G6 was identified as the causative gene in a subgroup of patients with autosomal recessive early-onset dystonia-parkinsonism. Neuropathological examination revealed widespread Lewy body pathology and the accumulation of hyperphosphorylated tau, supporting a link between PLA2G6 mutations and parkinsonian disorders. Here we show that knockout of the Drosophila homologue of the PLA2G6 gene, iPLA2-VIA, results in reduced survival, locomotor deficits and organismal hypersensitivity to oxidative stress. Furthermore, we demonstrate that loss of iPLA2-VIA function leads to a number of mitochondrial abnormalities, including mitochondrial respiratory chain dysfunction, reduced ATP synthesis and abnormal mitochondrial morphology. Moreover, we show that loss of iPLA2-VIA is strongly associated with increased lipid peroxidation levels. We confirmed our findings using cultured fibroblasts taken from two patients with mutations in the PLA2G6 gene. Similar abnormalities were seen including elevated mitochondrial lipid peroxidation and mitochondrial membrane defects, as well as raised levels of cytoplasmic and mitochondrial reactive oxygen species. Finally, we demonstrated that deuterated polyunsaturated fatty acids, which inhibit lipid peroxidation, were able to partially rescue the locomotor abnormalities seen in aged flies lacking iPLA2-VIA gene function, and restore mitochondrial membrane potential in fibroblasts from patients with PLA2G6 mutations. Taken together, our findings demonstrate that loss of normal PLA2G6 gene activity leads to lipid peroxidation, mitochondrial dysfunction and subsequent mitochondrial membrane

  17. Mitochondrial Dysfunction in Neurodegenerative Diseases

    PubMed Central

    Johri, Ashu

    2012-01-01

    Neurodegenerative diseases are a large group of disabling disorders of the nervous system, characterized by the relative selective death of neuronal subtypes. In most cases, there is overwhelming evidence of impaired mitochondrial function as a causative factor in these diseases. More recently, evidence has emerged for impaired mitochondrial dynamics (shape, size, fission-fusion, distribution, movement etc.) in neurodegenerative diseases such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Here, we provide a concise overview of the major findings in recent years highlighting the importance of healthy mitochondria for a healthy neuron. PMID:22700435

  18. Abnormalities in subset distribution, activation, and differentiation of T cells isolated from large intestine biopsies in HIV infection. The Berlin Diarrhoea/Wasting Syndrome Study Group.

    PubMed Central

    Schneider, T; Ullrich, R; Bergs, C; Schmidt, W; Riecken, E O; Zeitz, M

    1994-01-01

    Intestinal T cells have a unique state of activation and differentiation which might specifically affect or be affected by HIV infection. Lymphocyte subsets in the peripheral blood are well characterized, but our knowledge about intestinal lymphocytes in HIV infection is incomplete. We therefore analysed lymphocytes isolated from large intestine biopsies of AIDS patients and controls by three-colour cytofluorometry. In the large intestine of HIV-infected patients CD4 T cells were reduced and CD8 T cells were increased compared with controls. Most of the CD8 T cells in the colorectal mucosa of AIDS patients were of the cytotoxic phenotype. Activated and resting CD4 T cells were similarly reduced, the expression of CD25 and HLA-DR of CD8 T cells was unaltered and increased, respectively. In intestinal CD4 T cells the expression of CD29 was decreased, but the expression of CD45RO and HML-1 was normal. CD8 T cells had a decreased expression of all these differentiation markers. Our findings demonstrate substantial alterations in subset distribution, activation, and differentiation of large intestine T cells, which may contribute to the secondary infections and malignancies commonly observed in the gut of AIDS patients. PMID:8137540

  19. [Abnormal cerebral blood flow distributions during the post-ictal phase of febrile status epilepticus in three pediatric patients measured by arterial spin labeling perfusion MRI].

    PubMed

    Hirano, Keiko; Fukuda, Tokiko

    2016-05-01

    The ability to visualize brain perfusion is important for identifying epileptic foci. We present three pediatric cases showing asymmetrical cerebral blood flow (CBF) distributions during the post-ictal phase of febrile status epilepticus measured by arterial spin labeling (ASL) perfusion MRI. During the acute phase, regional CBF measurements in the areas considered including epileptic foci were higher than in the corresponding area of the contralateral hemisphere, though the exact quantitative value varied between cases. We could not identify the correct epileptogenic foci, because those ASL images were taken after the prolonged and extraordinary activation of neurons in the affected area. During the recovery phase, the differences reduced and the average regional CBF measurement was 54.6 ± 6.1 ml/100 g per minute, which was a little less than the number of previous ASL studies. ASL perfusion MRI imaging provides a method for evaluating regional CBF by using magnetically labeled arterial blood water as an endogenous tracer. With this technique, we can repeatedly evaluate both the brain structure and the level of perfusion at the same time. ASL is noninvasive and easily accessible, and therefore it could become a routine tool for assessment of perfusion in daily practice of pediatric neurology. PMID:27349086

  20. "Jeopardy" in Abnormal Psychology.

    ERIC Educational Resources Information Center

    Keutzer, Carolin S.

    1993-01-01

    Describes the use of the board game, Jeopardy, in a college level abnormal psychology course. Finds increased student interaction and improved application of information. Reports generally favorable student evaluation of the technique. (CFR)

  1. Abnormal Uterine Bleeding

    MedlinePlus

    ... Abnormal uterine bleeding is any bleeding from the uterus (through your vagina) other than your normal monthly ... or fibroids (small and large growths) in the uterus can also cause bleeding. Rarely, a thyroid problem, ...

  2. Abnormal Uterine Bleeding FAQ

    MedlinePlus

    ... as cancer of the uterus, cervix, or vagina • Polycystic ovary syndrome How is abnormal bleeding diagnosed? Your health care ... before the fetus can survive outside the uterus. Polycystic Ovary Syndrome: A condition characterized by two of the following ...

  3. Mitochondrial loss, dysfunction and altered dynamics in Huntington's disease

    PubMed Central

    Kim, Jinho; Moody, Jennifer P.; Edgerly, Christina K.; Bordiuk, Olivia L.; Cormier, Kerry; Smith, Karen; Beal, M. Flint; Ferrante, Robert J.

    2010-01-01

    Although a direct causative pathway from the gene mutation to the selective neostriatal neurodegeneration remains unclear in Huntington's disease (HD), one putative pathological mechanism reported to play a prominent role in the pathogenesis of this neurological disorder is mitochondrial dysfunction. We examined mitochondria in preferentially vulnerable striatal calbindin-positive neurons in moderate-to-severe grade HD patients, using antisera against mitochondrial markers of COX2, SOD2 and cytochrome c. Combined calbindin and mitochondrial marker immunofluorescence showed a significant and progressive grade-dependent reduction in the number of mitochondria in spiny striatal neurons, with marked alteration in size. Consistent with mitochondrial loss, there was a reduction in COX2 protein levels using western analysis that corresponded with disease severity. In addition, both mitochondrial transcription factor A, a regulator of mtDNA, and peroxisome proliferator-activated receptor-co-activator gamma-1 alpha, a key transcriptional regulator of energy metabolism and mitochondrial biogenesis, were also significantly reduced with increasing disease severity. Abnormalities in mitochondrial dynamics were observed, showing a significant increase in the fission protein Drp1 and a reduction in the expression of the fusion protein mitofusin 1. Lastly, mitochondrial PCR array profiling in HD caudate nucleus specimens showed increased mRNA expression of proteins involved in mitochondrial localization, membrane translocation and polarization and transport that paralleled mitochondrial derangement. These findings reveal that there are both mitochondrial loss and altered mitochondrial morphogenesis with increased mitochondrial fission and reduced fusion in HD. These findings provide further evidence that mitochondrial dysfunction plays a critical role in the pathogenesis of HD. PMID:20660112

  4. Mitochondrial dysfunction in liver failure requiring transplantation.

    PubMed

    Lane, Maria; Boczonadi, Veronika; Bachtari, Sahar; Gomez-Duran, Aurora; Langer, Thorsten; Griffiths, Alexandra; Kleinle, Stephanie; Dineiger, Christine; Abicht, Angela; Holinski-Feder, Elke; Schara, Ulrike; Gerner, Patrick; Horvath, Rita

    2016-05-01

    Liver failure is a heterogeneous condition which may be fatal and the primary cause is frequently unknown. We investigated mitochondrial oxidative phosphorylation in patients undergoing liver transplantation. We studied 45 patients who had liver transplantation due to a variety of clinical presentations. Blue native polyacrylamide gel electrophoresis with immunodetection of respiratory chain complexes I-V, biochemical activity of respiratory chain complexes II and IV and quantification of mitochondrial DNA (mtDNA) copy number were investigated in liver tissue collected from the explanted liver during transplantation. Abnormal mitochondrial function was frequently present in this cohort: ten of 40 patients (25 %) had a defect of one or more respiratory chain enzyme complexes on blue native gels, 20 patients (44 %) had low activity of complex II and/or IV and ten (22 %) had a reduced mtDNA copy number. Combined respiratory chain deficiency and reduced numbers of mitochondria were detected in all three patients with acute liver failure. Low complex IV activity in biliary atresia and complex II defects in cirrhosis were common findings. All six patients diagnosed with liver tumours showed variable alterations in mitochondrial function, probably due to the heterogeneity of the presenting tumour. In conclusion, mitochondrial dysfunction is common in severe liver failure in non-mitochondrial conditions. Therefore, in contrast to the common practice detection of respiratory chain abnormalities in liver should not restrict the inclusion of patients for liver transplantation. Furthermore, improving mitochondrial function may be targeted as part of a complex therapy approach in different forms of liver diseases. PMID:27053192

  5. Chromosomal Abnormalities and Schizophrenia

    PubMed Central

    BASSETT, ANNE S.; CHOW, EVA W.C.; WEKSBERG, ROSANNA

    2011-01-01

    Schizophrenia is a common and serious psychiatric illness with strong evidence for genetic causation, but no specific loci yet identified. Chromosomal abnormalities associated with schizophrenia may help to understand the genetic complexity of the illness. This paper reviews the evidence for associations between chromosomal abnormalities and schizophrenia and related disorders. The results indicate that 22q11.2 microdeletions detected by fluorescence in-situ hybridization (FISH) are significantly associated with schizophrenia. Sex chromosome abnormalities seem to be increased in schizophrenia but insufficient data are available to indicate whether schizophrenia or related disorders are increased in patients with sex chromosome aneuploidies. Other reports of chromosomal abnormalities associated with schizophrenia have the potential to be important adjuncts to linkage studies in gene localization. Advances in molecular cytogenetic techniques (i.e., FISH) have produced significant increases in rates of identified abnormalities in schizophrenia, particularly in patients with very early age at onset, learning difficulties or mental retardation, or dysmorphic features. The results emphasize the importance of considering behavioral phenotypes, including adult onset psychiatric illnesses, in genetic syndromes and the need for clinicians to actively consider identifying chromosomal abnormalities and genetic syndromes in selected psychiatric patients. PMID:10813803

  6. Alterations in Mitochondrial Quality Control in Alzheimer’s Disease

    PubMed Central

    Cai, Qian; Tammineni, Prasad

    2016-01-01

    Mitochondrial dysfunction is one of the earliest and most prominent features in the brains of Alzheimer’s disease (AD) patients. Recent studies suggest that mitochondrial dysfunction plays a pivotal role in the pathogenesis of AD. Neurons are metabolically active cells, causing them to be particularly dependent on mitochondrial function for survival and maintenance. As highly dynamic organelles, mitochondria are characterized by a balance of fusion and fission, transport, and mitophagy, all of which are essential for maintaining mitochondrial integrity and function. Mitochondrial dynamics and mitophagy can therefore be identified as key pathways in mitochondrial quality control. Tremendous progress has been made in studying changes in these key aspects of mitochondrial biology in the vulnerable neurons of AD brains and mouse models, and the potential underlying mechanisms of such changes. This review highlights recent findings on alterations in the mitochondrial dynamics and mitophagy in AD and discusses how these abnormalities impact mitochondrial quality control and thus contribute to mitochondrial dysfunction in AD. PMID:26903809

  7. Genetic Ablation of Calcium-independent Phospholipase A2γ Leads to Alterations in Hippocampal Cardiolipin Content and Molecular Species Distribution, Mitochondrial Degeneration, Autophagy, and Cognitive Dysfunction*

    PubMed Central

    Mancuso, David J.; Kotzbauer, Paul; Wozniak, David F.; Sims, Harold F.; Jenkins, Christopher M.; Guan, Shaoping; Han, Xianlin; Yang, Kui; Sun, Gang; Malik, Ibrahim; Conyers, Sara; Green, Karen G.; Schmidt, Robert E.; Gross, Richard W.

    2009-01-01

    Genetic ablation of calcium-independent phospholipase A2γ (iPLA2γ) results in profound alterations in hippocampal phospholipid metabolism and mitochondrial phospholipid homeostasis resulting in enlarged and degenerating mitochondria leading to autophagy and cognitive dysfunction. Shotgun lipidomics demonstrated multiple alterations in hippocampal lipid metabolism in iPLA2γ−/− mice including: 1) a markedly elevated hippocampal cardiolipin content with an altered molecular species composition characterized by a shift to shorter chain length molecular species; 2) alterations in both choline and ethanolamine glycerophospholipids, including a decreased plasmenylethanolamine content; 3) increased oxidized phosphatidylethanolamine molecular species; and 4) an increased content of ceramides. Electron microscopic examination demonstrated the presence of enlarged heteromorphic lamellar structures undergoing degeneration accompanied by the presence of ubiquitin positive spheroid inclusion bodies. Purification of these enlarged heteromorphic lamellar structures by buoyant density centrifugation and subsequent SDS-PAGE and proteomics identified them as degenerating mitochondria. Collectively, these results identify the obligatory role of iPLA2γ in neuronal mitochondrial lipid metabolism and membrane structure demonstrating that iPLA2γ loss of function results in a mitochondrial neurodegenerative disorder characterized by degenerating mitochondria, autophagy, and cognitive dysfunction. PMID:19840936

  8. Mitochondrial traffic jams in Alzheimer's disease - pinpointing the roadblocks.

    PubMed

    Correia, Sónia C; Perry, George; Moreira, Paula I

    2016-10-01

    The vigorous axonal transport of mitochondria, which serves to distribute these organelles in a dynamic and non-uniform fashion, is crucial to fulfill neuronal energetic requirements allowing the maintenance of neurons structure and function. Particularly, axonal transport of mitochondria and their spatial distribution among the synapses are directly correlated with synaptic activity and integrity. Despite the basis of Alzheimer's disease (AD) remains enigmatic, axonal pathology and synaptic dysfunction occur prior the occurrence of amyloid-β (Aβ) deposition and tau aggregation, the two classical hallmarks of this devastating neurodegenerative disease. Importantly, the early stages of AD are marked by defects on axonal transport of mitochondria as denoted by the abnormal accumulation of mitochondria within large swellings along dystrophic and degenerating neuritis. Within this scenario, this review is devoted to identify the molecular "roadblocks" underlying the abnormal axonal transport of mitochondria and consequent synaptic "starvation" and neuronal degeneration in AD. Understanding the molecular nature of defective mitochondrial transport may provide a new avenue to counteract AD pathology. PMID:27460705

  9. Inherited peripheral neuropathies due to mitochondrial disorders.

    PubMed

    Cassereau, J; Codron, P; Funalot, B

    2014-05-01

    Mitochondrial disorders (MIDs) are frequently responsible for neuropathies with variable severity. Mitochondrial diseases causing peripheral neuropathies (PNP) may be due to mutations of mitochondrial DNA (mtDNA), as is the case in MERRF and MELAS syndromes, or to mutations of nuclear genes. Secondary abnormalities of mtDNA (such as multiple deletions of muscle mtDNA) may result from mitochondrial disorders due to mutations in nuclear genes involved in mtDNA maintenance. This is the case in several syndromes caused by impaired mtDNA maintenance, such as Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoplegia (SANDO) due to recessive mutations in the POLG gene, which encodes the catalytic subunit of mtDNA polymerase (DNA polymerase gamma), or Mitochondrial Neuro-Gastro-Intestinal Encephalomyopathy (MNGIE), due to recessive mutations in the TYMP gene, which encodes thymidine phosphorylase. The last years have seen a growing list of evidence demonstrating that mitochondrial bioenergetics and dynamics might be dysfunctional in axonal Charcot-Marie-Tooth disease (CMT2), and these mechanisms might present a common link between dissimilar CMT2-causing genes. PMID:24768438

  10. Thymidine phosphorylase deficiency causes MNGIE: an autosomal recessive mitochondrial disorder.

    PubMed

    Hirano, M; Martí, R; Spinazzola, A; Nishino, I; Nishigaki, Y

    2004-10-01

    Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by mutations in the gene encoding thymidine phosphorylase (TP). The disease is characterized clinically by impaired eye movements, gastrointestinal dysmotility, cachexia, peripheral neuropathy, myopathy, and leukoencephalopathy. Molecular genetic studies of MNGIE patients' tissues have revealed multiple deletions, depletion, and site-specific point mutations of mitochondrial DNA. TP is a cytosolic enzyme required for nucleoside homeostasis. In MNGIE, TP activity is severely reduced and consequently levels of thymidine and deoxyuridine in plasma are dramatically elevated. We have hypothesized that the increased levels of intracellular thymidine and deoxyuridine cause imbalances of mitochondrial nucleotide pools that, in turn, lead to the mtDNA abnormalities. MNGIE was the first molecularly characterized genetic disorder caused by abnormal mitochondrial nucleoside/nucleotide metabolism. Future studies are likely to reveal further insight into this expanding group of diseases. PMID:15571233

  11. Mitochondrial Biology and Neurological Diseases.

    PubMed

    Arun, Siddharth; Liu, Lei; Donmez, Gizem

    2016-01-01

    Mitochondria are extremely active organelles that perform a variety of roles in the cell including energy production, regulation of calcium homeostasis, apoptosis, and population maintenance through fission and fusion. Mitochondrial dysfunction in the form of oxidative stress and mutations can contribute to the pathogenesis of various neurodegenerative diseases such as Parkinson's (PD), Alzheimer's (AD), and Huntington's diseases (HD). Abnormalities of Complex I function in the electron transport chain have been implicated in some neurodegenerative diseases, inhibiting ATP production and generating reactive oxygen species that can cause major damage to mitochondria. Mutations in both nuclear and mitochondrial DNA can contribute to neurodegenerative disease, although the pathogenesis of these conditions tends to focus on nuclear mutations. In PD, nuclear genome mutations in the PINK1 and parkin genes have been implicated in neurodegeneration [1], while mutations in APP, PSEN1 and PSEN2 have been implicated in a variety of clinical symptoms of AD [5]. Mutant htt protein is known to cause HD [2]. Much progress has been made to determine some causes of these neurodegenerative diseases, though permanent treatments have yet to be developed. In this review, we discuss the roles of mitochondrial dysfunction in the pathogenesis of these diseases. PMID:26903445

  12. Mitochondrial Biology and Neurological Diseases

    PubMed Central

    Arun, Siddharth; Liu, Lei; Donmez, Gizem

    2016-01-01

    Mitochondria are extremely active organelles that perform a variety of roles in the cell including energy production, regulation of calcium homeostasis, apoptosis, and population maintenance through fission and fusion. Mitochondrial dysfunction in the form of oxidative stress and mutations can contribute to the pathogenesis of various neurodegenerative diseases such as Parkinson’s (PD), Alzheimer’s (AD), and Huntington’s diseases (HD). Abnormalities of Complex I function in the electron transport chain have been implicated in some neurodegenerative diseases, inhibiting ATP production and generating reactive oxygen species that can cause major damage to mitochondria Mutations in both nuclear and mitochondrial DNA can contribute to neurodegenerative disease, although the pathogenesis of these conditions tends to focus on nuclear mutations. In PD, nuclear genome mutations in the PINK1 and parkin genes have been implicated in neurodegeneration [1], while mutations in APP, PSEN1 and PSEN2 have been implicated in a variety of clinical symptoms of AD [5]. Mutant htt protein is known to cause HD [2]. Much progress has been made to determine some causes of these neurodegenerative diseases, though permanent treatments have yet to be developed. In this review, we discuss the roles of mitochondrial dysfunction in the pathogenesis of these diseases. PMID:26903445

  13. p53 and Mitochondrial Function in Neurons

    PubMed Central

    Wang, David B.; Kinoshita, Chizuru; Kinoshita, Yoshito; Morrison, Richard S.

    2014-01-01

    The p53 tumor suppressor plays a central role in dictating cell survival and death as a cellular sensor for a myriad of stresses including DNA damage, oxidative and nutritional stress, ischemia and disruption of nucleolar function. Activation of p53-dependent apoptosis leads to mitochondrial apoptotic changes via the intrinsic and extrinsic pathways triggering cell death execution most notably by release of cytochrome c and activation of the caspase cascade. Although it was previously believed that p53 induces apoptotic mitochondrial changes exclusively through transcription-dependent mechanisms, recent studies suggest that p53 also regulates apoptosis via a transcription-independent action at the mitochondria. Recent evidence further suggests that p53 can regulate necrotic cell death and autophagic activity including mitophagy. An increasing number of cytosolic and mitochondrial proteins involved in mitochondrial metabolism and respiration are regulated by p53, which influences mitochondrial ROS production as well. Cellular redox homeostasis is also directly regulated by p53 through modified expression of pro- and anti-oxidant proteins. Proper regulation of mitochondrial size and shape through fission and fusion assures optimal mitochondrial bioenergetic function while enabling adequate mitochondrial transport to accommodate local energy demands unique to neuronal architecture. Abnormal regulation of mitochondrial dynamics has been increasingly implicated in neurodegeneration, where elevated levels of p53 may have a direct contribution as the expression of some fission/fusion proteins are directly regulated by p53. Thus, p53 may have a much wider influence on mitochondrial integrity and function than one would expect from its well-established ability to transcriptionally induce mitochondrial apoptosis. However, much of the evidence demonstrating that p53 can influence mitochondria through nuclear, cytosolic or intra-mitochondrial sites of action has yet to be

  14. Lack of GDAP1 Induces Neuronal Calcium and Mitochondrial Defects in a Knockout Mouse Model of Charcot-Marie-Tooth Neuropathy

    PubMed Central

    Civera-Tregón, Azahara; Yndriago, Laura; Pla-Martin, David; Zenker, Jennifer; Cuevas-Martín, Carmen; Estela, Anna; Sánchez-Aragó, María; Forteza-Vila, Jerónimo; Cuezva, José M.; Chrast, Roman; Palau, Francesc

    2015-01-01

    Mutations in GDAP1, which encodes protein located in the mitochondrial outer membrane, cause axonal recessive (AR-CMT2), axonal dominant (CMT2K) and demyelinating recessive (CMT4A) forms of Charcot-Marie-Tooth (CMT) neuropathy. Loss of function recessive mutations in GDAP1 are associated with decreased mitochondrial fission activity, while dominant mutations result in impairment of mitochondrial fusion with increased production of reactive oxygen species and susceptibility to apoptotic stimuli. GDAP1 silencing in vitro reduces Ca2+ inflow through store-operated Ca2+ entry (SOCE) upon mobilization of endoplasmic reticulum (ER) Ca2+, likely in association with an abnormal distribution of the mitochondrial network. To investigate the functional consequences of lack of GDAP1 in vivo, we generated a Gdap1 knockout mouse. The affected animals presented abnormal motor behavior starting at the age of 3 months. Electrophysiological and biochemical studies confirmed the axonal nature of the neuropathy whereas histopathological studies over time showed progressive loss of motor neurons (MNs) in the anterior horn of the spinal cord and defects in neuromuscular junctions. Analyses of cultured embryonic MNs and adult dorsal root ganglia neurons from affected animals demonstrated large and defective mitochondria, changes in the ER cisternae, reduced acetylation of cytoskeletal α-tubulin and increased autophagy vesicles. Importantly, MNs showed reduced cytosolic calcium and SOCE response. The development and characterization of the GDAP1 neuropathy mice model thus revealed that some of the pathophysiological changes present in axonal recessive form of the GDAP1-related CMT might be the consequence of changes in the mitochondrial network biology and mitochondria–endoplasmic reticulum interaction leading to abnormalities in calcium homeostasis. PMID:25860513

  15. Alzheimer's disease: diverse aspects of mitochondrial malfunctioning

    PubMed Central

    Santos, Renato X; Correia, Sónia C; Wang, Xinglong; Perry, George; Smith, Mark A; Moreira, Paula I; Zhu, Xiongwei

    2010-01-01

    Alzheimer's disease is a progressive neurodegenerative disorder, either assuming a sporadic, age-associated, late-onset form, or a familial form, with early onset, in a smaller fraction of the cases. Whereas in the familial cases several mutations have been identified in genes encoding proteins related with the pathogenesis of the disease, for the sporadic form several causes have been proposed and are currently under debate. Mitochondrial dysfunction has surfaced as one of the most discussed hypotheses acting as a trigger for the pathogenesis of Alzheimer's disease. Mitochondria assume central functions in the cell, including ATP production, calcium homeostasis, reactive oxygen species generation, and apoptotic signaling. Although their role as the cause of the disease may be controversial, there is no doubt that mitochondrial dysfunction, abnormal mitochondrial dynamics and degradation by mitophagy occur during the disease process, contributing to its onset and progression. PMID:20661404

  16. Mitochondrial dysfunction and resuscitation in sepsis.

    PubMed

    Ruggieri, Albert J; Levy, Richard J; Deutschman, Clifford S

    2010-07-01

    Sepsis is among the most common causes of death in patients in intensive care units in North America and Europe. In the United States, it accounts for upwards of 250,000 deaths each year. Investigations into the pathobiology of sepsis have most recently focused on common cellular and subcellular processes. One possibility would be a defect in the production of energy, which translates to an abnormality in the production of adenosine triphosphate and therefore in the function of mitochondria. This article presents a clear role for mitochondrial dysfunction in the pathogenesis and pathophysiology of sepsis. What is less clear is the teleology underlying this response. Prolonged mitochondrial dysfunction and impaired biogenesis clearly are detrimental. However, early inhibition of mitochondrial function may be adaptive. PMID:20643307

  17. Mitochondrial disease and epilepsy.

    PubMed

    Rahman, Shamima

    2012-05-01

    Mitochondrial respiratory chain disorders are relatively common inborn errors of energy metabolism, with a combined prevalence of one in 5000. These disorders typically affect tissues with high energy requirements, and cerebral involvement occurs frequently in childhood, often manifesting in seizures. Mitochondrial diseases are genetically heterogeneous; to date, mutations have been reported in all 37 mitochondrially encoded genes and more than 80 nuclear genes. The major genetic causes of mitochondrial epilepsy are mitochondrial DNA mutations (including those typically associated with the mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes [MELAS] and myoclonic epilepsy with ragged red fibres [MERRF] syndromes); mutations in POLG (classically associated with Alpers syndrome but also presenting as the mitochondrial recessive ataxia syndrome [MIRAS], spinocerebellar ataxia with epilepsy [SCAE], and myoclonus, epilepsy, myopathy, sensory ataxia [MEMSA] syndromes in older individuals) and other disorders of mitochondrial DNA maintenance; complex I deficiency; disorders of coenzyme Q(10) biosynthesis; and disorders of mitochondrial translation such as RARS2 mutations. It is not clear why some genetic defects, but not others, are particularly associated with seizures. Epilepsy may be the presenting feature of mitochondrial disease but is often part of a multisystem clinical presentation. Mitochondrial epilepsy may be very difficult to manage, and is often a poor prognostic feature. At present there are no curative treatments for mitochondrial disease. Individuals with mitochondrial epilepsy are frequently prescribed multiple anticonvulsants, and the role of vitamins and other nutritional supplements and the ketogenic diet remain unproven. PMID:22283595

  18. Exercise-induced mitochondrial dysfunction: a myth or reality?

    PubMed

    Ostojic, Sergej M

    2016-08-01

    Beneficial effects of physical activity on mitochondrial health are well substantiated in the scientific literature, with regular exercise improving mitochondrial quality and quantity in normal healthy population, and in cardiometabolic and neurodegenerative disorders and aging. However, several recent studies questioned this paradigm, suggesting that extremely heavy or exhaustive exercise fosters mitochondrial disturbances that could permanently damage its function in health and disease. Exercise-induced mitochondrial dysfunction (EIMD) might be a key proxy for negative outcomes of exhaustive exercise, being a pathophysiological substrate of heart abnormalities, chronic fatigue syndrome (CFS) or muscle degeneration. Here, we overview possible factors that mediate negative effects of exhaustive exercise on mitochondrial function and structure, and put forward alternative solutions for the management of EIMD. PMID:27389587

  19. Abnormal calcium homeostasis in peripheral neuropathies

    PubMed Central

    Fernyhough, Paul; Calcutt, Nigel A.

    2010-01-01

    Abnormal neuronal calcium (Ca2+) homeostasis has been implicated in numerous diseases of the nervous system. The pathogenesis of two increasingly common disorders of the peripheral nervous system, namely neuropathic pain and diabetic polyneuropathy, has been associated with aberrant Ca2+ channel expression and function. Here we review the current state of knowledge regarding the role of Ca2+ dyshomeostasis and associated mitochondrial dysfunction in painful and diabetic neuropathies. The central impact of both alterations of Ca2+ signalling at the plasma membrane and also intracellular Ca2+ handling on sensory neuron function is discussed and related to abnormal endoplasmic reticulum performance. We also present new data highlighting sub-optimal axonal Ca 2+ signalling in diabetic neuropathy and discuss the putative role for this abnormality in the induction of axonal degeneration in peripheral neuropathies. The accumulating evidence implicating Ca2+ dysregulation with both painful and degenerative neuropathies, along with recent advances in understanding of regional variations in Ca2+ channel and pump structures, makes modulation of neuronal Ca2+ handling an increasingly viable approach for therapeutic interventions against the painful and degenerative aspects of many peripheral neuropathies. PMID:20034667

  20. Multiple Pathways Influence Mitochondrial Inheritance in Budding Yeast

    PubMed Central

    Frederick, Rebecca L.; Okamoto, Koji; Shaw, Janet M.

    2008-01-01

    Yeast mitochondria form a branched tubular network. Mitochondrial inheritance is tightly coupled with bud emergence, ensuring that daughter cells receive mitochondria from mother cells during division. Proteins reported to influence mitochondrial inheritance include the mitochondrial rho (Miro) GTPase Gem1p, Mmr1p, and Ypt11p. A synthetic genetic array (SGA) screen revealed interactions between gem1Δ and deletions of genes that affect mitochondrial function or inheritance, including mmr1Δ. Synthetic sickness of gem1Δ mmr1Δ double mutants correlated with defective mitochondrial inheritance by large buds. Additional studies demonstrated that GEM1, MMR1, and YPT11 each contribute to mitochondrial inheritance. Mitochondrial accumulation in buds caused by overexpression of either Mmr1p or Ypt11p did not depend on Gem1p, indicating these three proteins function independently. Physical linkage of mitochondria with the endoplasmic reticulum (ER) has led to speculation that distribution of these two organelles is coordinated. We show that yeast mitochondrial inheritance is not required for inheritance or spreading of cortical ER in the bud. Moreover, Ypt11p overexpression, but not Mmr1p overexpression, caused ER accumulation in the bud, revealing a potential role for Ypt11p in ER distribution. This study demonstrates that multiple pathways influence mitochondrial inheritance in yeast and that Miro GTPases have conserved roles in mitochondrial distribution. PMID:18245340

  1. The use of neuroimaging in the diagnosis of mitochondrial disease.

    PubMed

    Friedman, Seth D; Shaw, Dennis W W; Ishak, Gisele; Gropman, Andrea L; Saneto, Russell P

    2010-01-01

    Mutations in nuclear and mitochondrial DNA impacting mitochondrial function result in disease manifestations ranging from early death to abnormalities in all major organ systems and to symptoms that can be largely confined to muscle fatigue. The definitive diagnosis of a mitochondrial disorder can be difficult to establish. When the constellation of symptoms is suggestive of mitochondrial disease, neuroimaging features may be diagnostic and suggestive, can help direct further workup, and can help to further characterize the underlying brain abnormalities. Magnetic resonance imaging changes may be nonspecific, such as atrophy (both general and involving specific structures, such as cerebellum), more suggestive of particular disorders such as focal and often bilateral lesions confined to deep brain nuclei, or clearly characteristic of a given disorder such as stroke-like lesions that do not respect vascular boundaries in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS). White matter hyperintensities with or without associated gray matter involvement may also be observed. Across patients and discrete disease subtypes (e.g., MELAS, Leigh syndrome, etc.), patterns of these features are helpful for diagnosis. However, it is also true that marked variability in expression occurs in all mitochondrial disease subtypes, illustrative of the complexity of the disease process. The present review summarizes the role of neuroimaging in the diagnosis and characterization of patients with suspected mitochondrial disease. PMID:20818727

  2. Primary Mitochondrial Disease and Secondary Mitochondrial Dysfunction: Importance of Distinction for Diagnosis and Treatment.

    PubMed

    Niyazov, Dmitriy M; Kahler, Stephan G; Frye, Richard E

    2016-07-01

    Mitochondrial disease refers to a heterogeneous group of disorders resulting in defective cellular energy production due to abnormal oxidative phosphorylation (oxphos). Primary mitochondrial disease (PMD) is diagnosed clinically and ideally, but not always, confirmed by a known or indisputably pathogenic mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) mutation. The PMD genes either encode oxphos proteins directly or they affect oxphos function by impacting production of the complex machinery needed to run the oxphos process. However, many disorders have the 'mitochondrial' phenotype without an identifiable mtDNA or nDNA mutation or they have a variant of unknown clinical significance. Secondary mitochondrial dysfunction (SMD) can be caused by genes encoding neither function nor production of the oxphos proteins and accompanies many hereditary non-mitochondrial diseases. SMD may also be due to nongenetic causes such as environmental factors. In our practice, we see many patients with clinical signs of mitochondrial dysfunction based on phenotype, biomarkers, imaging, muscle biopsy, or negative/equivocal mtDNA or nDNA test results. In these cases, it is often tempting to assign a patient's phenotype to 'mitochondrial disease', but SMD is often challenging to distinguish from PMD. Fortunately, rapid advances in molecular testing, made possible by next generation sequencing, have been effective at least in some cases in establishing accurate diagnoses to distinguish between PMD and SMD. This is important, since their treatments and prognoses can be quite different. However, even in the absence of the ability to distinguish between PMD and SMD, treating SMD with standard treatments for PMD can be effective. We review the latest findings regarding mitochondrial disease/dysfunction and give representative examples in which differentiation between PMD and SMD has been crucial for diagnosis and treatment. PMID:27587988

  3. Infantile Encephalopathy and Defective Mitochondrial DNA Translation in Patients with Mutations of Mitochondrial Elongation Factors EFG1 and EFTu

    PubMed Central

    Valente, Lucia; Tiranti, Valeria; Marsano, René Massimiliano; Malfatti, Edoardo; Fernandez-Vizarra, Erika; Donnini, Claudia; Mereghetti, Paolo; De Gioia, Luca; Burlina, Alberto; Castellan, Claudio; Comi, Giacomo P.; Savasta, Salvatore; Ferrero, Iliana; Zeviani, Massimo

    2007-01-01

    Mitochondrial protein translation is a complex process performed within mitochondria by an apparatus composed of mitochondrial DNA (mtDNA)–encoded RNAs and nuclear DNA–encoded proteins. Although the latter by far outnumber the former, the vast majority of mitochondrial translation defects in humans have been associated with mutations in RNA-encoding mtDNA genes, whereas mutations in protein-encoding nuclear genes have been identified in a handful of cases. Genetic investigation involving patients with defective mitochondrial translation led us to the discovery of novel mutations in the mitochondrial elongation factor G1 (EFG1) in one affected baby and, for the first time, in the mitochondrial elongation factor Tu (EFTu) in another one. Both patients were affected by severe lactic acidosis and rapidly progressive, fatal encephalopathy. The EFG1-mutant patient had early-onset Leigh syndrome, whereas the EFTu-mutant patient had severe infantile macrocystic leukodystrophy with micropolygyria. Structural modeling enabled us to make predictions about the effects of the mutations at the molecular level. Yeast and mammalian cell systems proved the pathogenic role of the mutant alleles by functional complementation in vivo. Nuclear-gene abnormalities causing mitochondrial translation defects represent a new, potentially broad field of mitochondrial medicine. Investigation of these defects is important to expand the molecular characterization of mitochondrial disorders and also may contribute to the elucidation of the complex control mechanisms, which regulate this fundamental pathway of mtDNA homeostasis. PMID:17160893

  4. Mitochondrial RNA granules: Compartmentalizing mitochondrial gene expression.

    PubMed

    Jourdain, Alexis A; Boehm, Erik; Maundrell, Kinsey; Martinou, Jean-Claude

    2016-03-14

    In mitochondria, DNA replication, gene expression, and RNA degradation machineries coexist within a common nondelimited space, raising the question of how functional compartmentalization of gene expression is achieved. Here, we discuss the recently characterized "mitochondrial RNA granules," mitochondrial subdomains with an emerging role in the regulation of gene expression. PMID:26953349

  5. Mitochondrial impact of human immunodeficiency virus and antiretrovirals on infected pediatric patients with or without lipodystrophy.

    PubMed

    Morén, Constanza; Noguera-Julian, Antoni; Rovira, Núria; Corrales, Ester; Garrabou, Glòria; Hernández, Sandra; Nicolás, Mireia; Tobías, Ester; Cardellach, Francesc; Miró, Oscar; Fortuny, Clàudia

    2011-11-01

    We determined the mitochondrial status of a group of HIV-infected children, some with body fat abnormalities (BFA). We included 24 controls, 16 HIV-infected untreated, 26 HIV-infected treated, 6 BFA-untreated, and 21 BFA-treated patients. Genetic, translational, and functional mitochondrial values were measured. As compared with controls, mitochondrial DNA depletion and a reduction in functionality were found in BFA groups. PMID:21697766

  6. Dynamics of the mitochondrial network during mitosis.

    PubMed

    Kanfer, Gil; Kornmann, Benoît

    2016-04-15

    During mitosis, cells undergo massive deformation and reorganization, impacting on all cellular structures. Mitochondria, in particular, are highly dynamic organelles, which constantly undergo events of fission, fusion and cytoskeleton-based transport. This plasticity ensures the proper distribution of the metabolism, and the proper inheritance of functional organelles. During cell cycle, mitochondria undergo dramatic changes in distribution. In this review, we focus on the dynamic events that target mitochondria during mitosis. We describe how the cell-cycle-dependent microtubule-associated protein centromeric protein F (Cenp-F) is recruited to mitochondria by the mitochondrial Rho GTPase (Miro) to promote mitochondrial transport and re-distribution following cell division. PMID:27068963

  7. Mitochondrial DNA Alterations and Reduced Mitochondrial Function in Aging

    PubMed Central

    Hebert, Sadie L.; Lanza, Ian R.; Nair, K. Sreekumaran

    2010-01-01

    Oxidative damage to mitochondrial DNA increases with aging. This damage has the potential to affect mitochondrial DNA replication and transcription which could alter the abundance or functionality of mitochondrial proteins. This review describes mitochondrial DNA alterations and changes in mitochondrial function that occur with aging. Age-related alterations in mitochondrial DNA as a possible contributor to the reduction in mitochondrial function are discussed. PMID:20307565

  8. Modeling of Mitochondrial Donut Formation.

    PubMed

    Long, Qi; Zhao, Danyun; Fan, Weimin; Yang, Liang; Zhou, Yanshuang; Qi, Juntao; Wang, Xin; Liu, Xingguo

    2015-09-01

    Mitochondria are highly dynamic cell organelles. Continual cycles of fusion and fission play an important role in mitochondrial metabolism and cellular signaling. Previously, a novel mitochondrial morphology, the donut, was reported in cells after hypoxia-reoxygenation or osmotic pressure changes. However, the mechanism of donut formation remained elusive. Here, we obtained the distribution of donut diameters (D = 2R) and found that 95% are >0.8 μm. We also performed highly precise measurements of the mitochondrial tubule diameters using superresolution and electron microscopy. Then, we set up a model by calculating the mitochondrial bending energy and osmotic potential during donut formation. It shows that the bending energy is increased as the radius of curvature, R, gets smaller in the process of donut formation, especially for radii <0.4 μm, creating a barrier to donut formation. The calculations also show that osmotic potential energy release can balance the rising bending energy through volume expansion. Finally, we revealed the donut formation process in a Gibbs free-energy-dependent model combining calculations and measurements. PMID:26331247

  9. Human Mitochondrial Protein Database

    National Institute of Standards and Technology Data Gateway

    SRD 131 Human Mitochondrial Protein Database (Web, free access)   The Human Mitochondrial Protein Database (HMPDb) provides comprehensive data on mitochondrial and human nuclear encoded proteins involved in mitochondrial biogenesis and function. This database consolidates information from SwissProt, LocusLink, Protein Data Bank (PDB), GenBank, Genome Database (GDB), Online Mendelian Inheritance in Man (OMIM), Human Mitochondrial Genome Database (mtDB), MITOMAP, Neuromuscular Disease Center and Human 2-D PAGE Databases. This database is intended as a tool not only to aid in studying the mitochondrion but in studying the associated diseases.

  10. Morphological abnormalities in elasmobranchs.

    PubMed

    Moore, A B M

    2015-08-01

    A total of 10 abnormal free-swimming (i.e., post-birth) elasmobranchs are reported from The (Persian-Arabian) Gulf, encompassing five species and including deformed heads, snouts, caudal fins and claspers. The complete absence of pelvic fins in a milk shark Rhizoprionodon acutus may be the first record in any elasmobranch. Possible causes, including the extreme environmental conditions and the high level of anthropogenic pollution particular to The Gulf, are briefly discussed. PMID:25903257

  11. Chromosome abnormalities in glioma

    SciTech Connect

    Li, Y.S.; Ramsay, D.A.; Fan, Y.S.

    1994-09-01

    Cytogenetic studies were performed in 25 patients with gliomas. An interesting finding was a seemingly identical abnormality, an extra band on the tip of the short arm of chromosome 1, add(1)(p36), in two cases. The abnormality was present in all cells from a patient with a glioblastoma and in 27% of the tumor cells from a patient with a recurrent irradiated anaplastic astrocytoma; in the latter case, 7 unrelated abnormal clones were identified except 4 of those clones shared a common change, -Y. Three similar cases have been described previously. In a patient with pleomorphic astrocytoma, the band 1q42 in both homologues of chromosome 1 was involved in two different rearrangements. A review of the literature revealed that deletion of the long arm of chromosome 1 including 1q42 often occurs in glioma. This may indicate a possible tumor suppressor gene in this region. Cytogenetic follow-up studies were carried out in two patients and emergence of unrelated clones were noted in both. A total of 124 clonal breakpoints were identified in the 25 patients. The breakpoints which occurred three times or more were: 1p36, 1p22, 1q21, 1q25, 3q21, 7q32, 8q22, 9q22, 16q22, and 22q13.

  12. [Congenital foot abnormalities].

    PubMed

    Delpont, M; Lafosse, T; Bachy, M; Mary, P; Alves, A; Vialle, R

    2015-03-01

    The foot may be the site of birth defects. These abnormalities are sometimes suspected prenatally. Final diagnosis depends on clinical examination at birth. These deformations can be simple malpositions: metatarsus adductus, talipes calcaneovalgus and pes supinatus. The prognosis is excellent spontaneously or with a simple orthopedic treatment. Surgery remains outstanding. The use of a pediatric orthopedist will be considered if malposition does not relax after several weeks. Malformations (clubfoot, vertical talus and skew foot) require specialized care early. Clubfoot is characterized by an equine and varus hindfoot, an adducted and supine forefoot, not reducible. Vertical talus combines equine hindfoot and dorsiflexion of the forefoot, which is performed in the midfoot instead of the ankle. Skew foot is suspected when a metatarsus adductus is resistant to conservative treatment. Early treatment is primarily orthopedic at birth. Surgical treatment begins to be considered after walking age. Keep in mind that an abnormality of the foot may be associated with other conditions: malposition with congenital hip, malformations with syndromes, neurological and genetic abnormalities. PMID:25524290

  13. [Mitochondrial disease and mitochondrial DNA depletion syndromes].

    PubMed

    Huang, Chin-Chang; Hsu, Chang-Huang

    2009-12-01

    Mitochondria is an intracellular double membrane-bound structure and it can provide energy for intracellular metabolism. The metabolism includes Krebs cycle, beta-oxidation and lipid synthesis. The density of mitochondria is different in various tissues dependent upon the demands of oxidative phosphorylation. Mitochondrial diseases can occur by defects either in mitochondrial DNA or nuclear DNA. Human mitochondrial DNA (mtDNA) encoding for 22 tRNAs, 2 rRNAs and 13 mRNAs that are translated in the mitochondria. Mitochondrial genetic diseases are most resulted from defects in the mtDNA which may be point mutations, deletions, or mitochondrial DNA depletion. These patterns of inheritance in mitochondrial diseases include sporadic, maternally inherited, or of Mendelian inheritance. Mitochondrial DNA depletion is caused by defects in the nuclear genes that are responsible for maintenance of integrity of mtDNA or deoxyribonucelotide pools and mtDNA biogenesis. The mtDNA depletion syndrome (MDS) includes the following categories: progressive external ophthalmoplegia (PEO), predominant myopathy, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), sensory-ataxic neuropathy, dysarthria, and ophthalmoplegia (SANDO) and hepato-encephalopathy. The most common tissues or organs involved in MDS and related disorders include the brain, liver and muscles. These involved genes are divided into two groups including 1) DNA polymerase gamma (POLG, POLG2) and Twinkle genes whose products function directly at the mtDNA replication fork, and 2) adenine nucleotide translocator 1, thymidine phosphorylase, thymidine kinase 2, deoxyguanosine kinase, ADP-forming succinyl-CoA synthetase ligase, MPV17 whose products supply the mitochondria with deoxyribonucleotide triphosphate pools needed for mtDNA replication, and possible mutation in the RRM2B gene. The development has provided new information about the importance of the biosynthetic pathway of the nucleotides for mtDNA replication

  14. Abnormal pressures as hydrodynamic phenomena

    USGS Publications Warehouse

    Neuzil, C.E.

    1995-01-01

    So-called abnormal pressures, subsurface fluid pressures significantly higher or lower than hydrostatic, have excited speculation about their origin since subsurface exploration first encountered them. Two distinct conceptual models for abnormal pressures have gained currency among earth scientists. The static model sees abnormal pressures generally as relict features preserved by a virtual absence of fluid flow over geologic time. The hydrodynamic model instead envisions abnormal pressures as phenomena in which flow usually plays an important role. This paper develops the theoretical framework for abnormal pressures as hydrodynamic phenomena, shows that it explains the manifold occurrences of abnormal pressures, and examines the implications of this approach. -from Author

  15. Feeling Abnormal: Simulation of Deviancy in Abnormal and Exceptionality Courses.

    ERIC Educational Resources Information Center

    Fernald, Charles D.

    1980-01-01

    Describes activity in which student in abnormal psychology and psychology of exceptional children classes personally experience being judged abnormal. The experience allows the students to remember relevant research, become sensitized to the feelings of individuals classified as deviant, and use caution in classifying individuals as abnormal.…

  16. Demyelination increases axonal stationary mitochondrial size and the speed of axonal mitochondrial transport

    PubMed Central

    Kiryu-Seo, Sumiko; Ohno, Nobuhiko; Kidd, Grahame J.; Komuro, Hitoshi; Trapp, Bruce D.

    2010-01-01

    Axonal degeneration contributes to permanent neurological disability in inherited and acquired diseases of myelin. Mitochondrial dysfunction has been proposed as a major contributor to this axonal degeneration. It remains to be determined, however, if myelination, demyelination or remyelination alter the size and distribution of axonal mitochondrial stationary sites or the rates of axonal mitochondrial transport. Using live myelinated rat dorsal root ganglion (DRG) cultures, we investigated whether myelination and lysolecithin-induced demyelination affect axonal mitochondria. Myelination increased the size of axonal stationary mitochondrial sites by 2.3 fold. Following demyelination, the size of axonal stationary mitochondrial sites was increased by an additional 2.2 fold and the transport velocity of motile mitochondria was increased by 47%. These measures returned to the levels of myelinated axons following remyelination. Demyelination induced activating transcription factor (ATF) 3 in DRG neurons. Knockdown of neuronal ATF3 by shRNA abolished the demyelination-induced increase in axonal mitochondrial transport and increased nitrotyrosine immunoreactivity in axonal mitochondria, suggesting that neuronal ATF3 expression and increased mitochondrial transport protect demyelinated axons from oxidative damage. In response to insufficient ATP production, demyelinated axons increase the size of stationary mitochondrial sites and thereby balance ATP production with the increased energy needs of nerve conduction. PMID:20463228

  17. Mitochondrial Dysfunction and Pathology in Bipolar Disorder and Schizophrenia

    PubMed Central

    Clay, Hayley; Sillivan, Stephanie; Konradi, Christine

    2010-01-01

    Bipolar disorder (BPD) and schizophrenia (SZ) are severe psychiatric illnesses with a combined prevalence of 4%. A disturbance of energy metabolism is frequently observed in these disorders. Several pieces of evidence point to an underlying dysfunction of mitochondria: i) decreased mitochondrial respiration; (ii) changes in mitochondrial morphology; iii) increases in mitochondrial DNA (mtDNA) polymorphisms and in levels of mtDNA mutations; iv) downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration; v) decreased high-energy phosphates and decreased pH in the brain; and vi) psychotic and affective symptoms, and cognitive decline in mitochondrial disorders. Furthermore, transgenic mice with mutated mitochondrial DNA polymerase show mood disorder-like phenotypes. In this review, we will discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BPD and SZ. We will furthermore describe the role of mitochondria during brain development and the effect of current drugs for mental illness on mitochondrial function. Understanding the role of mitochondria, both developmentally as well as in the ailing brain, is of critical importance to elucidate pathophysiological mechanisms in psychiatric disorders. PMID:20833242

  18. Mitochondrial Approaches to Protect Against Cardiac Ischemia and Reperfusion Injury

    PubMed Central

    Camara, Amadou K. S.; Bienengraeber, Martin; Stowe, David F.

    2011-01-01

    The mitochondrion is a vital component in cellular energy metabolism and intracellular signaling processes. Mitochondria are involved in a myriad of complex signaling cascades regulating cell death vs. survival. Importantly, mitochondrial dysfunction and the resulting oxidative and nitrosative stress are central in the pathogenesis of numerous human maladies including cardiovascular diseases, neurodegenerative diseases, diabetes, and retinal diseases, many of which are related. This review will examine the emerging understanding of the role of mitochondria in the etiology and progression of cardiovascular diseases and will explore potential therapeutic benefits of targeting the organelle in attenuating the disease process. Indeed, recent advances in mitochondrial biology have led to selective targeting of drugs designed to modulate or manipulate mitochondrial function, to the use of light therapy directed to the mitochondrial function, and to modification of the mitochondrial genome for potential therapeutic benefit. The approach to rationally treat mitochondrial dysfunction could lead to more effective interventions in cardiovascular diseases that to date have remained elusive. The central premise of this review is that if mitochondrial abnormalities contribute to the etiology of cardiovascular diseases (e.g., ischemic heart disease), alleviating the mitochondrial dysfunction will contribute to mitigating the severity or progression of the disease. To this end, this review will provide an overview of our current understanding of mitochondria function in cardiovascular diseases as well as the potential role for targeting mitochondria with potential drugs or other interventions that lead to protection against cell injury. PMID:21559063

  19. Dynamics of Mitochondrial Transport in Axons.

    PubMed

    Niescier, Robert F; Kwak, Sang Kyu; Joo, Se Hun; Chang, Karen T; Min, Kyung-Tai

    2016-01-01

    The polarized structure and long neurites of neurons pose a unique challenge for proper mitochondrial distribution. It is widely accepted that mitochondria move from the cell body to axon ends and vice versa; however, we have found that mitochondria originating from the axon ends moving in the retrograde direction never reach to the cell body, and only a limited number of mitochondria moving in the anterograde direction from the cell body arrive at the axon ends of mouse hippocampal neurons. Furthermore, we have derived a mathematical formula using the Fokker-Planck equation to characterize features of mitochondrial transport, and the equation could determine altered mitochondrial transport in axons overexpressing parkin. Our analysis will provide new insights into the dynamics of mitochondrial transport in axons of normal and unhealthy neurons. PMID:27242435

  20. Dynamics of Mitochondrial Transport in Axons

    PubMed Central

    Niescier, Robert F.; Kwak, Sang Kyu; Joo, Se Hun; Chang, Karen T.; Min, Kyung-Tai

    2016-01-01

    The polarized structure and long neurites of neurons pose a unique challenge for proper mitochondrial distribution. It is widely accepted that mitochondria move from the cell body to axon ends and vice versa; however, we have found that mitochondria originating from the axon ends moving in the retrograde direction never reach to the cell body, and only a limited number of mitochondria moving in the anterograde direction from the cell body arrive at the axon ends of mouse hippocampal neurons. Furthermore, we have derived a mathematical formula using the Fokker-Planck equation to characterize features of mitochondrial transport, and the equation could determine altered mitochondrial transport in axons overexpressing parkin. Our analysis will provide new insights into the dynamics of mitochondrial transport in axons of normal and unhealthy neurons. PMID:27242435

  1. Parsing abnormal grain growth in specialty aluminas

    NASA Astrophysics Data System (ADS)

    Lawrence, Abigail Kremer

    Grain growth in alumina is strongly affected by the impurities present in the material. Certain impurity elements are known to have characteristic effects on abnormal grain growth in alumina. Specialty alumina powders contain multiple impurity species including MgO, CaO, SiO2, and Na 2O. In this work, sintered samples made from alumina powders containing various amounts of the impurities in question were characterized by their grain size and aspect ratio distributions. Multiple quantitative methods were used to characterize and classify samples with varying microstructures. The grain size distributions were used to partition the grain size population into subpopulations depending on the observed deviation from normal behavior. Using both grain size and aspect ratio a new visual representation for a microstructure was introduced called a morphology frequency map that gives a fingerprint for the material. The number of subpopulations within a sample and the shape of the distribution on the morphology map provided the basis for a classification scheme for different types of microstructures. Also using the two parameters a series of five metrics were calculated that describe the character of the abnormal grains in the sample, these were called abnormal character values. The abnormal character values describe the fraction of grains that are considered abnormal, the average magnitude of abnormality (including both grain size and aspect ratio), the average size, and variance in size. The final metric is the correlation between grain size and aspect ratio for the entire population of grains. The abnormal character values give a sense of how different from "normal" the sample is, given the assumption that a normal sample has a lognormal distribution of grain size and a Gaussian distribution of aspect ratios. In the second part of the work the quantified measures of abnormality were correlated with processing parameters such as composition and heat treatment conditions. A

  2. Abnormal human sex chromosome constitutions

    SciTech Connect

    1993-12-31

    Chapter 22, discusses abnormal human sex chromosome constitution. Aneuploidy of X chromosomes with a female phenotype, sex chromosome aneuploidy with a male phenotype, and various abnormalities in X chromosome behavior are described. 31 refs., 2 figs.

  3. Exercises to Improve Gait Abnormalities

    MedlinePlus

    ... Home About iChip Articles Directories Videos Resources Contact Exercises to Improve Gait Abnormalities Home » Article Categories » Exercise and Fitness Font Size: A A A A Exercises to Improve Gait Abnormalities Next Page The manner ...

  4. Deficiency in the inner mitochondrial membrane peptidase 2-like (Immp21) gene increases ischemic brain damage and impairs mitochondrial function

    PubMed Central

    Ma, Yi; Mehta, Suresh L.; Lu, Baisong; Andy Li, P.

    2011-01-01

    Mitochondrial dysfunction plays an important role in mediating ischemic brain damage. Immp2l is an inner mitochondrial membrane peptidase that processes mitochondrial proteins cytochrome c1 (Cyc1). Homozygous mutation of Immp2l (Immp2lTg(Tyr)979Ove or Immp2l−/−) elevates mitochondrial membrane potential, increases superoxide (•O2−) production in the brain and impairs fertility. The objectives of this study are to explore the effects of heterozygous mutation of lmmp2l (Immp2l+/−) on ischemic outcome and to determine the influence of Immp2l deficiency on brain mitochondria after stroke. Male Immp2l+/− and wild-type (WT) mice were subjected to 1-h focal cerebral ischemia. Their brains were harvested after 5 and 24-h of reperfusion. The results showed that infarct volume and DNA oxidative damage significantly increased in the Immp2l+/− mice. There were no obvious cerebral vasculature abnormalities between the two types of mice viewed by Indian ink perfusion. The increased damage in Immp2l+/− mice was associated with early increase in •O2− production. Mitochondrial respiratory rate, total mitochondrial respiratory capacity and mitochondrial respiratory complex activities were decreased at 5-h of recirculation in Immp2l+/− mice compared to WT mice. Our results suggest that lmmp2l deficiency increases ischemic brain damage by enhancing •O2− production and damaging mitochondrial functional performance. PMID:21824519

  5. Mitochondrial phospholipids: role in mitochondrial function.

    PubMed

    Mejia, Edgard M; Hatch, Grant M

    2016-04-01

    Mitochondria are essential components of eukaryotic cells and are involved in a diverse set of cellular processes that include ATP production, cellular signalling, apoptosis and cell growth. These organelles are thought to have originated from a symbiotic relationship between prokaryotic cells in an effort to provide a bioenergetic jump and thus, the greater complexity observed in eukaryotes (Lane and Martin 2010). Mitochondrial processes are required not only for the maintenance of cellular homeostasis, but also allow cell to cell and tissue to tissue communication (Nunnari and Suomalainen 2012). Mitochondrial phospholipids are important components of this system. Phospholipids make up the characteristic outer and inner membranes that give mitochondria their shape. In addition, these membranes house sterols, sphingolipids and a wide variety of proteins. It is the phospholipids that also give rise to other characteristic mitochondrial structures such as cristae (formed from the invaginations of the inner mitochondrial membrane), the matrix (area within cristae) and the intermembrane space (IMS) which separates the outer mitochondrial membrane (OMM) and inner mitochondrial membrane (IMM). Phospholipids are the building blocks that make up these structures. However, the phospholipid composition of the OMM and IMM is unique in each membrane. Mitochondria are able to synthesize some of the phospholipids it requires, but the majority of cellular lipid biosynthesis takes place in the endoplasmic reticulum (ER) in conjunction with the Golgi apparatus (Fagone and Jackowski 2009). In this review, we will focus on the role that mitochondrial phospholipids play in specific cellular functions and discuss their biosynthesis, metabolism and transport as well as the differences between the OMM and IMM phospholipid composition. Finally, we will focus on the human diseases that result from disturbances to mitochondrial phospholipids and the current research being performed to help

  6. Separating Population Structure from Population History: A Cladistic Analysis of the Geographical Distribution of Mitochondrial DNA Haplotypes in the Tiger Salamander, Ambystoma Tigrinum

    PubMed Central

    Templeton, A. R.; Routman, E.; Phillips, C. A.

    1995-01-01

    Nonrandom associations of alleles or haplotypes with geographical location can arise from restricted gene flow, historical events (fragmentation, range expansion, colonization), or any mixture of these factors. In this paper, we show how a nested cladistic analysis of geographical distances can be used to test the null hypothesis of no geographical association of haplotypes, test the hypothesis that significant associations are due to restricted gene flow, and identify patterns of significant association that are due to historical events. In this last case, criteria are given to discriminate among contiguous range expansion, long-distance colonization, and population fragmentation. The ability to make these discriminations depends critically upon an adequate geographical sampling design. These points are illustrated with a worked example: mitochondrial DNA haplotypes in the salamander Ambystoma tigrinum. For this example, prior information exists about restricted gene flow and likely historical events, and the nested cladistic analyses were completely concordant with this prior information. This concordance establishes the plausibility of this nested cladistic approach, but much future work will be necessary to demonstrate robustness and to explore the power and accuracy of this procedure. PMID:7498753

  7. Mitochondrial dysfunction and intracellular calcium dysregulation in ALS

    PubMed Central

    Kawamata, Hibiki; Manfredi, Giovanni

    2010-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that affects the aging population. A progressive loss of motor neurons in the spinal cord and brain leads to muscle paralysis and death. As in other common neurodegenerative diseases, aging-related mitochondrial dysfunction is increasingly being considered among the pathogenic factors. Mitochondria are critical for cell survival: they provide energy to the cell, buffer intracellular calcium, and regulate apoptotic cell death. Whether mitochondrial abnormalities are a trigger or a consequence of the neurodegenerative process and the mechanisms whereby mitochondrial dysfunction contributes to disease are not clear yet. Calcium homeostasis is a major function of mitochondria in neurons, and there is ample evidence that intracellular calcium is dysregulated in ALS. The impact of mitochondrial dysfunction on intracellular calcium homeostasis and its role in motor neuron demise are intriguing issues that warrants in depth discussion. Clearly, unraveling the causal relationship between mitochondrial dysfunction, calcium dysregulation, and neuronal death is critical for the understanding of ALS pathogenesis. In this review, we will outline the current knowledge of various aspects of mitochondrial dysfunction in ALS, with a special emphasis on the role of these abnormalities on intracellular calcium handling. PMID:20493207

  8. Impaired Lung Mitochondrial Respiration Following Perinatal Nicotine Exposure in Rats.

    PubMed

    Cannon, Daniel T; Liu, Jie; Sakurai, Reiko; Rossiter, Harry B; Rehan, Virender K

    2016-04-01

    Perinatal smoke/nicotine exposure predisposes to chronic lung disease and morbidity. Mitochondrial abnormalities may contribute as the PPARγ pathway is involved in structural and functional airway deficits after perinatal nicotine exposure. We hypothesized perinatal nicotine exposure results in lung mitochondrial dysfunction that can be rescued by rosiglitazone (RGZ; PPARγ receptor agonist). Sprague-Dawley dams received placebo (CON), nicotine (NIC, 1 mg kg(-1)), or NIC + RGZ (3 mg kg(-1)) daily from embryonic day 6 to postnatal day 21. Parenchymal lung (~10 mg) was taken from adult male offspring for mitochondrial assessment in situ. ADP-stimulated O2 consumption was less in NIC and NIC + RGZ compared to CON (F[2,14] = 17.8; 4.5 ± 0.8 and 4.1 ± 1.4 vs. 8.8 ± 2.5 pmol s mg(-1); p < 0.05). The respiratory control ratio for ADP, an index of mitochondrial coupling, was reduced in NIC and remediated in NIC + RGZ (F[2,14] = 3.8; p < 0.05). Reduced mitochondrial oxidative capacity and abnormal coupling were evident after perinatal nicotine exposure. RGZ improved mitochondrial function through tighter coupling of oxidative phosphorylation. PMID:26899624

  9. [Characteristics of molecular genetics and research progress on mitochondrial diseases].

    PubMed

    Zhang, Meng; Si, Yanmei; Zhao, Juan

    2016-10-01

    Mitochondrial diseases is a group of metabolic disorders caused by abnormal structure and dysfunction of mitochondrial DNA (mtDNA). Abnormalities of mtDNA include point mutations, deletions, and rearrangements and depletion of mtDNA. These may affect the ability of mitochondria to generate energy in cells of various tissues and organs. As many factors are involved in the regulation of mtDNA mutations, most mitochondrial diseases may manifest great genetic heterogeneity and a wide spectrum of clinical manifestations. On the other hand, for the low prevalence of single disease, these disorders may be easily missed or with delayed diagnosis. This review focuses on the pathological mutations and benign variations of mtDNA, and research progress on such disorders. PMID:27577231

  10. Mitochondrial DNA, mitochondrial dysfunction, and cardiac manifestations.

    PubMed

    Lee, Sung Ryul; Kim, Nari; Noh, Yeonhee; Xu, Zhelong; Ko, Kyung Soo; Rhee, Byoung Doo; Han, Jin

    2016-01-01

    Mitochondria, the powerhouses of cells, have their own DNA (mtDNA). They regulate the transport of metabolites and ions, which determine cell physiology, survival, and death. Mitochondrial dysfunction, including impaired oxidative phosphorylation, preferentially affects heart function via imbalance of energy supply and demand. Recently, mitochondrial mutations and associated mitochondrial dysfunction were suggested as a causal factor of cardiac manifestations. Oxidative stress largely influences mtDNA stability due to oxidative modifications of mtDNA. Furthermore, the continuous replicative state of mtDNA and presence of minimal nucleoid structure render mitochondria vulnerable to oxidative damage and subsequent mutations, which impair mitochondrial functions. However, the occurrence of mtDNA heteroplasmy in the same mitochondrion or cell and presence of nuclear DNA-encoded mtDNA repair systems raise questions regarding whether oxidative stress-mediated mtDNA mutations are the major driving force in accumulation of mtDNA mutations. Here, we address the possible causes of mitochondrial DNA mutations and their involvement in cardiac manifestations. Current strategies for treatment related to mitochondrial mutations and/or dysfunction in cardiac manifestations are briefly discussed. PMID:27100514

  11. Spirometric abnormalities among welders

    SciTech Connect

    Rastogi, S.K.; Gupta, B.N.; Husain, T.; Mathur, N.; Srivastava, S. )

    1991-10-01

    A group of manual welders age group 13-60 years having a mean exposure period of 12.4 {plus minus} 1.12 years were subjected to spirometry to evaluate the prevalence of spirometric abnormalities. The welders showed a significantly higher prevalence of respiratory impairment than that observed among the unexposed controls as a result of exposure to welding gases which comprised fine particles of lead, zinc, chromium, and manganese. This occurred despite the lower concentration of the pollutants at the work place. In the expose group, the smoking welders showed a prevalence of respiratory impairment significantly higher than that observed in the nonsmoking welders. The results of the pulmonary function tests showed a predominantly restrictive type of pulmonary impairment followed by a mixed ventilatory defect among the welders. The effect of age on pulmonary impairment was not discernible. Welders exposed for over 10 years showed a prevalence of respiratory abnormalities significantly higher than those exposed for less than 10 years. Smoking also had a contributory role.

  12. Decreased mitochondrial tRNALys steady-state levels and aminoacylation are associated with the pathogenic G8313A mitochondrial DNA mutation.

    PubMed Central

    Bacman, Sandra R; Atencio, David P; Moraes, Carlos T

    2003-01-01

    Mutations in human mitochondrial tRNA genes cause a number of multisystemic disorders. A G-to-A transition at position 8313 (G8313A) transition in the mitochondrial tRNALys gene has been associated with a childhood syndrome characterized by gastrointestinal-system involvement and encephaloneuropathy. We have used transmitochondrial cybrid clones harbouring patient-derived mitochondrial DNA with the G8313A mutation for the study of the molecular pathogenesis. Our results showed that mutant mitochondrial cybrids respired poorly, and had severely defective mitochondrial protein synthesis and respiratory-chain-enzyme activity. Mutant cybrids also showed a marked decrease in tRNALys steady-state levels and aminoacylation, suggesting that these molecular abnormalities may underlie the pathogenesis of the mitochondrial G8313A mutation. PMID:12737626

  13. Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome

    PubMed Central

    Hodurova, Zuzana; Mandel, Merle; Zeb, Akbar; Choubey, Vinay; Safiulina, Dzhamilja; Vasar, Eero; Veksler, Vladimir; Kaasik, Allen

    2016-01-01

    Deficiency of the protein Wolfram syndrome 1 (WFS1) is associated with multiple neurological and psychiatric abnormalities similar to those observed in pathologies showing alterations in mitochondrial dynamics. The aim of this study was to examine the hypothesis that WFS1 deficiency affects neuronal function via mitochondrial abnormalities. We show that down-regulation of WFS1 in neurons leads to dramatic changes in mitochondrial dynamics (inhibited mitochondrial fusion, altered mitochondrial trafficking, and augmented mitophagy), delaying neuronal development. WFS1 deficiency induces endoplasmic reticulum (ER) stress, leading to inositol 1,4,5-trisphosphate receptor (IP3R) dysfunction and disturbed cytosolic Ca2+ homeostasis, which, in turn, alters mitochondrial dynamics. Importantly, ER stress, impaired Ca2+ homeostasis, altered mitochondrial dynamics, and delayed neuronal development are causatively related events because interventions at all these levels improved the downstream processes. Our data shed light on the mechanisms of neuronal abnormalities in Wolfram syndrome and point out potential therapeutic targets. This work may have broader implications for understanding the role of mitochondrial dynamics in neuropsychiatric diseases. PMID:27434582

  14. Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome.

    PubMed

    Cagalinec, Michal; Liiv, Mailis; Hodurova, Zuzana; Hickey, Miriam Ann; Vaarmann, Annika; Mandel, Merle; Zeb, Akbar; Choubey, Vinay; Kuum, Malle; Safiulina, Dzhamilja; Vasar, Eero; Veksler, Vladimir; Kaasik, Allen

    2016-07-01

    Deficiency of the protein Wolfram syndrome 1 (WFS1) is associated with multiple neurological and psychiatric abnormalities similar to those observed in pathologies showing alterations in mitochondrial dynamics. The aim of this study was to examine the hypothesis that WFS1 deficiency affects neuronal function via mitochondrial abnormalities. We show that down-regulation of WFS1 in neurons leads to dramatic changes in mitochondrial dynamics (inhibited mitochondrial fusion, altered mitochondrial trafficking, and augmented mitophagy), delaying neuronal development. WFS1 deficiency induces endoplasmic reticulum (ER) stress, leading to inositol 1,4,5-trisphosphate receptor (IP3R) dysfunction and disturbed cytosolic Ca2+ homeostasis, which, in turn, alters mitochondrial dynamics. Importantly, ER stress, impaired Ca2+ homeostasis, altered mitochondrial dynamics, and delayed neuronal development are causatively related events because interventions at all these levels improved the downstream processes. Our data shed light on the mechanisms of neuronal abnormalities in Wolfram syndrome and point out potential therapeutic targets. This work may have broader implications for understanding the role of mitochondrial dynamics in neuropsychiatric diseases. PMID:27434582

  15. Regulation of Mitochondrial Transport in Neurons

    PubMed Central

    Lin, Mei-Yao; Sheng, Zu-Hang

    2015-01-01

    Mitochondria are cellular power plants that supply ATP to power various biological activities essential for neuronal growth, survival, and function. Due to unique morphological features, neurons face exceptional challenges to maintain ATP and Ca2+ homeostasis. Neurons require specialized mechanisms distributing mitochondria to distal areas where energy and Ca2+ buffering are in high demand, such as synapses and axonal branches. These distal compartments also undergo development- and activity-dependent remodeling, thereby altering mitochondrial trafficking and distribution. Mitochondria move bi-directionally, pause briefly, and move again, frequently changing direction. In mature neurons, only one-third of axonal mitochondria are motile. Stationary mitochondria serve as local energy sources and buffer intracellular Ca2+. The balance between motile and stationary mitochondria responds quickly to changes in axonal and synaptic physiology. Furthermore, neurons are postmitotic cells surviving for the lifetime of the organism; thus, mitochondria need to be removed when they become aged or dysfunction. Mitochondria also alter their motility under stress conditions or when their integrity is impaired. Therefore, regulation of mitochondrial transport is essential to meet altered metabolic requirements and to remove aged and damaged mitochondria or replenish healthy ones to distal terminals. Defects in mitochondrial transport and altered distribution are implicated in the pathogenesis of several major neurological disorders. Thus, research into the mechanisms regulating mitochondrial motility is an important emerging frontier in neurobiology. This short review provides an updated overview on motor-adaptor machineries that drive and regulate mitochondrial transport and docking receptors that anchor axonal mitochondria in response to the changes in synaptic activity, metabolic requirement, and altered mitochondrial integrity. The review focuses on microtubule (MT

  16. Mitochondrial dysfunction during sepsis.

    PubMed

    Azevedo, Luciano Cesar Pontes

    2010-09-01

    Sepsis and multiple organ failure remain leading causes of death in intensive care patients. Recent advances in our understanding of the pathophysiology of these syndromes include a likely prominent role for mitochondria. Patient studies have shown that the degree of mitochondrial dysfunction is related to the eventual outcome. Associated mechanisms include damage to mitochondria or inhibition of the electron transport chain enzymes by nitric oxide and other reactive oxygen species (the effects of which are amplified by co-existing tissue hypoxia), hormonal influences that decrease mitochondrial activity, and downregulation of mitochondrial protein expression. Notably, despite these findings, there is minimal cell death seen in most affected organs, and these organs generally regain reasonably normal function should the patient survive. It is thus plausible that multiple organ failure following sepsis may actually represent an adaptive state whereby the organs temporarily 'shut down' their normal metabolic functions in order to protect themselves from an overwhelming and prolonged insult. A decrease in energy supply due to mitochondrial inhibition or injury may trigger this hibernation/estivation-like state. Likewise, organ recovery may depend on restoration of normal mitochondrial respiration. Data from animal studies show histological recovery of mitochondria after a septic insult that precedes clinical improvement. Stimulation of mitochondrial biogenesis could offer a new therapeutic approach for patients in multi-organ failure. This review will cover basic aspects of mitochondrial function, mechanisms of mitochondrial dysfunction in sepsis, and approaches to prevent, mitigate or speed recovery from mitochondrial injury. PMID:20509844

  17. Mitochondrial threshold effects.

    PubMed Central

    Rossignol, Rodrigue; Faustin, Benjamin; Rocher, Christophe; Malgat, Monique; Mazat, Jean-Pierre; Letellier, Thierry

    2003-01-01

    The study of mitochondrial diseases has revealed dramatic variability in the phenotypic presentation of mitochondrial genetic defects. To attempt to understand this variability, different authors have studied energy metabolism in transmitochondrial cell lines carrying different proportions of various pathogenic mutations in their mitochondrial DNA. The same kinds of experiments have been performed on isolated mitochondria and on tissue biopsies taken from patients with mitochondrial diseases. The results have shown that, in most cases, phenotypic manifestation of the genetic defect occurs only when a threshold level is exceeded, and this phenomenon has been named the 'phenotypic threshold effect'. Subsequently, several authors showed that it was possible to inhibit considerably the activity of a respiratory chain complex, up to a critical value, without affecting the rate of mitochondrial respiration or ATP synthesis. This phenomenon was called the 'biochemical threshold effect'. More recently, quantitative analysis of the effects of various mutations in mitochondrial DNA on the rate of mitochondrial protein synthesis has revealed the existence of a 'translational threshold effect'. In this review these different mitochondrial threshold effects are discussed, along with their molecular bases and the roles that they play in the presentation of mitochondrial diseases. PMID:12467494

  18. MYC and Mitochondrial Biogenesis

    PubMed Central

    Morrish, Fionnuala; Hockenbery, David

    2014-01-01

    Mitochondria, the powerhouses of the cell, face two imperatives concerning biogenesis. The first is the requirement for dividing cells to replicate their mitochondrial content by growth of existing mitochondria. The second is the dynamic regulation of mitochondrial content in response to organismal and cellular cues (e.g., exercise, caloric restriction, energy status, temperature). MYC provides the clearest example of a programmed expansion of mitochondrial content linked to the cell cycle. As an oncogene, MYC also presents intriguing questions about the role of its mitochondrial targets in cancer-related phenotypes, such as the Warburg effect and MYC-dependent apoptosis. PMID:24789872

  19. Yeast Mitochondrial Transcriptomics

    PubMed Central

    Garcia, Mathilde; Darzacq, Xavier; Devaux, Frederic; Singer, Robert H.; Jacq, Claude

    2016-01-01

    Although 30 years ago it was strongly suggested that some cytoplasmic ribosomes are bound to the surface of yeast mitochondria, the mechanisms and the raison d’ětre of this process are not understood. For instance, it is not perfectly known which of the several hundred nuclearly encoded genes have to be translated to the mitochondrial vicinity to guide the import of the corresponding proteins. One can take advantage of several modern methods to address a number of aspects of the site-specific translation process of messenger ribonucleic acid (mRNA) coding for proteins imported into mitochondria. Three complementary approaches are presented to analyze the spatial distribution of mRNAs coding for proteins imported into mitochondria. Starting from biochemical purifications of mitochondria-bound polysomes, we describe a genomewide approach to classify all the cellular mRNAs according to their physical proximity with mitochondria; we also present real-time quantitative reverse transcription polymerase chain reaction monitoring of mRNA distribution to provide a quantified description of this localization. Finally, a fluorescence microscopy approach on a single living cell is described to visualize the in vivo localization of mRNAs involved in mitochondria biogenesis. PMID:18314748

  20. Mitochondrial genomes and divergence times of crocodile newts: inter-islands distribution of Echinotriton andersoni and the origin of a unique repetitive sequence found in Tylototriton mt genomes.

    PubMed

    Kurabayashi, Atsushi; Nishitani, Takuma; Katsuren, Seiki; Oumi, Shohei; Sumida, Masayuki

    2012-01-01

    Crocodile newts, which constitute the genera Echinotriton and Tylototriton, are known as living fossils, and these genera comprise many endangered species. To identify mitochondrial (mt) genes suitable for future population genetic analyses for endangered taxa, we determined the complete nucleotide sequences of the mt genomes of the Japanese crocodile newt Echinotriton andersoni and Himalayan crocodile newt Tylototriton verrucosus. Although the control region (CR) is known as the most variable mtDNA region in many animal taxa, the CRs of crocodile newts are highly conservative. Rather, the genes of NADH dehydrogenase subunits and ATPase subunit 6 were found to have high sequence divergences and to be usable for population genetics studies. To estimate the inter-population divergence ages of E. andersoni endemic to the Ryukyu Islands, we performed molecular dating analysis using whole and partial mt genomic data. The estimated divergence ages of the inter-island individuals are older than the paleogeographic segmentation ages of the islands, suggesting that the lineage splits of E. andersoni populations were not caused by vicariant events. Our phylogenetic analysis with partial mt sequence data also suggests the existence of at least two more undescribed species in the genus Tylototriton. We also found unusual repeat sequences containing the 3' region of cytochrome apoenzyme b gene, whole tRNA-Thr gene, and a noncoding region (the T-P noncoding region characteristic in caudate mtDNAs) from T. verrucosus mtDNA. Similar repeat sequences were found in two other Tylototriton species. The Tylototriton taxa with the repeats become a monophyletic group, indicating a single origin of the repeat sequences. The intra-and inter-specific comparisons of the repeat sequences suggest the occurrences of homologous recombination-based concerted evolution among the repeat sequences. PMID:22531793

  1. Mitochondrial emitted electromagnetic signals mediate retrograde signaling.

    PubMed

    Bagkos, Georgios; Koufopoulos, Kostas; Piperi, Christina

    2015-12-01

    Recent evidence shows that mitochondria regulate nuclear transcriptional activity both in normal and cell stress conditions, known as retrograde signaling. Under normal mitochondrial function, retrograde signaling is associated with mitochondrial biogenesis, normal cell phenotype and metabolic profile. In contrast, mitochondrial dysfunction leads to abnormal (oncogenic) cell phenotype and altered bio-energetic profile (nucleus reprogramming). Despite intense research efforts, a concrete mechanism through which mitochondria determine the group of genes expressed by the nucleus is still missing. The present paper proposes a novel hypothesis regarding retrograde signaling. More specifically, it reveals the mitochondrial membrane potential (MMP) and the accompanied strong electromagnetic field (EF) as key regulatory factors of nuclear activity. Mitochondrial emitted EFs extend in long distance and affect the function of nuclear membrane receptors. Depending on their frequencies, EFs can directly activate or deactivate different groups of nuclear receptors and so determine nuclear gene expression. One of the key features of the above hypothesis is that nuclear membrane receptors, besides their own endogenous or chemical ligands (hormones, lipids, etc.), can also be activated by electromagnetic signals. Moreover, normal MMP values (about -140 mV) are associated with the production of high ATP quantities and small levels of reactive oxygen species (ROS) while the hyperpolarization observed in all cancer cell types leads to a dramatic fall in ATP production and an analogous increase in ROS. The diminished ATP and increased ROS production negatively affect the function of all cellular systems including nucleus. Restoration of mitochondrial function, which is characterized by the fluctuation of MMP and EF values within a certain (normal) range, is proposed as a necessary condition for normal nuclear function and cancer therapy. PMID:26474928

  2. Mitochondrial Disease-related Mutation G167P in Cytochrome b of Rhodobacter capsulatus Cytochrome bc1 (S151P in Human) Affects the Equilibrium Distribution of [2Fe-2S] Cluster and Generation of Superoxide*

    PubMed Central

    Borek, Arkadiusz; Kuleta, Patryk; Ekiert, Robert; Pietras, Rafał; Sarewicz, Marcin; Osyczka, Artur

    2015-01-01

    Cytochrome bc1 is one of the key enzymes of many bioenergetic systems. Its operation involves a large scale movement of a head domain of iron-sulfur protein (ISP-HD), which functionally connects the catalytic quinol oxidation Qo site in cytochrome b with cytochrome c1. The Qo site under certain conditions can generate reactive oxygen species in the reaction scheme depending on the actual position of ISP-HD in respect to the Qo site. Here, using a bacterial system, we show that mutation G167P in cytochrome b shifts the equilibrium distribution of ISP-HD toward positions remote from the Qo site. This renders cytochrome bc1 non-functional in vivo. This effect is remediated by addition of alanine insertions (1Ala and 2Ala) in the neck region of the ISP subunit. These insertions, which on their own shift the equilibrium distribution of ISP-HD in the opposite direction (i.e. toward the Qo site), also act in this manner in the presence of G167P. Changes in the equilibrium distribution of ISP-HD in G167P lead to an increased propensity of cytochrome bc1 to generate superoxide, which becomes evident when the concentration of quinone increases. This result corroborates the recently proposed model in which “semireverse” electron transfer back to the Qo site, occurring when ISP-HD is remote from the site, favors reactive oxygen species production. G167P suggests possible molecular effects of S151P (corresponding in sequence to G167P) identified as a mitochondrial disease-related mutation in human cytochrome b. These effects may be valid for other human mutations that change the equilibrium distribution of ISP-HD in a manner similar to G167P. PMID:26245902

  3. Mitochondrial Disease-related Mutation G167P in Cytochrome b of Rhodobacter capsulatus Cytochrome bc1 (S151P in Human) Affects the Equilibrium Distribution of [2Fe-2S] Cluster and Generation of Superoxide.

    PubMed

    Borek, Arkadiusz; Kuleta, Patryk; Ekiert, Robert; Pietras, Rafał; Sarewicz, Marcin; Osyczka, Artur

    2015-09-25

    Cytochrome bc1 is one of the key enzymes of many bioenergetic systems. Its operation involves a large scale movement of a head domain of iron-sulfur protein (ISP-HD), which functionally connects the catalytic quinol oxidation Qo site in cytochrome b with cytochrome c1. The Qo site under certain conditions can generate reactive oxygen species in the reaction scheme depending on the actual position of ISP-HD in respect to the Qo site. Here, using a bacterial system, we show that mutation G167P in cytochrome b shifts the equilibrium distribution of ISP-HD toward positions remote from the Qo site. This renders cytochrome bc1 non-functional in vivo. This effect is remediated by addition of alanine insertions (1Ala and 2Ala) in the neck region of the ISP subunit. These insertions, which on their own shift the equilibrium distribution of ISP-HD in the opposite direction (i.e. toward the Qo site), also act in this manner in the presence of G167P. Changes in the equilibrium distribution of ISP-HD in G167P lead to an increased propensity of cytochrome bc1 to generate superoxide, which becomes evident when the concentration of quinone increases. This result corroborates the recently proposed model in which "semireverse" electron transfer back to the Qo site, occurring when ISP-HD is remote from the site, favors reactive oxygen species production. G167P suggests possible molecular effects of S151P (corresponding in sequence to G167P) identified as a mitochondrial disease-related mutation in human cytochrome b. These effects may be valid for other human mutations that change the equilibrium distribution of ISP-HD in a manner similar to G167P. PMID:26245902

  4. The ageing neuromuscular system and sarcopenia: a mitochondrial perspective.

    PubMed

    Rygiel, Karolina A; Picard, Martin; Turnbull, Doug M

    2016-08-15

    Skeletal muscles undergo structural and functional decline with ageing, culminating in sarcopenia. The underlying neuromuscular mechanisms have been the subject of intense investigation, revealing mitochondrial abnormalities as potential culprits within both nerve and muscle cells. Implicated mechanisms involve impaired mitochondrial dynamics, reduced organelle biogenesis and quality control via mitophagy, accumulation of mitochondrial DNA (mtDNA) damage and respiratory chain defect, metabolic disturbance, pro-apoptotic signalling, and oxidative stress. This article provides an overview of the cellular mechanisms whereby mitochondria may promote maladaptive changes within motor neurons, the neuromuscular junction (NMJ) and muscle fibres. Lifelong physical activity, which promotes mitochondrial health across tissues, is emerging as an effective countermeasure for sarcopenia. PMID:26921061

  5. Mitochondrial dynamics: Orchestrating the journey to advanced age.

    PubMed

    Biala, Agnieszka K; Dhingra, Rimpy; Kirshenbaum, Lorrie A

    2015-06-01

    Aging is a degenerative process that unfortunately is an inevitable part of life and risk factor for cardiovascular disease including heart failure. Among the several theories purported to explain the effects of age on cardiac dysfunction, the mitochondrion has emerged a central regulator of this process. Hence, it is not surprising that abnormalities in mitochondrial quality control including biogenesis and turnover have such detrimental effects on cardiac function. In fact mitochondria serve as a conduit for biological signals for apoptosis, necrosis and autophagy respectively. The removal of damaged mitochondria by autophagy/mitophagy is essential for mitochondrial quality control and cardiac homeostasis. Defects in mitochondrial dynamism fission/fusion events have been linked to cardiac senescence and heart failure. In this review we discuss the impact of aging on mitochondrial dynamics and senescence on cardiovascular health. This article is part of a Special Issue entitled: CV Aging. PMID:25918048

  6. Eye movement abnormalities.

    PubMed

    Moncayo, Jorge; Bogousslavsky, Julien

    2012-01-01

    Generation and control of eye movements requires the participation of the cortex, basal ganglia, cerebellum and brainstem. The signals of this complex neural network finally converge on the ocular motoneurons of the brainstem. Infarct or hemorrhage at any level of the oculomotor system (though more frequent in the brain-stem) may give rise to a broad spectrum of eye movement abnormalities (EMAs). Consequently, neurologists and particularly stroke neurologists are routinely confronted with EMAs, some of which may be overlooked in the acute stroke setting and others that, when recognized, may have a high localizing value. The most complex EMAs are due to midbrain stroke. Horizontal gaze disorders, some of them manifesting unusual patterns, may occur in pontine stroke. Distinct varieties of nystagmus occur in cerebellar and medullary stroke. This review summarizes the most representative EMAs from the supratentorial level to the brainstem. PMID:22377853

  7. Digestive smooth muscle mitochondrial myopathy in patients with mitochondrial-neuro-gastro-intestinal encephalomyopathy (MNGIE).

    PubMed

    Blondon, Hugues; Polivka, Marc; Joly, Francisca; Flourie, Bernard; Mikol, Jacqueline; Messing, Bernard

    2005-01-01

    We report 3 new cases of Mitochondrial-Neuro-Gastro-Intestinal Encephalomyopathy (MNGIE) (or Pseudo-Obstruction-Leukoencephalopathy-Intestinal-Pseudoobstruction Syndrome [POLIP]), a rare disease that associates chronic intestinal pseudo-obstruction (CIPO) and neurological symptoms. A review of the 72 reported cases together with these 3 cases revealed that this condition was associated with (a) a specific cluster of neurological symptoms including leukoencephalopathy (96%), polyneuropathy (96%), ophthalmoplegia (91%) and hearing loss (55%); (b) a CIPO syndrome with the presence of small bowel diverticulae (53%); and (c) mitochondrial cytopathy in 36 of the 37 tested patients (2 of our 3 cases), and thymidine phosphorylase gene mutations in all the 37 tested patients (2 of our cases). The etiology of POLIP/MNGIE syndrome appears therefore to be due to a mitochondrial cytopathy secondary to thymidine phosphorylase gene mutation(s). In 3 cases, including 2 of our 3 patients, mitochondrial abnormalities were evidenced at the ultrastructural level in digestive smooth muscle demonstrating that the pathogenesis of gastrointestinal involvement was directly related to mitochondrial alterations in digestive smooth muscle cells. PMID:16294144

  8. Mutations in FBXL4, Encoding a Mitochondrial Protein, Cause Early-Onset Mitochondrial Encephalomyopathy

    PubMed Central

    Gai, Xiaowu; Ghezzi, Daniele; Johnson, Mark A.; Biagosch, Caroline A.; Shamseldin, Hanan E.; Haack, Tobias B.; Reyes, Aurelio; Tsukikawa, Mai; Sheldon, Claire A.; Srinivasan, Satish; Gorza, Matteo; Kremer, Laura S.; Wieland, Thomas; Strom, Tim M.; Polyak, Erzsebet; Place, Emily; Consugar, Mark; Ostrovsky, Julian; Vidoni, Sara; Robinson, Alan J.; Wong, Lee-Jun; Sondheimer, Neal; Salih, Mustafa A.; Al-Jishi, Emtethal; Raab, Christopher P.; Bean, Charles; Furlan, Francesca; Parini, Rossella; Lamperti, Costanza; Mayr, Johannes A.; Konstantopoulou, Vassiliki; Huemer, Martina; Pierce, Eric A.; Meitinger, Thomas; Freisinger, Peter; Sperl, Wolfgang; Prokisch, Holger; Alkuraya, Fowzan S.; Falk, Marni J.; Zeviani, Massimo

    2013-01-01

    Whole-exome sequencing and autozygosity mapping studies, independently performed in subjects with defective combined mitochondrial OXPHOS-enzyme deficiencies, identified a total of nine disease-segregating FBXL4 mutations in seven unrelated mitochondrial disease families, composed of six singletons and three siblings. All subjects manifested early-onset lactic acidemia, hypotonia, and developmental delay caused by severe encephalomyopathy consistently associated with progressive cerebral atrophy and variable involvement of the white matter, deep gray nuclei, and brainstem structures. A wide range of other multisystem features were variably seen, including dysmorphism, skeletal abnormalities, poor growth, gastrointestinal dysmotility, renal tubular acidosis, seizures, and episodic metabolic failure. Mitochondrial respiratory chain deficiency was present in muscle or fibroblasts of all tested individuals, together with markedly reduced oxygen consumption rate and hyperfragmentation of the mitochondrial network in cultured cells. In muscle and fibroblasts from several subjects, substantially decreased mtDNA content was observed. FBXL4 is a member of the F-box family of proteins, some of which are involved in phosphorylation-dependent ubiquitination and/or G protein receptor coupling. We also demonstrate that FBXL4 is targeted to mitochondria and localizes in the intermembrane space, where it participates in an approximately 400 kDa protein complex. These data strongly support a role for FBXL4 in controlling bioenergetic homeostasis and mtDNA maintenance. FBXL4 mutations are a recurrent cause of mitochondrial encephalomyopathy onset in early infancy. PMID:23993194

  9. Mitochondrial dysfunction in neuromuscular disorders.

    PubMed

    Katsetos, Christos D; Koutzaki, Sirma; Melvin, Joseph J

    2013-09-01

    This review deciphers aspects of mitochondrial (mt) dysfunction among nosologically, pathologically, and genetically diverse diseases of the skeletal muscle, lower motor neuron, and peripheral nerve, which fall outside the traditional realm of mt cytopathies. Special emphasis is given to well-characterized mt abnormalities in collagen VI myopathies (Ullrich congenital muscular dystrophy and Bethlem myopathy), megaconial congenital muscular dystrophy, limb-girdle muscular dystrophy type 2 (calpainopathy), centronuclear myopathies, core myopathies, inflammatory myopathies, spinal muscular atrophy, Charcot-Marie-Tooth neuropathy type 2, and drug-induced peripheral neuropathies. Among inflammatory myopathies, mt abnormalities are more prominent in inclusion body myositis and a subset of polymyositis with mt pathology, both of which are refractory to corticosteroid treatment. Awareness is raised about instances of phenotypic mimicry between cases harboring primary mtDNA depletion, in the context of mtDNA depletion syndrome, and established neuromuscular disorders such as spinal muscular atrophy. A substantial body of experimental work, derived from animal models, attests to a major role of mitochondria (mt) in the early process of muscle degeneration. Common mechanisms of mt-related cell injury include dysregulation of the mt permeability transition pore opening and defective autophagy. The therapeutic use of mt permeability transition pore modifiers holds promise in various neuromuscular disorders, including muscular dystrophies. PMID:24331362

  10. Spatio-Temporal Distribution of Aedes aegypti (Diptera: Culicidae) Mitochondrial Lineages in Cities with Distinct Dengue Incidence Rates Suggests Complex Population Dynamics of the Dengue Vector in Colombia

    PubMed Central

    Jaimes-Dueñez, Jeiczon; Arboleda, Sair; Triana-Chávez, Omar; Gómez-Palacio, Andrés

    2015-01-01

    Background Aedes aegypti is the primary vector of the four serotypes of dengue virus (DENV1-4), Chikungunya and yellow fever virus to humans. Previous population genetic studies have revealed a particular genetic structure among the vector populations in the Americas that suggests differences in the ability to transmit DENV. In Colombia, despite its high epidemiologic importance, the genetic population structure and the phylogeographic depiction of Ae. aegypti, as well as its relationship with the epidemiologic landscapes in cities with heterogeneous incidence levels, remains unknown. We conducted a spatiotemporal analysis with the aim of determining the genetic structure and phylogeography of Colombian populations of Ae. aegypti among cities with different eco-epidemiologic characteristics with regard to DENV. Methods/Findings Mitochondrial cytochrome oxidase C subunit 1 (COI) - NADH dehydrogenase subunit 4 (ND4) genes were sequenced and analyzed from 341 adult mosquitoes collected during 2012 and 2013 in the Colombian cities of Bello, Riohacha and Villavicencio, which exhibit low, medium and high levels of incidence of DENV, respectively. The results demonstrated a low genetic differentiation over time and a high genetic structure between the cities due to changes in the frequency of two highly supported genetic groups. The phylogeographic analyses indicated that one group (associated with West African populations) was found in all the cities throughout the sampling while the second group (associated with East African populations) was found in all the samples from Bello and in only one sampling from Riohacha. Environmental factors such as the use of chemical insecticides showed a significant correlation with decreasing genetic diversity, indicating that environmental factors affect the population structure of Ae. aegypti across time and space in these cities. Conclusions Our results suggest that two Ae. aegypti lineages are present in Colombia; one that is

  11. Liver condition of Holstein cows affects mitochondrial function and fertilization ability of oocytes

    PubMed Central

    TANAKA, Hiroshi; TAKEO, Shun; ABE, Takahito; KIN, Airi; SHIRASUNA, Koumei; KUWAYAMA, Takehito; IWATA, Hisataka

    2016-01-01

    The aim of the present study was to examine the fertilization ability and mitochondrial function of oocytes derived from cows with or without liver damage. Oocytes were collected from the ovaries of cows with damaged livers (DL) and those of cows with healthy livers (HL), subjected to in vitro maturation, and fertilized in vitro. A significantly high abnormal fertilization rate was observed for oocytes from DL cows compared to oocytes from HL cows. The time to dissolve the zona pellucida by protease before fertilization was similar between the two liver conditions, whereas after fertilization treatment this time was shorter for DL cows than for HL cows. The percentage of oocytes with equivalent cortical granule distributions underneath the membrane was greater for in vitro matured oocytes from HL cows, whereas an immature distribution pattern was observed for oocytes from DL cows. In addition, a greater percentage of oocytes derived from HL cows released cortical granules following fertilization compared with oocytes from DL cows. Mitochondrial function determined by ATP content and membrane potential were similar at the germinal vesicle stage, but post-in vitro maturation, the oocytes derived from HL cows showed higher values than DL cows. The mitochondrial DNA copy number in oocytes was similar between the two liver conditions for both the germinal vesicle and post-in vitro maturation oocytes. In conclusion, liver damage induces low fertilization, likely because of incomplete cortical granule distribution and release, and the maturation of oocytes from DL cows contain low-functioning mitochondria compared to their HL counterparts. PMID:26832309

  12. Liver condition of Holstein cows affects mitochondrial function and fertilization ability of oocytes.

    PubMed

    Tanaka, Hiroshi; Takeo, Shun; Abe, Takahito; Kin, Airi; Shirasuna, Koumei; Kuwayama, Takehito; Iwata, Hisataka

    2016-06-17

    The aim of the present study was to examine the fertilization ability and mitochondrial function of oocytes derived from cows with or without liver damage. Oocytes were collected from the ovaries of cows with damaged livers (DL) and those of cows with healthy livers (HL), subjected to in vitro maturation, and fertilized in vitro. A significantly high abnormal fertilization rate was observed for oocytes from DL cows compared to oocytes from HL cows. The time to dissolve the zona pellucida by protease before fertilization was similar between the two liver conditions, whereas after fertilization treatment this time was shorter for DL cows than for HL cows. The percentage of oocytes with equivalent cortical granule distributions underneath the membrane was greater for in vitro matured oocytes from HL cows, whereas an immature distribution pattern was observed for oocytes from DL cows. In addition, a greater percentage of oocytes derived from HL cows released cortical granules following fertilization compared with oocytes from DL cows. Mitochondrial function determined by ATP content and membrane potential were similar at the germinal vesicle stage, but post-in vitro maturation, the oocytes derived from HL cows showed higher values than DL cows. The mitochondrial DNA copy number in oocytes was similar between the two liver conditions for both the germinal vesicle and post-in vitro maturation oocytes. In conclusion, liver damage induces low fertilization, likely because of incomplete cortical granule distribution and release, and the maturation of oocytes from DL cows contain low-functioning mitochondria compared to their HL counterparts. PMID:26832309

  13. Impaired mitochondrial function in human placenta with increased maternal adiposity

    PubMed Central

    Mele, James; Muralimanoharan, Sribalasubashini; Maloyan, Alina

    2014-01-01

    The placenta plays a key role in regulation of fetal growth and development and in mediating in utero developmental programming. Obesity, which is associated with chronic inflammation and mitochondrial dysfunction in many tissues, exerts a programming effect in pregnancy. We determined the effect of increasing maternal adiposity and of fetal sex on placental ATP generation, mitochondrial biogenesis, expression of electron transport chain subunits, and mitochondrial function in isolated trophoblasts. Placental tissue was collected from women with prepregnancy BMI ranging from 18.5 to 45 following C-section at term with no labor. Increasing maternal adiposity was associated with excessive production of reactive oxygen species and a significant reduction in placental ATP levels in placentae with male and female fetuses. To explore the potential mechanism of placental mitochondrial dysfunction, levels of transcription factors regulating the expression of genes involved in electron transport and mitochondrial biogenesis were measured. Our in vitro studies showed significant reduction in mitochondrial respiration in cultured primary trophoblasts with increasing maternal obesity along with an abnormal metabolic flexibility of these cells. This reduction in placental mitochondrial respiration in pregnancies complicated by maternal obesity could compromise placental function and potentially underlie the increased susceptibility of these pregnancies to fetal demise in late gestation and to developmental programming. PMID:25028397

  14. The small GTPase Arf1 modulates mitochondrial morphology and function

    PubMed Central

    Ackema, Karin B; Hench, Jürgen; Böckler, Stefan; Wang, Shyi Chyi; Sauder, Ursula; Mergentaler, Heidi; Westermann, Benedikt; Bard, Frédéric; Frank, Stephan; Spang, Anne

    2014-01-01

    The small GTPase Arf1 plays critical roles in membrane traffic by initiating the recruitment of coat proteins and by modulating the activity of lipid-modifying enzymes. Here, we report an unexpected but evolutionarily conserved role for Arf1 and the ArfGEF GBF1 at mitochondria. Loss of function of ARF-1 or GBF-1 impaired mitochondrial morphology and activity in Caenorhabditis elegans. Similarly, mitochondrial defects were observed in mammalian and yeast cells. In Saccharomyces cerevisiae, aberrant clusters of the mitofusin Fzo1 accumulated in arf1-11 mutants and were resolved by overexpression of Cdc48, an AAA-ATPase involved in ER and mitochondria-associated degradation processes. Yeast Arf1 co-fractionated with ER and mitochondrial membranes and interacted genetically with the contact site component Gem1. Furthermore, similar mitochondrial abnormalities resulted from knockdown of either GBF-1 or contact site components in worms, suggesting that the role of Arf1 in mitochondrial functioning is linked to ER–mitochondrial contacts. Thus, Arf1 is involved in mitochondrial homeostasis and dynamics, independent of its role in vesicular traffic. PMID:25190516

  15. Mitochondrial syndromes with leukoencephalopathies.

    PubMed

    Wong, Lee-Jun C

    2012-02-01

    White matter involvement has recently been recognized as a common feature in patients with multisystem mitochondrial disorders that may be caused by molecular defects in either the mitochondrial genome or the nuclear genes. It was first realized in classical mitochondrial syndromes associated with mitochondrial DNA (mtDNA) mutations, such as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), Leigh's disease, and Kearns-Sayre's syndrome. Deficiencies in respiratory chain complexes I, II, IV, and V often cause Leigh's disease; most of them are due to nuclear defects that may lead to severe early-onset leukoencephalopathies. Defects in a group of nuclear genes involved in the maintenance of mtDNA integrity may also affect the white matter; for example, mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) caused by thymidine phosphorylase deficiency, Navajo neurohepatopathy (NNH) due to MPV17 mutations, and Alpers syndrome due to defects in DNA polymerase gamma (POLG). More recently, leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) has been reported to be caused by autosomal recessive mutations in a mitochondrial aspartyl-tRNA synthetase, DARS2 gene. A patient with leukoencephalopathy and neurologic complications in addition to a multisystem involvement warrants a complete evaluation for mitochondrial disorders. A definite diagnosis may be achieved by molecular analysis of candidate genes based on the biochemical, clinical, and imaging results. PMID:22422207

  16. Myoclonus in mitochondrial disorders.

    PubMed

    Mancuso, Michelangelo; Orsucci, Daniele; Angelini, Corrado; Bertini, Enrico; Catteruccia, Michela; Pegoraro, Elena; Carelli, Valerio; Valentino, Maria L; Comi, Giacomo P; Minetti, Carlo; Bruno, Claudio; Moggio, Maurizio; Ienco, Elena Caldarazzo; Mongini, Tiziana; Vercelli, Liliana; Primiano, Guido; Servidei, Serenella; Tonin, Paola; Scarpelli, Mauro; Toscano, Antonio; Musumeci, Olimpia; Moroni, Isabella; Uziel, Graziella; Santorelli, Filippo M; Nesti, Claudia; Filosto, Massimiliano; Lamperti, Costanza; Zeviani, Massimo; Siciliano, Gabriele

    2014-05-01

    Myoclonus is a possible manifestation of mitochondrial disorders, and its presence is considered, in association with epilepsy and the ragged red fibers, pivotal for the syndromic diagnosis of MERRF (myoclonic epilepsy with ragged red fibers). However, its prevalence in mitochondrial diseases is not known. The aims of this study are the evaluation of the prevalence of myoclonus in a big cohort of mitochondrial patients and the clinical characterization of these subjects. Based on the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases," we reviewed the clinical and molecular data of mitochondrial patients with myoclonus among their clinical features. Myoclonus is a rather uncommon clinical feature of mitochondrial diseases (3.6% of 1,086 patients registered in our database). It is not strictly linked to a specific genotype or phenotype, and only 1 of 3 patients with MERRF harbors the 8344A>G mutation (frequently labeled as "the MERRF mutation"). Finally, myoclonus is not inextricably linked to epilepsy in MERRF patients, but more to cerebellar ataxia. In a myoclonic patient, evidences of mitochondrial dysfunction must be investigated, even though myoclonus is not a common sign of mitochondriopathy. Clinical, histological, and biochemical data may predict the finding of a mitochondrial or nuclear DNA mutation. Finally, this study reinforces the notion that myoclonus is not inextricably linked to epilepsy in MERRF patients, and therefore the term "myoclonic epilepsy" seems inadequate and potentially misleading. PMID:24510442

  17. Twin Mitochondrial Sequence Analysis.

    PubMed

    Bouhlal, Yosr; Martinez, Selena; Gong, Henry; Dumas, Kevin; Shieh, Joseph T C

    2013-09-01

    When applying genome-wide sequencing technologies to disease investigation, it is increasingly important to resolve sequence variation in regions of the genome that may have homologous sequences. The human mitochondrial genome challenges interpretation given the potential for heteroplasmy, somatic variation, and homologous nuclear mitochondrial sequences (numts). Identical twins share the same mitochondrial DNA (mtDNA) from early life, but whether the mitochondrial sequence remains similar is unclear. We compared an adult monozygotic twin pair using high throughput-sequencing and evaluated variants with primer extension and mitochondrial pre-enrichment. Thirty-seven variants were shared between the twin individuals, and the variants were verified on the original genomic DNA. These studies support highly identical genetic sequence in this case. Certain low-level variant calls were of high quality and homology to the mitochondrial DNA, and they were further evaluated. When we assessed calls in pre-enriched mitochondrial DNA templates, we found that these may represent numts, which can be differentiated from mtDNA variation. We conclude that twin identity extends to mitochondrial DNA, and it is critical to differentiate between numts and mtDNA in genome sequencing, particularly since significant heteroplasmy could influence genome interpretation. Further studies on mtDNA and numts will aid in understanding how variation occurs and persists. PMID:24040623

  18. The human mitochondrial transcriptome

    PubMed Central

    Mercer, Tim R.; Neph, Shane; Dinger, Marcel E.; Crawford, Joanna; Smith, Martin A.; Shearwood, Anne-Marie J.; Haugen, Eric; Bracken, Cameron P.; Rackham, Oliver; Stamatoyannopoulos, John A.; Filipovska, Aleksandra; Mattick, John S.

    2011-01-01

    Summary The human mitochondrial genome comprises a distinct genetic system transcribed as precursor polycistronic transcripts that are subsequently cleaved to generate individual mRNAs, tRNAs and rRNAs. Here we provide a comprehensive analysis of the human mitochondrial transcriptome across multiple cell lines and tissues. Using directional deep sequencing and parallel analysis of RNA ends, we demonstrate wide variation in mitochondrial transcript abundance and precisely resolve transcript processing and maturation events. We identify previously undescribed transcripts, including small RNAs, and observe the enrichment of several nuclear RNAs in mitochondria. Using high-throughput in vivo DNaseI footprinting, we establish the global profile of DNA-binding protein occupancy across the mitochondrial genome at single nucleotide resolution, revealing regulatory features at mitochondrial transcription initiation sites and functional insights into disease-associated variants. This integrated analysis of the mitochondrial transcriptome reveals unexpected complexity in the regulation, expression, and processing of mitochondrial RNA, and provides a resource for future studies of mitochondrial function (accessed at mitochondria.matticklab.com). PMID:21854988

  19. Mutation in the Novel Nuclear-Encoded Mitochondrial Protein CHCHD10 in a Family with Autosomal Dominant Mitochondrial Myopathy

    PubMed Central

    Ajroud-Driss, Senda; Fecto, Faisal; Ajroud, Kaouther; Lalani, Irfan; Calvo, Sarah E.; Mootha, Vamsi K.; Deng, Han-Xiang; Siddique, Nailah; Tahmoush, Albert J.; Heiman-Patterson, Terry D.; Siddique, Teepu

    2016-01-01

    Mitochondrial myopathies belong to a larger group of systemic diseases caused by morphological or biochemical abnormalities of mitochondria. Mitochondrial disorders can be caused by mutations in either the mitochondrial or the nuclear genome. Only 5% of all mitochondrial disorders are autosomal dominant. We analyzed DNA from members of a previously reported Puerto Rican kindred with an autosomal dominant mitochondrial myopathy (Heimann-Patterson et al. 1997). Linkage analysis suggested a putative locus on the pericentric region of the long arm of chromosome 22 (22q11). Using the tools of integrative genomics, we established C22orf16 (later designated as CHCHD10) as the only high scoring mitochondrial candidate gene in our minimal candidate region. Sequence analysis revealed a double missense mutation (R15S; G58R) in cis in CHCHD10 which encodes a coiled-coil helix coiled-coil helix protein of unknown function. These two mutations completely co-segregated with the disease phenotype and were absent in 1481 Caucasian and 80 Hispanic (including 32 Puerto Rican) controls. Expression profiling showed that CHCHD10 is enriched in skeletal muscle. Mitochondrial localization of the CHCHD10 protein was confirmed using immunofluorescence in cells expressing either wild-type or mutant CHCHD10. We found that expression of the G58R, but not the R15S, mutation induced mitochondrial fragmentation. Our findings identify a novel gene causing mitochondrial myopathy, thereby expanding the spectrum of mitochondrial myopathies caused by nuclear genes. Our findings also suggest a role for CHCHD10 in the morphologic remodeling of the mitochondria. PMID:25193783

  20. Mitochondrial Therapeutics for Cardioprotection

    PubMed Central

    Carreira, Raquel S.; Lee, Pamela; Gottlieb, Roberta A.

    2013-01-01

    Mitochondria represent approximately one-third of the mass of the heart and play a critical role in maintaining cellular function—however, they are also a potent source of free radicals and pro-apoptotic factors. As such, maintaining mitochondrial homeostasis is essential to cell survival. As the dominant source of ATP, continuous quality control is mandatory to ensure their ongoing optimal function. Mitochondrial quality control is accomplished by the dynamic interplay of fusion, fission, autophagy, and mitochondrial biogenesis. This review examines these processes in the heart and considers their role in the context of ischemia-reperfusion injury. Interventions that modulate mitochondrial turnover, including pharmacologic agents, exercise, and caloric restriction are discussed as a means to improve mitochondrial quality control, ameliorate cardiovascular dysfunction, and enhance longevity. PMID:21718247

  1. Negative regulation of mitochondrial transcription by mitochondrial topoisomerase I

    PubMed Central

    Sobek, Stefan; Dalla Rosa, Ilaria; Pommier, Yves; Bornholz, Beatrice; Kalfalah, Faiza; Zhang, Hongliang; Wiesner, Rudolf J.; von Kleist-Retzow, Jürgen-Christoph; Hillebrand, Frank; Schaal, Heiner; Mielke, Christian; Christensen, Morten O.; Boege, Fritz

    2013-01-01

    Mitochondrial topoisomerase I is a genetically distinct mitochondria-dedicated enzyme with a crucial but so far unknown role in the homeostasis of mitochondrial DNA metabolism. Here, we present data suggesting a negative regulatory function in mitochondrial transcription or transcript stability. Deficiency or depletion of mitochondrial topoisomerase I increased mitochondrial transcripts, whereas overexpression lowered mitochondrial transcripts, depleted respiratory complexes I, III and IV, decreased cell respiration and raised superoxide levels. Acute depletion of mitochondrial topoisomerase I triggered neither a nuclear mito-biogenic stress response nor compensatory topoisomerase IIβ upregulation, suggesting the concomitant increase in mitochondrial transcripts was due to release of a local inhibitory effect. Mitochondrial topoisomerase I was co-immunoprecipitated with mitochondrial RNA polymerase. It selectively accumulated and rapidly exchanged at a subset of nucleoids distinguished by the presence of newly synthesized RNA and/or mitochondrial RNA polymerase. The inactive Y559F-mutant behaved similarly without affecting mitochondrial transcripts. In conclusion, mitochondrial topoisomerase I dampens mitochondrial transcription and thereby alters respiratory capacity. The mechanism involves selective association of the active enzyme with transcriptionally active nucleoids and a direct interaction with mitochondrial RNA polymerase. The inhibitory role of topoisomerase I in mitochondrial transcription is strikingly different from the stimulatory role of topoisomerase I in nuclear transcription. PMID:23982517

  2. Quality improvement of transgenic cloned bovine embryos using an aggregation method: Effects on cell number, cell ratio, embryo perimeter, mitochondrial distribution, and gene expression profile.

    PubMed

    Bang, J I; Jin, J I; Ghanem, N; Choi, B H; Fakruzzaman, M; Ha, A N; Lee, K L; Uhm, S J; Ko, D H; Koo, B C; Lee, J G; Kong, I K

    2015-09-01

    The production of cloned embryos using conventional methods has extremely low success rates owing to low embryo quality. To improve the quality of cloned bovine embryos expressing enhanced green fluorescent protein (EGFP), we applied an aggregation culture method. The EGFP gene was transfected into bovine fetal fibroblasts using a retroviral vector system. Somatic cell nuclear transfer was performed using these cells, and the resulting embryos were cultured in aggregates or individually. Gene expression was analyzed by a microarray, and differentially expressed genes were validated by quantitative real-time polymerase chain reaction. The total number of cells per blastocyst and the ratio of inner cell mass cells to trophectoderm cells were higher in aggregated transgenic cloned blastocysts (agBL; 368.7 ± 109.6 and 1:4.8, respectively) than in in vitro-fertilized blastocysts (ivfBL; 189.8 ± 65.8 and 1:2.6, respectively) and nonaggregated transgenic cloned blastocysts (sBL; 113.1 ± 36.3 and 1:1.5, respectively; P < 0.05 and P < 0.01, respectively). Moreover, the blastocyst perimeter was larger in the agBL group than in the ivfBL and sBL groups (1168.8 ± 200.23 vs. 887.33 ± 187.62 and 678 ± 226.1 μm; P < 0.05). In addition, mitochondrial fluorescence intensity was higher in the agBL group than in the ivfBL and sBL groups (P < 0.05). The number of apoptotic cells per blastocyst was lower in the ivfBL and agBL groups than in the sBL group (3.7 ± 2.2 and 3.4 ± 2.1 vs. 6.7 ± 6.8; P < 0.05). The genes identified in the microarray belonged to 18 categories. Expression of the Krüppel-like factor 4 gene, which is associated with cell proliferation, development, and transcription, was 7.2-fold higher in the agBL group than in the ivfBL group (P < 0.05) but did not differ between the sBL and ivfBL groups (P > 0.05). Expression of the heat shock 70-kDa protein 1A gene, which is associated with apoptosis, was 12-fold higher in the s

  3. Ictal Cardiac Ryhthym Abnormalities

    PubMed Central

    Ali, Rushna

    2016-01-01

    Cardiac rhythm abnormalities in the context of epilepsy are a well-known phenomenon. However, they are under-recognized and often missed. The pathophysiology of these events is unclear. Bradycardia and asystole are preceded by seizure onset suggesting ictal propagation into the cortex impacting cardiac autonomic function, and the insula and amygdala being possible culprits. Sudden unexpected death in epilepsy (SUDEP) refers to the unanticipated death of a patient with epilepsy not related to status epilepticus, trauma, drowning, or suicide. Frequent refractory generalized tonic-clonic seizures, anti-epileptic polytherapy, and prolonged duration of epilepsy are some of the commonly identified risk factors for SUDEP. However, the most consistent risk factor out of these is an increased frequency of generalized tonic–clonic seizures (GTC). Prevention of SUDEP is extremely important in patients with chronic, generalized epilepsy. Since increased frequency of GTCS is the most consistently reported risk factor for SUDEP, effective seizure control is the most important preventive strategy. PMID:27347227

  4. Abnormal uterine bleeding.

    PubMed

    Whitaker, Lucy; Critchley, Hilary O D

    2016-07-01

    Abnormal uterine bleeding (AUB) is a common and debilitating condition with high direct and indirect costs. AUB frequently co-exists with fibroids, but the relationship between the two remains incompletely understood and in many women the identification of fibroids may be incidental to a menstrual bleeding complaint. A structured approach for establishing the cause using the Fédération International de Gynécologie et d'Obstétrique (FIGO) PALM-COEIN (Polyp, Adenomyosis, Leiomyoma, Malignancy (and hyperplasia), Coagulopathy, Ovulatory disorders, Endometrial, Iatrogenic and Not otherwise classified) classification system will facilitate accurate diagnosis and inform treatment options. Office hysteroscopy and increasing sophisticated imaging will assist provision of robust evidence for the underlying cause. Increased availability of medical options has expanded the choice for women and many will no longer need to recourse to potentially complicated surgery. Treatment must remain individualised and encompass the impact of pressure symptoms, desire for retention of fertility and contraceptive needs, as well as address the management of AUB in order to achieve improved quality of life. PMID:26803558

  5. Mitochondrial DNA Variation Reveals a Sharp Genetic Break within the Distribution of the Blue Land Crab Cardisoma guanhumi in the Western Central Atlantic.

    PubMed

    Amaral, Maria Rosimere Xavier; Albrecht, Marc; McKinley, Alan Shane; de Carvalho, Adriana Márcia Ferreira; de Sousa Junior, Severino Cavalcante; Diniz, Fabio Mendonça

    2015-01-01

    The blue land crab Cardisoma guanhumi is widely distributed throughout tropical and subtropical estuarine regions in the Western Central Atlantic (WCA). Patterns of population genetic structure and historical demographics of the species were assessed by mtDNA control region sequence analysis to examine the connectivity among five populations (n = 97) within the region for future conservation strategies and decision-making of fishery management. A total of 234 polymorphic nucleotides were revealed within the sequence region, which have defined 93 distinct haplotypes. No dominant mtDNA haplotypes were found but instead a distribution of a few low-frequency recurrent haplotypes with a large number of singletons. A NJ-tree and a median-joining haplotype network revealed two distinct clusters, corresponding to individuals from estuaries located along the Caribbean Sea and Brazilian waters, respectively. AMOVA and FST statistics supported the hypothesis that two main geographic regions exists. Phylogeographical discontinuity was further demonstrated by the Bayesian assignment analysis and a significant pattern of isolation-by-distance. Additionally, tests of neutral evolution and analysis of mismatch distribution indicate a complex demographic history in the WCA, which corresponds to bottleneck and subsequent population growth. Overall, a sharp genetic break between Caribbean and Brazilian populations raised concerns over the conservation status of the blue land crab. PMID:26295384

  6. Treatment of Mitochondrial Disorders

    PubMed Central

    Avula, Sreenivas; Parikh, Sumit; Demarest, Scott; Kurz, Jonathan; Gropman, Andrea

    2014-01-01

    Opinion statement While numerous treatments for mitochondrial disorders have been suggested, relatively few have undergone controlled clinical trials. Treatment of these disorders is challenging, as only symptomatic therapy is available. In this review we will focus on newer drugs and treatment trials in mitochondrial diseases, with a special focus on medications to avoid in treating epilepsy and ICU patient with mitochondrial disease, which has not been included in such a review. Readers are also referred to the opinion statement in A Modern Approach to the Treatment of Mitochondrial Disease published in Current Treatment Options in Neurology 2009. Many of the supplements used for treatment were reviewed in the previous abstract, and dosing guidelines were provided. The focus of this review is on items not previously covered in depth, and our discussion includes more recently studied compounds as well as any relevant updates on older compounds. We review a variety of vitamins and xenobiotics, including dichloroacetate (DCA), arginine, coenzyme Q10, idebenone, EPI-743, and exercise training. Treatment of epilepsy, which is a common feature in many mitochondrial phenotypes, warrants special consideration due to the added toxicity of certain medications, and we provide a discussion of these unique treatment challenges. Interesting, however, with only a few exceptions, the treatment strategies for epilepsy in mitochondrial cytopathies are the same as for epilepsy without mitochondrial dysfunction. We also discuss intensive care management, building upon similar reviews, adding new dimensions, and demonstrating the complexity of overall care of these patients. PMID:24700433

  7. Electrocardiograph abnormalities revealed during laparoscopy

    PubMed Central

    Nijjer, Sukhjinder; Dubrey, Simon William

    2010-01-01

    This brief case presents a well patient in whom an electrocardiograph abnormality consistent with an accessory pathway was found during a routine procedure. We present the electrocardiographs, explain the underlying condition, and consider why the abnormality was revealed in this manner. PMID:22419949

  8. Abnormal pressure in hydrocarbon environments

    USGS Publications Warehouse

    Law, B.E.; Spencer, C.W.

    1998-01-01

    Abnormal pressures, pressures above or below hydrostatic pressures, occur on all continents in a wide range of geological conditions. According to a survey of published literature on abnormal pressures, compaction disequilibrium and hydrocarbon generation are the two most commonly cited causes of abnormally high pressure in petroleum provinces. In young (Tertiary) deltaic sequences, compaction disequilibrium is the dominant cause of abnormal pressure. In older (pre-Tertiary) lithified rocks, hydrocarbon generation, aquathermal expansion, and tectonics are most often cited as the causes of abnormal pressure. The association of abnormal pressures with hydrocarbon accumulations is statistically significant. Within abnormally pressured reservoirs, empirical evidence indicates that the bulk of economically recoverable oil and gas occurs in reservoirs with pressure gradients less than 0.75 psi/ft (17.4 kPa/m) and there is very little production potential from reservoirs that exceed 0.85 psi/ft (19.6 kPa/m). Abnormally pressured rocks are also commonly associated with unconventional gas accumulations where the pressuring phase is gas of either a thermal or microbial origin. In underpressured, thermally mature rocks, the affected reservoirs have most often experienced a significant cooling history and probably evolved from an originally overpressured system.

  9. Mitochondrial diseases and epilepsy.

    PubMed

    Bindoff, Laurence A; Engelsen, Bernt A

    2012-09-01

    The mitochondrial respiratory chain is the final common pathway for energy production. Defects affecting this pathway can give rise to disease that presents at any age and affects any tissue. However, irrespective of genetic defect, epilepsy is common and there is a significant risk of status epilepticus. This review summarizes our current understanding of the epilepsy that occurs in mitochondrial disease, focusing on three of the most common disorders: mitochondrial myopathy encephalopathy, lactic acidosis and stroke-like episodes (MELAS), myoclonus epilepsy and ragged-red fibers (MERRF), and polymerase gamma (POLG) related disease. In addition, we review the pathogenesis and possible treatment of these disorders. PMID:22946726

  10. A novel mitochondrial sphingomyelinase in zebrafish cells.

    PubMed

    Yabu, Takeshi; Shimuzu, Akio; Yamashita, Michiaki

    2009-07-24

    Sphingolipids are important signaling molecules in many biological processes, but little is known regarding their physiological roles in the mitochondrion. We focused on the biochemical characters of a novel sphingomyelinase (SMase) and its function in mitochondrial ceramide generation in zebrafish embryonic cells. The cloned SMase cDNA encoded a polypeptide of 545 amino acid residues (putative molecular weight, 61,300) containing a mitochondrial localization signal (MLS) and a predicted transmembrane domain. The mature endogenous enzyme was predicted to have a molecular weight of 57,000, and matrix-assisted laser de sorption ionization time-of-flight mass spectrometry analysis indicated that the N-terminal amino acid residue of the mature enzyme was Ala-36. The purified enzyme optimally hydrolyzed [(14)C]sphingomyelin in the presence of 10 mm Mg(2+) at pH 7.5. In HEK293 cells that overexpressed SMase cDNA, the enzyme was localized to the mitochondrial fraction, whereas mutant proteins lacking MLS or both the MLS and the transmembrane domain were absent from the mitochondrial fraction. Endogenous SMase protein co-localized with a mitochondrial cytostaining marker. Using a protease protection assay, we found that SMase was distributed throughout the intermembrane space and/or the inner membrane of the mitochondrion. Furthermore, the overexpression of SMase in HEK293 cells induced ceramide generation and sphingomyelin hydrolysis in the mitochondrial fraction. Antisense phosphorothioate oligonucleotide-induced knockdown repressed ceramide generation and sphingomyelin hydrolysis in the mitochondrial fraction in zebrafish embryonic cells. These observations indicate that SMase catalyzes the hydrolysis of sphingomyelin and generates ceramide in mitochondria in fish cells. PMID:19429680

  11. Mitochondrial biogenesis: pharmacological approaches.

    PubMed

    Valero, Teresa

    2014-01-01

    Organelle biogenesis is concomitant to organelle inheritance during cell division. It is necessary that organelles double their size and divide to give rise to two identical daughter cells. Mitochondrial biogenesis occurs by growth and division of pre-existing organelles and is temporally coordinated with cell cycle events [1]. However, mitochondrial biogenesis is not only produced in association with cell division. It can be produced in response to an oxidative stimulus, to an increase in the energy requirements of the cells, to exercise training, to electrical stimulation, to hormones, during development, in certain mitochondrial diseases, etc. [2]. Mitochondrial biogenesis is therefore defined as the process via which cells increase their individual mitochondrial mass [3]. Recent discoveries have raised attention to mitochondrial biogenesis as a potential target to treat diseases which up to date do not have an efficient cure. Mitochondria, as the major ROS producer and the major antioxidant producer exert a crucial role within the cell mediating processes such as apoptosis, detoxification, Ca2+ buffering, etc. This pivotal role makes mitochondria a potential target to treat a great variety of diseases. Mitochondrial biogenesis can be pharmacologically manipulated. This issue tries to cover a number of approaches to treat several diseases through triggering mitochondrial biogenesis. It contains recent discoveries in this novel field, focusing on advanced mitochondrial therapies to chronic and degenerative diseases, mitochondrial diseases, lifespan extension, mitohormesis, intracellular signaling, new pharmacological targets and natural therapies. It contributes to the field by covering and gathering the scarcely reported pharmacological approaches in the novel and promising field of mitochondrial biogenesis. There are several diseases that have a mitochondrial origin such as chronic progressive external ophthalmoplegia (CPEO) and the Kearns- Sayre syndrome (KSS

  12. Schwann cell mitochondrial metabolism supports long-term axonal survival and peripheral nerve function

    PubMed Central

    Viader, Andreu; Golden, Judith P.; Baloh, Robert H.; Schmidt, Robert E.; Hunter, Daniel A.; Milbrandt, Jeffrey

    2011-01-01

    Mitochondrial dysfunction is a common cause of peripheral neuropathies. While the role of neuron and axonal mitochondria in peripheral nerve disease is well appreciated, whether Schwann cell (SC) mitochondrial deficits contribute to peripheral neuropathies is unclear. Here we examine how SC mitochondrial dysfunction affects axonal survival and contributes to the decline of peripheral nerve function by generating mice with SC-specific mitochondrial deficits. These mice (Tfam-SCKOs) were produced through the tissue-specific deletion of the mitochondrial transcription factor A gene (Tfam), which is essential for mitochondrial DNA (mtDNA) transcription and maintenance. Tfam-SCKOs were viable but, as they aged, they developed a progressive peripheral neuropathy characterized by nerve conduction abnormalities as well as extensive muscle denervation. Morphological examination of Tfam-SCKO nerves revealed early preferential loss of small unmyelinated fibers followed by prominent demyelination and degeneration of larger-caliber axons. Tfam-SCKOs displayed sensory and motor deficits consistent with this pathology. Remarkably, the severe mtDNA depletion and respiratory chain abnormalities in Tfam-SCKO mice did not affect SC proliferation or survival. Mitochondrial function in SCs is therefore essential for maintenance of axonal survival and normal peripheral nerve function, suggesting that SC mitochondrial dysfunction contributes to human peripheral neuropathies. PMID:21752989

  13. Translating the basic knowledge of mitochondrial functions to metabolic therapy: role of L-carnitine.

    PubMed

    Marcovina, Santica M; Sirtori, Cesare; Peracino, Andrea; Gheorghiade, Mihai; Borum, Peggy; Remuzzi, Giuseppe; Ardehali, Hossein

    2013-02-01

    Mitochondria play important roles in human physiological processes, and therefore, their dysfunction can lead to a constellation of metabolic and nonmetabolic abnormalities such as a defect in mitochondrial gene expression, imbalance in fuel and energy homeostasis, impairment in oxidative phosphorylation, enhancement of insulin resistance, and abnormalities in fatty acid metabolism. As a consequence, mitochondrial dysfunction contributes to the pathophysiology of insulin resistance, obesity, diabetes, vascular disease, and chronic heart failure. The increased knowledge on mitochondria and their role in cellular metabolism is providing new evidence that these disorders may benefit from mitochondrial-targeted therapies. We review the current knowledge of the contribution of mitochondrial dysfunction to chronic diseases, the outcomes of experimental studies on mitochondrial-targeted therapies, and explore the potential of metabolic modulators in the treatment of selected chronic conditions. As an example of such modulators, we evaluate the efficacy of the administration of L-carnitine and its analogues acetyl and propionyl L-carnitine in several chronic diseases. L-carnitine is intrinsically involved in mitochondrial metabolism and function as it plays a key role in fatty acid oxidation and energy metabolism. In addition to the transportation of free fatty acids across the inner mitochondrial membrane, L-carnitine modulates their oxidation rate and is involved in the regulation of vital cellular functions such as apoptosis. Thus, L-carnitine and its derivatives show promise in the treatment of chronic conditions and diseases associated with mitochondrial dysfunction but further translational studies are needed to fully explore their potential. PMID:23138103

  14. Alterations of Mitochondrial Function and Insulin Sensitivity in Human Obesity and Diabetes Mellitus.

    PubMed

    Koliaki, Chrysi; Roden, Michael

    2016-07-17

    Mitochondrial function refers to a broad spectrum of features such as resting mitochondrial activity, (sub)maximal oxidative phosphorylation capacity (OXPHOS), and mitochondrial dynamics, turnover, and plasticity. The interaction between mitochondria and insulin sensitivity is bidirectional and varies depending on tissue, experimental model, methodological approach, and features of mitochondrial function tested. In human skeletal muscle, mitochondrial abnormalities may be inherited (e.g., lower mitochondrial content) or acquired (e.g., impaired OXPHOS capacity and plasticity). Abnormalities ultimately lead to lower mitochondrial functionality due to or resulting in insulin resistance and type 2 diabetes mellitus. Similar mechanisms can also operate in adipose tissue and heart muscle. In contrast, mitochondrial oxidative capacity is transiently upregulated in the liver of obese insulin-resistant humans with or without fatty liver, giving rise to oxidative stress and declines in advanced fatty liver disease. These data suggest a highly tissue-specific interaction between insulin sensitivity and oxidative metabolism during the course of metabolic diseases in humans. PMID:27146012

  15. Mitochondrial dynamics and the cell cycle

    PubMed Central

    Kianian, Penny M. A.; Kianian, Shahryar F.

    2014-01-01

    Nuclear-mitochondrial (NM) communication impacts many aspects of plant development including vigor, sterility, and viability. Dynamic changes in mitochondrial number, shape, size, and cellular location takes place during the cell cycle possibly impacting the process itself and leading to distribution of this organelle into daughter cells. The genes that underlie these changes are beginning to be identified in model plants such as Arabidopsis. In animals disruption of the drp1 gene, a homolog to the plant drp3A and drp3B, delays mitochondrial division. This mutation results in increased aneuploidy due to chromosome mis-segregation. It remains to be discovered if a similar outcome is observed in plants. Alloplasmic lines provide an opportunity to understand the communication between the cytoplasmic organelles and the nucleus. Examples of studies in these lines, especially from the extensive collection in wheat, point to the role of mitochondria in chromosome movement, pollen fertility and other aspects of development. PMID:24904617

  16. Loss of the mitochondrial protein-only ribonuclease P complex causes aberrant tRNA processing and lethality in Drosophila.

    PubMed

    Sen, Aditya; Karasik, Agnes; Shanmuganathan, Aranganathan; Mirkovic, Elena; Koutmos, Markos; Cox, Rachel T

    2016-07-27

    Proteins encoded by mitochondrial DNA are translated using mitochondrially encoded tRNAs and rRNAs. As with nuclear encoded tRNAs, mitochondrial tRNAs must be processed to become fully functional. The mitochondrial form of ribonuclease P (mt:RNase P) is responsible for 5'-end maturation and is comprised of three proteins; mitochondrial RNase P protein (MRPP) 1 and 2 together with proteinaceous RNase P (PRORP). However, its mechanism and impact on development is not yet known. Using homology searches, we have identified the three proteins composing Drosophila mt:RNase P: Mulder (PRORP), Scully (MRPP2) and Roswell (MRPP1). Here, we show that each protein is essential and localizes with mitochondria. Furthermore, reducing levels of each causes mitochondrial deficits, which appear to be due at least in part to defective mitochondrial tRNA processing. Overexpressing two members of the complex, Mulder and Roswell, is also lethal, and in the case of Mulder, causes abnormal mitochondrial morphology. These data are the first evidence that defective mt:RNase P causes mitochondrial dysfunction, lethality and aberrant mitochondrial tRNA processing in vivo, underscoring its physiological importance. This in vivo mt:RNase P model will advance our understanding of how loss of mitochondrial tRNA processing causes tissue failure, an important aspect of human mitochondrial disease. PMID:27131785

  17. Alteration of nucleotide metabolism: a new mechanism for mitochondrial disorders.

    PubMed

    Martí, Ramon; Nishigaki, Yutaka; Vilá, Maya R; Hirano, Michio

    2003-07-01

    Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP). TP deficiency alters the metabolism of the nucleosides thymidine and deoxyuridine, which, in turn, produces abnormalities of mitochondrial DNA (mtDNA) including depletion, deletions, and point mutations. MNGIE is the best characterized of the expanding number of mitochondrial disorders caused by alterations in the metabolism of nucleosides/nucleotides. Because mitochondria contain their own machinery for nucleoside and nucleotide metabolism and have physically separate nucleotide pools, it is not surprising that disorders of these pathways cause human diseases. Other diseases in this group include mtDNA depletion syndromes caused by mutations on the nuclear genes encoding the mitochondrial thymidine kinase and deoxyguanosine kinase; autosomal dominant progressive external ophthalmoplegia with multiple deletions of mtDNA due to mutations in the genes encoding the muscle-isoform of mitochondrial ADP/ATP translocator; and mitochondrial DNA depletion due to toxicities of nucleoside analogues. Mutations in the deoxynucleotide carrier, a transporter of deoxynucleoside diphosphates, have been identified as a cause of congenital microcephaly. However, alterations of mtDNA have not yet been established in this disorder. Future studies are likely to reveal additional diseases and provide further insight into this new subject. PMID:12940507

  18. Dysfunctional Mitochondrial Dynamics in the Pathophysiology of Neurodegenerative Diseases

    PubMed Central

    Haun, Florian; Nakamura, Tomohiro; Lipton, Stuart A

    2013-01-01

    Mitochondrial dysfunction occurs in neurodegenerative diseases, however molecular mechanisms underlying this process remain elusive. Emerging evidence suggests that nitrosative stress, mediated by reactive nitrogen species (RNS), may play a role in mitochondrial pathology. Here, we review findings that highlight the abnormal mitochondrial morphology observed in many neurodegenerative disorders including Alzheimer’s, Parkinson’s, and Huntington’s diseases. One mechanism whereby RNS can affect mitochondrial function and thus neuronal survival occurs via protein S-nitrosylation, representing chemical reaction of a nitric oxide (NO) group with a critical cysteine thiol. In this review, we focus on the signaling pathway whereby S-nitrosylation of the mitochondrial fission protein Drp1 (dynamin-related protein 1; forming S-nitrosothiol (SNO)-Drp1) precipitates excessive mitochondrial fission or fragmentation and consequent bioenergetic compromise. Subsequently, the formation of SNO-Drp1 leads to synaptic damage and neuronal death. Thus, intervention in the SNO-Drp1 pathway may provide therapeutic benefit in neurodegenerative diseases. PMID:24587691

  19. Mitochondrial dysfunction in psychiatric morbidity: current evidence and therapeutic prospects

    PubMed Central

    Toker, Lilach; Agam, Galila

    2015-01-01

    Cumulating evidence for the involvement of mitochondrial dysfunction in psychiatric disorders leaves little to no doubt regarding the involvement of this pathology in mood disorders. However, mitochondrial abnormalities are also observed in a wide range of disorders spanning from cancer and diabetes to various neurodegenerative and neurodevelopmental disorders such as Parkinson’s, Alzheimer’s, Huntington’s, autism, and amyotrophic lateral sclerosis. The apparent lack of specificity questions the role of mitochondrial dysfunction in psychiatric disorders, in general, and in mood disorders, in particular. Is mitochondrial dysfunction a general phenomenon, simplistically rendering brain cells to be more vulnerable to a variety of disease-specific perturbations? Or is it an epiphenomenon induced by various disease-specific factors? Or possibly, the severity and the anatomical region of the dysfunction are the ones responsible for the distinct features of the disorders. Whichever of the aforementioned ones, if any, is correct, “mitochondrial dysfunction” became more of a cliché than a therapeutic target. In this review, we summarize current studies supporting the involvement of mitochondrial dysfunction in different psychiatric disorders. We address the question of specificity and causality of the different findings and provide an alternative explanation for some of the aforementioned questions. PMID:26442764

  20. Deficient Autophagy Results in Mitochondrial Dysfunction and FSGS.

    PubMed

    Kawakami, Takahisa; Gomez, Ivan G; Ren, Shuyu; Hudkins, Kelly; Roach, Allie; Alpers, Charles E; Shankland, Stuart J; D'Agati, Vivette D; Duffield, Jeremy S

    2015-05-01

    FSGS is a heterogeneous fibrosing disease of the kidney, the cause of which remains poorly understood. In most cases, there is no effective treatment to halt or retard progression to renal failure. Increasing evidence points to mitochondrial dysfunction and the generation of reactive oxygen species in the pathogenesis of CKD. Autophagy, a major intracellular lysosomal degradation system, performs homeostatic functions linked to metabolism and organelle turnover. We prevented normal autophagic pathways in nephrons of mice by mutating critical autophagy genes ATG5 or ATG7 during nephrogenesis. Mutant mice developed mild podocyte and tubular dysfunction within 2 months, profound glomerular and tubular changes bearing close similarity to human disease by 4 months, and organ failure by 6 months. Ultrastructurally, podocytes and tubular cells showed vacuolization, abnormal mitochondria, and evidence of endoplasmic reticulum stress, features that precede the appearance of histologic or clinical disease. Similar changes were observed in human idiopathic FSGS kidney biopsy specimens. Biochemical analysis of podocytes and tubules of 2-month-old mutant mice revealed elevated production of reactive oxygen species, activation of endoplasmic reticulum stress pathways, phosphorylation of p38, and mitochondrial dysfunction. Furthermore, cultured proximal tubule cells isolated from mutant mice showed marked mitochondrial dysfunction and elevated mitochondrial reactive oxygen species generation that was suppressed by a mitochondrial superoxide scavenger. We conclude that mitochondrial dysfunction and endoplasmic reticulum stress due to impaired autophagic organelle turnover in podocytes and tubular epithelium are sufficient to cause many of the manifestations of FSGS in mice. PMID:25406339

  1. Deficient Autophagy Results in Mitochondrial Dysfunction and FSGS

    PubMed Central

    Kawakami, Takahisa; Gomez, Ivan G.; Ren, Shuyu; Hudkins, Kelly; Roach, Allie; Alpers, Charles E.; Shankland, Stuart J.; D’Agati, Vivette D.

    2015-01-01

    FSGS is a heterogeneous fibrosing disease of the kidney, the cause of which remains poorly understood. In most cases, there is no effective treatment to halt or retard progression to renal failure. Increasing evidence points to mitochondrial dysfunction and the generation of reactive oxygen species in the pathogenesis of CKD. Autophagy, a major intracellular lysosomal degradation system, performs homeostatic functions linked to metabolism and organelle turnover. We prevented normal autophagic pathways in nephrons of mice by mutating critical autophagy genes ATG5 or ATG7 during nephrogenesis. Mutant mice developed mild podocyte and tubular dysfunction within 2 months, profound glomerular and tubular changes bearing close similarity to human disease by 4 months, and organ failure by 6 months. Ultrastructurally, podocytes and tubular cells showed vacuolization, abnormal mitochondria, and evidence of endoplasmic reticulum stress, features that precede the appearance of histologic or clinical disease. Similar changes were observed in human idiopathic FSGS kidney biopsy specimens. Biochemical analysis of podocytes and tubules of 2-month-old mutant mice revealed elevated production of reactive oxygen species, activation of endoplasmic reticulum stress pathways, phosphorylation of p38, and mitochondrial dysfunction. Furthermore, cultured proximal tubule cells isolated from mutant mice showed marked mitochondrial dysfunction and elevated mitochondrial reactive oxygen species generation that was suppressed by a mitochondrial superoxide scavenger. We conclude that mitochondrial dysfunction and endoplasmic reticulum stress due to impaired autophagic organelle turnover in podocytes and tubular epithelium are sufficient to cause many of the manifestations of FSGS in mice. PMID:25406339

  2. Mitochondrial Ryanodine Receptors and Other Mitochondrial Ca2+ Permeable Channels

    PubMed Central

    Ryu, Shin-Young; Beutner, Gisela; Dirksen, Robert T.; Kinnally, Kathleen W.; Sheu, Shey-Shing

    2010-01-01

    Ca2+ channels that underlie mitochondrial Ca2+ transport first reported decades ago have now just recently been precisely characterized electrophysiologically. Numerous data indicate that mitochondrial Ca2+ uptake via these channels regulates multiple intracellular processes by shaping cytosolic and mitochondrial Ca2+ transients, as well as altering the cellular metabolic and redox state. On the other hand, mitochondrial Ca2+ overload also initiates a cascade of events that leads to cell death. Thus, characterization of mitochondrial Ca2+ channels is central to a comprehensive understanding of cell signaling. Here, we discuss recent progresses in the biophysical and electrophysiological characterization of several distinct mitochondrial Ca2+ channels. PMID:20096690

  3. The Role of Brain MRI in Mitochondrial Neurogastrointestinal Encephalomyopathy

    PubMed Central

    Scarpelli, Mauro; Ricciardi, Giuseppe Kenneth; Beltramello, Alberto; Zocca, Isabella; Calabria, Francesca; Russignan, Anna; Zappini, Francesca; Cotelli, Maria Sofia; Padovani, Alessandro; Tomelleri, Giuliano; Filosto, Massimiliano; Tonin, Paola

    2013-01-01

    Summary Leukoencephalopathy is a hallmark of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) a devastating disorder characterized by ptosis, ophthalmoparesis, gastrointestinal dysfunction and polyneuropathy. To characterize MNGIE-associated leukoencephalopathy and to correlate it with clinical, biochemical and molecular data, four MNGIE patients with heterogeneous clinical phenotypes (enteropathic arthritis, exercise intolerance, CIDP-like phenotype and typical presentation) were studied by magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Diffusion weighted imaging (DWI) with apparent diffusion coefficient (ADC) maps were also obtained. In two patients we also investigated the role of brain MRI in monitoring the evolution of leukoencephalopathy by performing follow-up imaging studies at an interval of one and two years. The extension and distribution of leukoencephalopathy were not clearly linked with age, phenotype or disease severity, and did not seem to be related to TYMP mutations, enzyme activity or pyrimidine levels. In the studied patients MRS revealed reduced N-acetyl-aspartate and increased choline signals. Although DWI appeared normal in all patients but one, ADC maps always showed moderate increased diffusivity. Leukoencephalopathy worsened over a two-year period in two patients, regardless of the clinical course, indicating a lack of correlation between clinical phenotype, size and progression of white matter abnormalities during this period. Brain MRI should be considered a very useful tool to diagnose both classical and atypical MNGIE. Serial MRIs in untreated and treated MNGIE patients will help to establish whether the leukoencephalopathy is a reversible condition or not. PMID:24199812

  4. The pathophysiology of mitochondrial disease as modeled in the mouse

    PubMed Central

    Wallace, Douglas C.; Fan, WeiWei

    2009-01-01

    It is now clear that mitochondrial defects are associated with a plethora of clinical phenotypes in man and mouse. This is the result of the mitochondria's central role in energy production, reactive oxygen species (ROS) biology, and apoptosis, and because the mitochondrial genome consists of roughly 1500 genes distributed across the maternal mitochondrial DNA (mtDNA) and the Mendelian nuclear DNA (nDNA). While numerous pathogenic mutations in both mtDNA and nDNA mitochondrial genes have been identified in the past 21 years, the causal role of mitochondrial dysfunction in the common metabolic and degenerative diseases, cancer, and aging is still debated. However, the development of mice harboring mitochondrial gene mutations is permitting demonstration of the direct cause-and-effect relationship between mitochondrial dysfunction and disease. Mutations in nDNA-encoded mitochondrial genes involved in energy metabolism, antioxidant defenses, apoptosis via the mitochondrial permeability transition pore (mtPTP), mitochondrial fusion, and mtDNA biogenesis have already demonstrated the phenotypic importance of mitochondrial defects. These studies are being expanded by the recent development of procedures for introducing mtDNA mutations into the mouse. These studies are providing direct proof that mtDNA mutations are sufficient by themselves to generate major clinical phenotypes. As more different mtDNA types and mtDNA gene mutations are introduced into various mouse nDNA backgrounds, the potential functional role of mtDNA variation in permitting humans and mammals to adapt to different environments and in determining their predisposition to a wide array of diseases should be definitively demonstrated. PMID:19651984

  5. Differences in the Kinetic of the First Meiotic Division and in Active Mitochondrial Distribution between Prepubertal and Adult Oocytes Mirror Differences in their Developmental Competence in a Sheep Model

    PubMed Central

    Leoni, Giovanni Giuseppe; Palmerini, Maria Grazia; Satta, Valentina; Succu, Sara; Pasciu, Valeria; Zinellu, Angelo; Carru, Ciriaco; Macchiarelli, Guido; Nottola, Stefania Annarita; Naitana, Salvatore; Berlinguer, Fiammetta

    2015-01-01

    Our aim is to verify if oocyte developmental potential is related to the timing of meiotic progression and to mitochondrial distribution and activity using prepubertal and adult oocytes as models of low and high developmental capacity respectively. Prepubertal and adult oocytes were incorporated in an in vitro maturation system to determine meiotic and developmental competence and to assess at different time points kinetic of meiotic maturation, 2D protein electrophoresis patterns, ATP content and mitochondria distribution. Maturation and fertilization rates did not differ between prepubertal and adult oocytes (95.1% vs 96.7% and 66.73% vs 70.62% respectively for prepubertal and adult oocytes). Compared to adults, prepubertal oocytes showed higher parthenogenesis (17.38% vs 2.08% respectively in prepubertals and adults; P<0.01) and polispermy (14.30% vs 2.21% respectively in prepubertals and adults; P<0.01), lower cleavage rates (60.00% vs 67.08% respectively in prepubertals and adults; P<0.05) and blastocyst output (11.94% vs 34.% respectively in prepubertals and adults; P<0.01). Prepubertal oocytes reached MI stage 1 hr later than adults and this delay grows as the first meiotic division proceeds. Simultaneously, the protein pattern was altered since in prepubertal oocytes it fluctuates, dropping and rising to levels similar to adults only at 24 hrs. In prepubertal oocytes ATP rise is delayed and did not reach levels comparable to adult ones. CLSM observations revealed that at MII, in the majority of prepubertal oocytes, the active mitochondria are homogenously distributed, while in adults they are aggregated in big clusters. Our work demonstrates that mitochondria and their functional aggregation during maturation play an active role to provide energy in terms of ATP. The oocyte ATP content determines the timing of the meiotic cycle and the acquisition of developmental competence. Taken together our data suggest that oocytes with low developmental competence

  6. Treatments for Biomedical Abnormalities Associated with Autism Spectrum Disorder

    PubMed Central

    Frye, Richard Eugene; Rossignol, Daniel A.

    2014-01-01

    Recent studies point to the effectiveness of novel treatments that address physiological abnormalities associated with autism spectrum disorder (ASD). This is significant because safe and effective treatments for ASD remain limited. These physiological abnormalities as well as studies addressing treatments of these abnormalities are reviewed in this article. Treatments commonly used to treat mitochondrial disease have been found to improve both core and associated ASD symptoms. Double-blind, placebo-controlled (DBPC) studies have investigated l-carnitine and a multivitamin containing B vitamins, antioxidants, vitamin E, and co-enzyme Q10 while non-blinded studies have investigated ubiquinol. Controlled and uncontrolled studies using folinic acid, a reduced form of folate, have reported marked improvements in core and associated ASD symptoms in some children with ASD and folate related pathway abnormities. Treatments that could address redox metabolism abnormalities include methylcobalamin with and without folinic acid in open-label studies and vitamin C and N-acetyl-l-cysteine in DBPC studies. These studies have reported improved core and associated ASD symptoms with these treatments. Lastly, both open-label and DBPC studies have reported improvements in core and associated ASD symptoms with tetrahydrobiopterin. Overall, these treatments were generally well-tolerated without significant adverse effects for most children, although we review the reported adverse effects in detail. This review provides evidence for potentially safe and effective treatments for core and associated symptoms of ASD that target underlying known physiological abnormalities associated with ASD. Further research is needed to define subgroups of children with ASD in which these treatments may be most effective as well as confirm their efficacy in DBPC, large-scale multicenter studies. PMID:25019065

  7. How mitochondrial dynamism orchestrates mitophagy

    PubMed Central

    Shirihai, Orian; Song, Moshi; Dorn, Gerald W

    2015-01-01

    Mitochondria are highly dynamic, except in adult cardiomyocytes. Yet, the fission and fusion-promoting proteins that mediate mitochondrial dynamism are highly expressed in, and essential to the normal functioning of, hearts. Here, we review accumulating evidence supporting important roles for mitochondrial fission and fusion in cardiac mitochondrial quality control, focusing on the PINK1-Parkin mitophagy pathway.Based in part on recent findings from in vivo mouse models in which mitofusin-mediated mitochondrial fusion or Drp1-mediated mitochondrial fission were conditionally interrupted in cardiac myocytes, we propose several new concepts that may provide insight into the cardiac mitochondrial dynamism-mitophagy interactome. PMID:25999423

  8. Molecular Genetics of Mitochondrial Biogenesis in Maize.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The mitochondrial genome encodes proteins essential for mitochondrial respiration and ATP synthesis. Nuclear gene products, however, are required for the expression of mitochondrial genes and the elaboration of functional mitochondrial protein complexes. We are exploiting a unique collection of maiz...

  9. Multiorgan disorder syndrome (MODS) in an octagenarian suggests mitochondrial disorder.

    PubMed

    Finsterer, Josef; Bastovansky, Adam

    2015-09-01

    Non-syndromic, multi-organ mitochondrial disorders (MIDs) are frequently missed if treating physicians are not aware of them. We report a 85 years old Caucasian male, referred for tonic-clonic seizures, presenting with a plethora of abnormalities, including neurodermitis, atopic dermatitis, diabetes, hypertension, renal insufficiency, non-specific colitis, urine bladder lithiasis, bilateral cataracts, atrial fibrillation, diverticulosis, polyneuropathy, vitamin-D-deficiency, renal cysts, left anterior hemi-block, right bundle branch block, pulmonary artery hypertension, and heart failure. Neurological investigations revealed ptosis, quadriparesis, fasciculations, dysarthria, dysdiadochokinesia, tremor, hyperkinesia, ataxia, leukoencephalopathy, and basal ganglia calcification. Based upon this combination of abnormalities a non-syndromic mitochondrial multi-organ disorder syndrome (MIMODS, encephalo-myo-cardiomyopathy) was diagnosed. PMID:26530206

  10. Mitochondrial Dysfunction may explain symptom variation in Phelan-McDermid Syndrome

    PubMed Central

    Frye, Richard E.; Cox, Devin; Slattery, John; Tippett, Marie; Kahler, Stephen; Granpeesheh, Doreen; Damle, Shirish; Legido, Agustin; Goldenthal, Michael J.

    2016-01-01

    Phelan-McDermid Syndrome (PMS), which is defined by a deletion within 22q13, demonstrates significant phenotypic variation. Given that six mitochondrial genes are located within 22q13, including complex I and IV genes, we hypothesize that mitochondrial complex activity abnormalities may explain phenotypic variation in PMS symptoms. Complex I, II, II + III and IV activity was measured in 51 PMS participants. Caretakers completed questionnaires and provided genetic information through the PMS foundation registry. Complex activity was abnormal in 59% of PMS participants. Abnormalities were found in complex I and IV but not complex II + III and II activity, consistent with disruption of genes within the 22q13 region. However, complex activity abnormalities were not related to specific gene deletions suggesting a “neighboring effect” of regional deletions on adjacent gene expression. A specific combination of symptoms (autism spectrum disorder, developmental regression, failure-to-thrive, exercise intolerance/fatigue) was associated with complex activity abnormalities. 64% of 106 individuals in the PMS foundation registry who did not have complex activity measured also endorsed this pattern of symptoms. These data suggest that mitochondrial abnormalities, specifically abnormalities in complex I and IV activity, may explain some phenotypic variation in PMS individuals. These results point to novel pathophysiology mechanisms and treatment targets for PMS patients. PMID:26822410

  11. Thymidine phosphorylase mutations cause instability of mitochondrial DNA.

    PubMed

    Hirano, Michio; Lagier-Tourenne, Clotilde; Valentino, Maria L; Martí, Ramon; Nishigaki, Yutaka

    2005-07-18

    Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder characterized by ptosis and progressive external ophthalmoplegia, peripheral neuropathy, severe gastrointestinal dysmotility, cachexia and leukoencephalopathy. Muscle biopsies of MNGIE patients have revealed morphologically abnormal mitochondria and defects of respiratory chain enzymes. In addition, patients harbor depletion, multiple deletions, and point mutations of mitochondrial DNA (mtDNA). This disorder is caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP) a cytosolic enzyme. In MNGIE patients, TP activity is very low or absent resulting in dramatically elevated levels of plasma thymidine and deoxyuridine. We have hypothesized that the increased levels of thymidine and deoxyuridine cause mitochondrial nucleotide pool imbalances that, in turn, generate mtDNA alterations. PMID:15975738

  12. Defective insulin signaling and mitochondrial dynamics in diabetic cardiomyopathy

    PubMed Central

    Westermeier, Francisco; Navarro-Marquez, Mario; López-Crisosto, Camila; Bravo-Sagua, Roberto; Quiroga, Clara; Bustamante, Mario; Verdejo, Hugo E.; Zalaquett, Ricardo; Ibacache, Mauricio; Parra, Valentina; Castro, Pablo F.; Rothermel, Beverly A.; Hill, Joseph A.; Lavandero, Sergio

    2015-01-01

    Diabetic cardiomyopathy (DCM) is a common consequence of longstanding type 2 diabetes mellitus (T2DM) and encompasses structural, morphological, functional, and metabolic abnormalities in the heart. Myocardial energy metabolism depends on mitochondria, which must generate sufficient ATP to meet the high energy demands of the myocardium. Dysfunctional mitochondria are involved in the pathophysiology of diabetic heart disease. A large body of evidence implicates myocardial insulin resistance in the pathogenesis of DCM. Recent studies show that insulin signaling influences myocardial energy metabolism by impacting cardiomyocyte mitochondrial dynamics and function under physiological conditions. However, comprehensive understanding of molecular mechanisms linking insulin signaling and changes in the architecture of the mitochondrial network in diabetic cardiomyopathy is lacking. This review summarizes our current understanding of how defective insulin signaling impacts cardiac function in diabetic cardiomyopathy and discusses the potential role of mitochondrial dynamics. PMID:25686534

  13. Mitochondrial Phosphatase PTPMT1 is essential for cardiolipin biosynthesis

    PubMed Central

    Zhang, Ji; Guan, Ziqiang; Murphy, Anne N.; Wiley, Sandra E.; Perkins, Guy A.; Worby, Carolyn A.; Engel, James L.; Heacock, Philip; Nguyen, Oanh Kim; Wang, Jonathan H.; Raetz, Christian R.H.; Dowhan, William; Dixon, Jack E.

    2011-01-01

    Summary PTPMT1 was the first protein tyrosine phosphatase found localized to the mitochondria, but its biological function was unknown. Herein, we demonstrate that whole body deletion of Ptpmt1 in mice leads to embryonic lethality, suggesting an indispensable role for PTPMT1 during development. Ptpmt1-deficiency in mouse embryonic fibroblasts compromises mitochondrial respiration and results in abnormal mitochondrial morphology. Lipid analysis of Ptpmt1-deficient fibroblasts reveals an accumulation of phosphatidylglycerophosphate (PGP) along with a concomitant decrease in phosphatidylglycerol. PGP is an essential intermediate in the biosynthetic pathway of cardiolipin, a mitochondrial-specific phospholipid regulating the membrane integrity and activities of the organelle. We further demonstrate that PTPMT1 specifically dephosphorylates PGP in vitro. Loss of PTPMT1 leads to dramatic diminution of cardiolipin, which can be partially reversed by the expression of catalytic active PTPMT1. Our study identifies PTPMT1 as the mammalian PGP phosphatase and points to its role as a regulator of cardiolipin biosynthesis. PMID:21641550

  14. Mitochondrial toxic effects of Aβ through mitofusins in the early pathogenesis of Alzheimer's disease.

    PubMed

    Wu, Zhaofei; Zhu, Yushan; Cao, Xingshui; Sun, Shufeng; Zhao, Baolu

    2014-12-01

    Mitochondrial dysfunction has been implicated in the pathogenesis of Alzheimer's disease (AD). However, it is obscure how amyloid-beta (Aβ) can impair mitochondria in the early stage of AD pathology. Using PrP-hAPP/hPS1 double-transgenic AD mouse model, we find that abnormal mitochondrial morphology and damaged mitochondrial structure in hippocampal neurons appear in the early stage of AD-like disease development. We also find consistent mitochondrial abnormalities in the SH-SY5Y cells, which express amyloid precursor protein (APP) Swedish mutation (APPsw) and have been used as a cell model of the early-onset AD. Significant changes of mitofusin GTPases (Mfn1 and Mfn2) were detected both in the PrP-hAPP/hPS1 brains and SH-SY5Y cells. Moreover, our results show that Aβ accumulation in neurons of PrP-hAPP/hPS1 mice can affect the neurogenesis prior to plaque formation. These findings suggest that mitochondrial impairment is a very early event in AD pathogenesis and abnormal expression of Mfn1 and Mfn2 caused by excessive intracellular Aβ is the possible molecular mechanism. Interestingly, L-theanine has significant effects on regulating mitochondrial fusion proteins in SH-SY5Y (APPsw) cells. Overall, our results not only suggest a new early mechanism of AD pathogenesis but also propose a preventive candidate, L-theanine, for the treatment of AD. PMID:24710686

  15. Altered Cytoskeleton as a Mitochondrial Decay Signature in the Retinal Pigment Epithelium.

    PubMed

    Sripathi, Srinivas R; He, Weilue; Sylvester, O'Donnell; Neksumi, Musa; Um, Ji-Yeon; Dluya, Thagriki; Bernstein, Paul S; Jahng, Wan Jin

    2016-06-01

    Mitochondria mediate energy metabolism, apoptosis, and aging, while mitochondrial disruption leads to age-related diseases that include age-related macular degeneration. Descriptions of mitochondrial morphology have been non-systematic and qualitative, due to lack of knowledge on the molecular mechanism of mitochondrial dynamics. The current study analyzed mitochondrial size, shape, and position quantitatively in retinal pigment epithelial cells (RPE) using a systematic computational model to suggest mitochondrial trafficking under oxidative environment. Our previous proteomic study suggested that prohibitin is a mitochondrial decay biomarker in the RPE. The current study examined the prohibitin interactome map using immunoprecipitation data to determine the indirect signaling on cytoskeletal changes and transcriptional regulation by prohibitin. Immunocytochemistry and immunoprecipitation demonstrated that there is a positive correlation between mitochondrial changes and altered filaments as well as prohibitin interactions with kinesin and unknown proteins in the RPE. Specific cytoskeletal and nuclear protein-binding mechanisms may exist to regulate prohibitin-mediated reactions as key elements, including vimentin and p53, to control apoptosis in mitochondria and the nucleus. Prohibitin may regulate mitochondrial trafficking through unknown proteins that include 110 kDa protein with myosin head domain and 88 kDa protein with cadherin repeat domain. Altered cytoskeleton may represent a mitochondrial decay signature in the RPE. The current study suggests that mitochondrial dynamics and cytoskeletal changes are critical for controlling mitochondrial distribution and function. Further, imbalance of retrograde versus anterograde mitochondrial trafficking may initiate the pathogenic reaction in adult-onset neurodegenerative diseases. PMID:27029380

  16. Mitochondrial Dysfunction in Cancer

    PubMed Central

    Boland, Michelle L.; Chourasia, Aparajita H.; Macleod, Kay F.

    2013-01-01

    A mechanistic understanding of how mitochondrial dysfunction contributes to cell growth and tumorigenesis is emerging beyond Warburg as an area of research that is under-explored in terms of its significance for clinical management of cancer. Work discussed in this review focuses less on the Warburg effect and more on mitochondria and how dysfunctional mitochondria modulate cell cycle, gene expression, metabolism, cell viability, and other established aspects of cell growth and stress responses. There is increasing evidence that key oncogenes and tumor suppressors modulate mitochondrial dynamics through important signaling pathways and that mitochondrial mass and function vary between tumors and individuals but the significance of these events for cancer are not fully appreciated. We explore the interplay between key molecules involved in mitochondrial fission and fusion and in apoptosis, as well as in mitophagy, biogenesis, and spatial dynamics of mitochondria and consider how these distinct mechanisms are coordinated in response to physiological stresses such as hypoxia and nutrient deprivation. Importantly, we examine how deregulation of these processes in cancer has knock on effects for cell proliferation and growth. We define major forms of mitochondrial dysfunction and address the extent to which the functional consequences of such dysfunction can be determined and exploited for cancer diagnosis and treatment. PMID:24350057

  17. Mitochondrial fusion and inheritance of the mitochondrial genome.

    PubMed

    Takano, Hiroyoshi; Onoue, Kenta; Kawano, Shigeyuki

    2010-03-01

    Although maternal or uniparental inheritance of mitochondrial genomes is a general rule, biparental inheritance is sometimes observed in protists and fungi,including yeasts. In yeast, recombination occurs between the mitochondrial genomes inherited from both parents.Mitochondrial fusion observed in yeast zygotes is thought to set up a space for DNA recombination. In the last decade,a universal mitochondrial fusion mechanism has been uncovered, using yeast as a model. On the other hand, an alternative mitochondrial fusion mechanism has been identified in the true slime mold Physarum polycephalum.A specific mitochondrial plasmid, mF, has been detected as the genetic material that causes mitochondrial fusion in P. polycephalum. Without mF, fusion of the mitochondria is not observed throughout the life cycle, suggesting that Physarum has no constitutive mitochondrial fusion mechanism.Conversely, mitochondria fuse in zygotes and during sporulation with mF. The complete mF sequence suggests that one gene, ORF640, encodes a fusogen for Physarum mitochondria. Although in general, mitochondria are inherited uniparentally, biparental inheritance occurs with specific sexual crossing in P. polycephalum.An analysis of the transmission of mitochondrial genomes has shown that recombinations between two parental mitochondrial genomes require mitochondrial fusion,mediated by mF. Physarum is a unique organism for studying mitochondrial fusion. PMID:20196232

  18. Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress

    PubMed Central

    Picard, Martin; McManus, Meagan J.; Gray, Jason D.; Nasca, Carla; Moffat, Cynthia; Kopinski, Piotr K.; Seifert, Erin L.; McEwen, Bruce S.; Wallace, Douglas C.

    2015-01-01

    The experience of psychological stress triggers neuroendocrine, inflammatory, metabolic, and transcriptional perturbations that ultimately predispose to disease. However, the subcellular determinants of this integrated, multisystemic stress response have not been defined. Central to stress adaptation is cellular energetics, involving mitochondrial energy production and oxidative stress. We therefore hypothesized that abnormal mitochondrial functions would differentially modulate the organism’s multisystemic response to psychological stress. By mutating or deleting mitochondrial genes encoded in the mtDNA [NADH dehydrogenase 6 (ND6) and cytochrome c oxidase subunit I (COI)] or nuclear DNA [adenine nucleotide translocator 1 (ANT1) and nicotinamide nucleotide transhydrogenase (NNT)], we selectively impaired mitochondrial respiratory chain function, energy exchange, and mitochondrial redox balance in mice. The resulting impact on physiological reactivity and recovery from restraint stress were then characterized. We show that mitochondrial dysfunctions altered the hypothalamic–pituitary–adrenal axis, sympathetic adrenal–medullary activation and catecholamine levels, the inflammatory cytokine IL-6, circulating metabolites, and hippocampal gene expression responses to stress. Each mitochondrial defect generated a distinct whole-body stress-response signature. These results demonstrate the role of mitochondrial energetics and redox balance as modulators of key pathophysiological perturbations previously linked to disease. This work establishes mitochondria as stress-response modulators, with implications for understanding the mechanisms of stress pathophysiology and mitochondrial diseases. PMID:26627253

  19. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3.

    PubMed

    Khan, Nahid A; Auranen, Mari; Paetau, Ilse; Pirinen, Eija; Euro, Liliya; Forsström, Saara; Pasila, Lotta; Velagapudi, Vidya; Carroll, Christopher J; Auwerx, Johan; Suomalainen, Anu

    2014-06-01

    Nutrient availability is the major regulator of life and reproduction, and a complex cellular signaling network has evolved to adapt organisms to fasting. These sensor pathways monitor cellular energy metabolism, especially mitochondrial ATP production and NAD(+)/NADH ratio, as major signals for nutritional state. We hypothesized that these signals would be modified by mitochondrial respiratory chain disease, because of inefficient NADH utilization and ATP production. Oral administration of nicotinamide riboside (NR), a vitamin B3 and NAD(+) precursor, was previously shown to boost NAD(+) levels in mice and to induce mitochondrial biogenesis. Here, we treated mitochondrial myopathy mice with NR. This vitamin effectively delayed early- and late-stage disease progression, by robustly inducing mitochondrial biogenesis in skeletal muscle and brown adipose tissue, preventing mitochondrial ultrastructure abnormalities and mtDNA deletion formation. NR further stimulated mitochondrial unfolded protein response, suggesting its protective role in mitochondrial disease. These results indicate that NR and strategies boosting NAD(+) levels are a promising treatment strategy for mitochondrial myopathy. PMID:24711540

  20. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3

    PubMed Central

    Khan, Nahid A; Auranen, Mari; Paetau, Ilse; Pirinen, Eija; Euro, Liliya; Forsström, Saara; Pasila, Lotta; Velagapudi, Vidya; Carroll, Christopher J; Auwerx, Johan; Suomalainen, Anu

    2014-01-01

    Nutrient availability is the major regulator of life and reproduction, and a complex cellular signaling network has evolved to adapt organisms to fasting. These sensor pathways monitor cellular energy metabolism, especially mitochondrial ATP production and NAD+/NADH ratio, as major signals for nutritional state. We hypothesized that these signals would be modified by mitochondrial respiratory chain disease, because of inefficient NADH utilization and ATP production. Oral administration of nicotinamide riboside (NR), a vitamin B3 and NAD+ precursor, was previously shown to boost NAD+ levels in mice and to induce mitochondrial biogenesis. Here, we treated mitochondrial myopathy mice with NR. This vitamin effectively delayed early- and late-stage disease progression, by robustly inducing mitochondrial biogenesis in skeletal muscle and brown adipose tissue, preventing mitochondrial ultrastructure abnormalities and mtDNA deletion formation. NR further stimulated mitochondrial unfolded protein response, suggesting its protective role in mitochondrial disease. These results indicate that NR and strategies boosting NAD+ levels are a promising treatment strategy for mitochondrial myopathy. PMID:24711540

  1. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis

    PubMed Central

    Rossignol, D A; Frye, R E

    2012-01-01

    A comprehensive literature search was performed to collate evidence of mitochondrial dysfunction in autism spectrum disorders (ASDs) with two primary objectives. First, features of mitochondrial dysfunction in the general population of children with ASD were identified. Second, characteristics of mitochondrial dysfunction in children with ASD and concomitant mitochondrial disease (MD) were compared with published literature of two general populations: ASD children without MD, and non-ASD children with MD. The prevalence of MD in the general population of ASD was 5.0% (95% confidence interval 3.2, 6.9%), much higher than found in the general population (∼0.01%). The prevalence of abnormal biomarker values of mitochondrial dysfunction was high in ASD, much higher than the prevalence of MD. Variances and mean values of many mitochondrial biomarkers (lactate, pyruvate, carnitine and ubiquinone) were significantly different between ASD and controls. Some markers correlated with ASD severity. Neuroimaging, in vitro and post-mortem brain studies were consistent with an elevated prevalence of mitochondrial dysfunction in ASD. Taken together, these findings suggest children with ASD have a spectrum of mitochondrial dysfunction of differing severity. Eighteen publications representing a total of 112 children with ASD and MD (ASD/MD) were identified. The prevalence of developmental regression (52%), seizures (41%), motor delay (51%), gastrointestinal abnormalities (74%), female gender (39%), and elevated lactate (78%) and pyruvate (45%) was significantly higher in ASD/MD compared with the general ASD population. The prevalence of many of these abnormalities was similar to the general population of children with MD, suggesting that ASD/MD represents a distinct subgroup of children with MD. Most ASD/MD cases (79%) were not associated with genetic abnormalities, raising the possibility of secondary mitochondrial dysfunction. Treatment studies for ASD/MD were limited, although

  2. Mitochondrial Ca2+ Remodeling is a Prime Factor in Oncogenic Behavior

    PubMed Central

    Rimessi, Alessandro; Patergnani, Simone; Bonora, Massimo; Wieckowski, Mariusz R.; Pinton, Paolo

    2015-01-01

    Cancer is sustained by defects in the mechanisms underlying cell proliferation, mitochondrial metabolism, and cell death. Mitochondrial Ca2+ ions are central to all these processes, serving as signaling molecules with specific spatial localization, magnitude, and temporal characteristics. Mutations in mtDNA, aberrant expression and/or regulation of Ca2+-handling/transport proteins and abnormal Ca2+-dependent relationships among the cytosol, endoplasmic reticulum, and mitochondria can cause the deregulation of mitochondrial Ca2+-dependent pathways that are related to these processes, thus determining oncogenic behavior. In this review, we propose that mitochondrial Ca2+ remodeling plays a pivotal role in shaping the oncogenic signaling cascade, which is a required step for cancer formation and maintenance. We will describe recent studies that highlight the importance of mitochondria in inducing pivotal “cancer hallmarks” and discuss possible tools to manipulate mitochondrial Ca2+ to modulate cancer survival. PMID:26161362

  3. Mitofusin 2 regulates the oocytes development and quality by modulating meiosis and mitochondrial function.

    PubMed

    Liu, Qun; Kang, Lina; Wang, Lingjuan; Zhang, Ling; Xiang, Wenpei

    2016-01-01

    Mitofusin-2 (Mfn2), one of the mitochondrial dynamic proteins plays a key role in maintaining the integrity of mitochondrial morphology and function. However, it is unknown if Mfn2 influences the quality of oocytes in the process of development by modulating mitochondrial function in vitro. In this study, immature oocytes were transfected with Mfn2-siRNA for 16 h. We found that the expression level of the Mfn2 gene was significantly lower than those of the control group. The rates of maturation and fertility were also found to have declined. Moreover, mitochondrial structure and function, especially the morphogenesis of spindles, were observed as abnormal during meiosis. Thus, the above findings indicate that down-regulation of Mfn2 may have an impact on the maturation and fertilization of immature oocytes in vitro by modulating meiosis and mitochondrial function. PMID:27469431

  4. Mitofusin 2 regulates the oocytes development and quality by modulating meiosis and mitochondrial function

    PubMed Central

    Liu, Qun; Kang, Lina; Wang, Lingjuan; Zhang, Ling; Xiang, Wenpei

    2016-01-01

    Mitofusin-2 (Mfn2), one of the mitochondrial dynamic proteins plays a key role in maintaining the integrity of mitochondrial morphology and function. However, it is unknown if Mfn2 influences the quality of oocytes in the process of development by modulating mitochondrial function in vitro. In this study, immature oocytes were transfected with Mfn2-siRNA for 16 h. We found that the expression level of the Mfn2 gene was significantly lower than those of the control group. The rates of maturation and fertility were also found to have declined. Moreover, mitochondrial structure and function, especially the morphogenesis of spindles, were observed as abnormal during meiosis. Thus, the above findings indicate that down-regulation of Mfn2 may have an impact on the maturation and fertilization of immature oocytes in vitro by modulating meiosis and mitochondrial function. PMID:27469431

  5. Distinct effects of TRAIL on the mitochondrial network in human cancer cells and normal cells: role of plasma membrane depolarization

    PubMed Central

    Suzuki-Karasaki, Yoshihiro; Fujiwara, Kyoko; Saito, Kosuke; Suzuki-Karasaki, Miki; Ochiai, Toyoko; Soma, Masayoshi

    2015-01-01

    Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a promising anticancer drug due to its tumor-selective cytotoxicity. Here we report that TRAIL exhibits distinct effects on the mitochondrial networks in malignant cells and normal cells. Live-cell imaging revealed that multiple human cancer cell lines and normal cells exhibited two different modes of mitochondrial responses in response to TRAIL and death receptor agonists. Mitochondria within tumor cells became fragmented into punctate and clustered in response to toxic stimuli. The mitochondrial fragmentation was observed at 4 h, then became more pronounced over time, and associated with apoptotic cell death. In contrast, mitochondria within normal cells such as melanocytes and fibroblasts became only modestly truncated, even when they were treated with toxic stimuli. Although TRAIL activated dynamin-related protein 1 (Drp1)-dependent mitochondrial fission, inhibition of this process by Drp1 knockdown or with the Drp1 inhibitor mdivi-1, potentiated TRAIL-induced apoptosis, mitochondrial fragmentation, and clustering. Moreover, mitochondrial reactive oxygen species (ROS)-mediated depolarization accelerated mitochondrial network abnormalities in tumor cells, but not in normal cells, and TRAIL caused higher levels of mitochondrial ROS accumulation and depolarization in malignant cells than in normal cells. Our findings suggest that tumor cells are more prone than normal cells to oxidative stress and depolarization, thereby being more vulnerable to mitochondrial network abnormalities and that this vulnerability may be relevant to the tumor-targeting killing by TRAIL. PMID:26057632

  6. Renal Mitochondrial Cytopathies

    PubMed Central

    Emma, Francesco; Montini, Giovanni; Salviati, Leonardo; Dionisi-Vici, Carlo

    2011-01-01

    Renal diseases in mitochondrial cytopathies are a group of rare diseases that are characterized by frequent multisystemic involvement and extreme variability of phenotype. Most frequently patients present a tubular defect that is consistent with complete De Toni-Debré-Fanconi syndrome in most severe forms. More rarely, patients present with chronic tubulointerstitial nephritis, cystic renal diseases, or primary glomerular involvement. In recent years, two clearly defined entities, namely 3243 A > G tRNALEU mutations and coenzyme Q10 biosynthesis defects, have been described. The latter group is particularly important because it represents the only treatable renal mitochondrial defect. In this paper, the physiopathologic bases of mitochondrial cytopathies, the diagnostic approaches, and main characteristics of related renal diseases are summarized. PMID:21811680

  7. Regulation of Skeletal Muscle Oxidative Capacity and Insulin Signaling by the Mitochondrial Rhomboid Protease PARL

    PubMed Central

    Civitarese, Anthony E.; MacLean, Paul S.; Carling, Stacy; Kerr-Bayles, Lyndal; McMillan, Ryan P.; Pierce, Anson; Becker, Thomas C.; Moro, Cedric; Finlayson, Jean; Lefort, Natalie; Newgard, Christopher B.; Mandarino, Lawrence; Cefalu, William; Walder, Ken; Collier, Greg R.; Hulver, Matthew W.; Smith, Steven R.; Ravussin, Eric

    2010-01-01

    SUMMARY Type 2 diabetes Mellitus (T2DM) and aging are characterized by insulin resistance, lower mitochondrial density and function and increased production of reactive oxygen species (ROS). In lower organisms continuous remodeling critically maintains the function and life cycle of mitochondria, in part by the protease pcp1 (PARL ortholog). We therefore examined whether variation in PARL protein content is associated with mitochondrial abnormalities and insulin resistance. Relative to healthy, young individuals (23±1y), PARL mRNA and mitochondrial mass were both reduced in elderly subjects (64.4±1.2 y; 51% and 44% respectively) and in subjects with T2DM (51.8±3 y; 31% and 41% respectively; all p<0.05). Muscle knock-down of PARL in mice resulted in lower mitochondrial content (−31±3%, p<0.05), lower OPA1 and PGC1α protein levels and impaired insulin signaling. Furthermore, mitochondrial cristae were malformed and resulted in elevated in vivo oxidative stress. Adenoviral suppression of PARL protein in healthy myotubes lowered mitochondrial mass (−33±8%), insulin stimulated glycogen synthesis (−33±9%) and increased ROS production (2-fold) (all p<0.05). We propose that lower PARL expression may contribute to the mitochondrial abnormalities seen in aging and T2DM. PMID:20444421

  8. Mitochondrial deficiency in Cockayne syndrome

    PubMed Central

    Scheibye-Knudsen, Morten; Croteau, Deborah L.; Bohr, Vilhelm A.

    2013-01-01

    Cockayne syndrome is a rare inherited disorder characterized by accelerated aging, cachectic dwarfism and many other features. Recent work has implicated mitochondrial dysfunction in the pathogenesis of this disease. This is particularly interesting since mitochondrial deficiencies are believed to be important in the aging process. In this review, we will discuss recent findings of mitochondrial pathology in Cockayne syndrome and suggest possible mechanisms for the mitochondrial dysfunction. PMID:23435289

  9. Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins

    PubMed Central

    Schwab, Marina A.; Sauer, Sven W.; Okun, Jürgen G.; Nijtmans, Leo G. J.; Rodenburg, Richard J. T.; van den Heuvel, Lambert P.; Dröse, Stefan; Brandt, Ulrich; Hoffmann, Georg F.; Ter Laak, Henk; Kölker, Stefan; Smeitink, Jan A. M.

    2006-01-01

    Mitochondrial dysfunction during acute metabolic crises is considered an important pathomechanism in inherited disorders of propionate metabolism, i.e. propionic and methylmalonic acidurias. Biochemically, these disorders are characterized by accumulation of propionyl-CoA and metabolites of alternative propionate oxidation. In the present study, we demonstrate uncompetitive inhibition of PDHc (pyruvate dehydrogenase complex) by propionyl-CoA in purified porcine enzyme and in submitochondrial particles from bovine heart being in the same range as the inhibition induced by acetyl-CoA, the physiological product and known inhibitor of PDHc. Evaluation of similar monocarboxylic CoA esters showed a chain-length specificity for PDHc inhibition. In contrast with CoA esters, non-esterified fatty acids did not inhibit PDHc activity. In addition to PDHc inhibition, analysis of respiratory chain and tricarboxylic acid cycle enzymes also revealed an inhibition by propionyl-CoA on respiratory chain complex III and α-ketoglutarate dehydrogenase complex. To test whether impairment of mitochondrial energy metabolism is involved in the pathogenesis of propionic aciduria, we performed a thorough bioenergetic analysis in muscle biopsy specimens of two patients. In line with the in vitro results, oxidative phosphorylation was severely compromised in both patients. Furthermore, expression of respiratory chain complexes I–IV and the amount of mitochondrial DNA were strongly decreased, and ultrastructural mitochondrial abnormalities were found, highlighting severe mitochondrial dysfunction. In conclusion, our results favour the hypothesis that toxic metabolites, in particular propionyl-CoA, are involved in the pathogenesis of inherited disorders of propionate metabolism, sharing mechanistic similarities with propionate toxicity in micro-organisms. PMID:16686602

  10. Mitochondrial DNA with a large-scale deletion causes two distinct mitochondrial disease phenotypes in mice.

    PubMed

    Katada, Shun; Mito, Takayuki; Ogasawara, Emi; Hayashi, Jun-Ichi; Nakada, Kazuto

    2013-09-01

    Studies in patients have suggested that the clinical phenotypes of some mitochondrial diseases might transit from one disease to another (e.g., Pearson syndrome [PS] to Kearns-Sayre syndrome) in single individuals carrying mitochondrial (mt) DNA with a common deletion (ΔmtDNA), but there is no direct experimental evidence for this. To determine whether ΔmtDNA has the pathologic potential to induce multiple mitochondrial disease phenotypes, we used trans-mitochondrial mice with a heteroplasmic state of wild-type mtDNA and ΔmtDNA (mito-miceΔ). Late-stage embryos carrying ≥50% ΔmtDNA showed abnormal hematopoiesis and iron metabolism in livers that were partly similar to PS (PS-like phenotypes), although they did not express sideroblastic anemia that is a typical symptom of PS. More than half of the neonates with PS-like phenotypes died by 1 month after birth, whereas the rest showed a decrease of ΔmtDNA load in the affected tissues, peripheral blood and liver, and they recovered from PS-like phenotypes. The proportion of ΔmtDNA in various tissues of the surviving mito-miceΔ increased with time, and Kearns-Sayre syndrome-like phenotypes were expressed when the proportion of mtDNA in various tissues reached >70-80%. Our model mouse study clearly showed that a single ΔmtDNA was responsible for at least two distinct disease phenotypes at different ages and suggested that the level and dynamics of mtDNA load in affected tissues would be important for the onset and transition of mitochondrial disease phenotypes in mice. PMID:23853091

  11. Cancer: Mitochondrial Origins

    PubMed Central

    Stefano, George B.; Kream, Richard M.

    2015-01-01

    The primacy of glucose derived from photosynthesis as an existential source of chemical energy across plant and animal phyla is universally accepted as a core principle in the biological sciences. In mammalian cells, initial processing of glucose to triose phosphate intermediates takes place within the cytosolic glycolytic pathway and terminates with temporal transport of reducing equivalents derived from pyruvate metabolism by membrane-associated respiratory complexes in the mitochondrial matrix. The intra-mitochondrial availability of molecular oxygen as the ultimate electron acceptor drives the evolutionary fashioned chemiosmotic production of ATP as a high-efficiency biological process. The mechanistic bases of carcinogenesis have demonstrated profound alteration of normative mitochondrial function, notably dysregulated respiratory processes. Accordingly, the classic Warburg effect functionally links aerobic glycolysis, aberrant production and release of lactate, and metabolic down-regulation of mitochondrial oxidative processes with the carcinogenetic phenotype. We surmise, however, that aerobic fermentation by cancer cells may also represent a developmental re-emergence of an evolutionarily conserved early phenotype, which was “sidelined” with the emergence of mitochondrial oxidative phosphorylation as a primary mechanism for ATP production in normal cells. Regardless of state-dependent physiological status in mixed populations of cancer cells, it has been established that mitochondria are functionally linked to the initiation of cancer and its progression. Biochemical, molecular, and physiological differences in cancer cell mitochondria, notably mtDNA heteroplasmy and allele-specific expression of selected nuclear genes, may represent major focal points for novel targeting and elimination of cancer cells in metastatic disease afflicting human populations. To date, and despite considerable research efforts, the practical realization of advanced

  12. Pharmacologic Effects on Mitochondrial Function

    ERIC Educational Resources Information Center

    Cohen, Bruce H.

    2010-01-01

    The vast majority of energy necessary for cellular function is produced in mitochondria. Free-radical production and apoptosis are other critical mitochondrial functions. The complex structure, electrochemical properties of the inner mitochondrial membrane (IMM), and genetic control from both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) are…

  13. Late Mitochondrial Acquisition, Really?

    PubMed Central

    Degli Esposti, Mauro

    2016-01-01

    This article provides a timely critique of a recent Nature paper by Pittis and Gabaldón that has suggested a late origin of mitochondria in eukaryote evolution. It shows that the inferred ancestry of many mitochondrial proteins has been incorrectly assigned by Pittis and Gabaldón to bacteria other than the aerobic proteobacteria from which the ancestor of mitochondria originates, thereby questioning the validity of their suggestion that mitochondrial acquisition may be a late event in eukaryote evolution. The analysis and approach presented here may guide future studies to resolve the true ancestry of mitochondria. PMID:27289097

  14. Abnormal grain growth in AISI 304L stainless steel

    SciTech Connect

    Shirdel, M.; Mirzadeh, H.; Parsa, M.H.

    2014-11-15

    The microstructural evolution during abnormal grain growth (secondary recrystallization) in 304L stainless steel was studied in a wide range of annealing temperatures and times. At relatively low temperatures, the grain growth mode was identified as normal. However, at homologous temperatures between 0.65 (850 °C) and 0.7 (900 °C), the observed transition in grain growth mode from normal to abnormal, which was also evident from the bimodality in grain size distribution histograms, was detected to be caused by the dissolution/coarsening of carbides. The microstructural features such as dispersed carbides were characterized by optical metallography, X-ray diffraction, scanning electron microscopy, energy dispersive X-ray analysis, and microhardness. Continued annealing to a long time led to the completion of secondary recrystallization and the subsequent reappearance of normal growth mode. Another instance of abnormal grain growth was observed at homologous temperatures higher than 0.8, which may be attributed to the grain boundary faceting/defaceting phenomenon. It was also found that when the size of abnormal grains reached a critical value, their size will not change too much and the grain growth behavior becomes practically stagnant. - Highlights: • Abnormal grain growth (secondary recrystallization) in AISI 304L stainless steel • Exaggerated grain growth due to dissolution/coarsening of carbides • The enrichment of carbide particles by titanium • Abnormal grain growth due to grain boundary faceting at very high temperatures • The stagnancy of abnormal grain growth by annealing beyond a critical time.

  15. Molecular abnormalities in Ewing's sarcoma.

    PubMed

    Burchill, Susan Ann

    2008-10-01

    Ewing's sarcoma is one of the few solid tumors for which the underlying molecular genetic abnormality has been described: rearrangement of the EWS gene on chromosome 22q12 with an ETS gene family member. These translocations define the Ewing's sarcoma family of tumors (ESFT) and provide a valuable tool for their accurate and unequivocal diagnosis. They also represent ideal targets for the development of tumor-specific therapeutics. Although secondary abnormalities occur in over 80% of primary ESFT the clinical utility of these is currently unclear. However, abnormalities in genes that regulate the G(1)/S checkpoint are frequently described and may be important in predicting outcome and response. Increased understanding of the molecular events that arise in ESFT and their role in the development and maintenance of the malignant phenotype will inform the improved stratification of patients for therapy and identify targets and pathways for the design of more effective cancer therapeutics. PMID:18925858

  16. Complex patterns of abnormal heartbeats

    NASA Technical Reports Server (NTRS)

    Schulte-Frohlinde, Verena; Ashkenazy, Yosef; Goldberger, Ary L.; Ivanov, Plamen Ch; Costa, Madalena; Morley-Davies, Adrian; Stanley, H. Eugene; Glass, Leon

    2002-01-01

    Individuals having frequent abnormal heartbeats interspersed with normal heartbeats may be at an increased risk of sudden cardiac death. However, mechanistic understanding of such cardiac arrhythmias is limited. We present a visual and qualitative method to display statistical properties of abnormal heartbeats. We introduce dynamical "heartprints" which reveal characteristic patterns in long clinical records encompassing approximately 10(5) heartbeats and may provide information about underlying mechanisms. We test if these dynamics can be reproduced by model simulations in which abnormal heartbeats are generated (i) randomly, (ii) at a fixed time interval following a preceding normal heartbeat, or (iii) by an independent oscillator that may or may not interact with the normal heartbeat. We compare the results of these three models and test their limitations to comprehensively simulate the statistical features of selected clinical records. This work introduces methods that can be used to test mathematical models of arrhythmogenesis and to develop a new understanding of underlying electrophysiologic mechanisms of cardiac arrhythmia.

  17. The complete mitochondrial genome of bearded pig, Sus barbatus, and comparative mitochondrial genomics of Cetartiodactyla.

    PubMed

    Zhang, Shan-Chuan; Xu, Bao-Hua; Liu, Hong-Chen

    2016-07-01

    In this study, the complete mitochondrial genome sequence of bearded pig, Sus barbatus, with the total length of 16,480 bp, is determined for the first time. This mitogenome harbors 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes, and one control region (D-loop). The overall base composition is A (34.80%), C (26.07%), G (13.12%), and T (26.01%), so the slight A-T bias (60.81%) was detected. Most of the genes are distributed on the H-strand, except for the ND6 subunit gene and eight tRNA genes. To obtain the phylogenetic relationship of the Cetartiodactyla, 11 mitochondrial genomes were used for phylogenetic analysis. The mitochondrial genome of S. barbatus presented here will contribute to a better understanding of the population genetics. PMID:26104157

  18. Mitochondrial nucleoid clusters protect newly synthesized mtDNA during Doxorubicin- and Ethidium Bromide-induced mitochondrial stress.

    PubMed

    Alán, Lukáš; Špaček, Tomáš; Pajuelo Reguera, David; Jabůrek, Martin; Ježek, Petr

    2016-07-01

    Mitochondrial DNA (mtDNA) is compacted in ribonucleoprotein complexes called nucleoids, which can divide or move within the mitochondrial network. Mitochondrial nucleoids are able to aggregate into clusters upon reaction with intercalators such as the mtDNA depletion agent Ethidium Bromide (EB) or anticancer drug Doxorobicin (DXR). However, the exact mechanism of nucleoid clusters formation remains unknown. Resolving these processes may help to elucidate the mechanisms of DXR-induced cardiotoxicity. Therefore, we addressed the role of two key nucleoid proteins; mitochondrial transcription factor A (TFAM) and mitochondrial single-stranded binding protein (mtSSB); in the formation of mitochondrial nucleoid clusters during the action of intercalators. We found that both intercalators cause numerous aberrations due to perturbing their native status. By blocking mtDNA replication, both agents also prevented mtDNA association with TFAM, consequently causing nucleoid aggregation into large nucleoid clusters enriched with TFAM, co-existing with the normal nucleoid population. In the later stages of intercalation (>48h), TFAM levels were reduced to 25%. In contrast, mtSSB was released from mtDNA and freely distributed within the mitochondrial network. Nucleoid clusters mostly contained nucleoids with newly replicated mtDNA, however the nucleoid population which was not in replication mode remained outside the clusters. Moreover, the nucleoid clusters were enriched with p53, an anti-oncogenic gatekeeper. We suggest that mitochondrial nucleoid clustering is a mechanism for protecting nucleoids with newly replicated DNA against intercalators mediating genotoxic stress. These results provide new insight into the common mitochondrial response to mtDNA stress and can be implied also on DXR-induced mitochondrial cytotoxicity. PMID:27102948

  19. [Emotion Disorders and Abnormal Perspiration].

    PubMed

    Umeda, Satoshi

    2016-08-01

    This article reviewed the relationship between emotional disorders and abnormal perspiration. First, I focused on local brain areas related to emotional processing, and summarized the functions of the emotional network involving those local areas. Functional disorders followed by the damage in the amygdala, orbitofrontal cortex, and insular cortex were reviewed, including related abnormal perspiration. I then addressed the mechanisms of how autonomic disorders influence emotional processing. Finally, possible future directions for integrated understanding of the connection between neural activities and bodily reactions were discussed. PMID:27503817

  20. Ultrasonographic assessment of abnormal pregnancy.

    PubMed

    England, G C

    1998-07-01

    Ultrasonographic imaging is widely used in small animal practice for the diagnosis of pregnancy and the determination of fetal number. Ultrasonography can also be used to monitor abnormal pregnancies, for example, conceptuses that are poorly developed for their gestational age (and therefore are likely to fail), and pregnancies in which there is embryonic resorption or fetal abortion. An ultrasound examination may reveal fetal abnormalities and therefore alter the management of the pregnant bitch or queen prior to parturition. There are, however, a number of ultrasonographic features of normal pregnancies that may mimic disease, and these must be recognized. PMID:9698618

  1. The effect of abnormal cell proportion on specimen classifier performance

    NASA Technical Reports Server (NTRS)

    Castleman, K. R.; White, B. S.

    1981-01-01

    An analysis is presented of the results obtained from a cell classifier which is confronted with an abnormal/normal cell ratio which is different from the ratio assumed in the calibration of the classifier. False negative and false positive error rates are determined in advance for classifier operation, along with the necessary sample size in order to validate the predicted distributions. Changes are demonstrated to happen only regarding the false negative rate, where reductions in the abnormal cell rate below the expected rates would cause totally unreliable data. Substantial overproduction of abnormal cells would be quickly noticeable, while production rates beyond, but close to, the expected rates would only require more extensive sampling. Classifier systems for 10% proportions of abnormal cells are concluded to be possible, but difficulties are present with much lower rates

  2. Diverticular Disease of the Colon: Neuromuscular Function Abnormalities.

    PubMed

    Bassotti, Gabrio; Villanacci, Vincenzo; Bernardini, Nunzia; Dore, Maria P

    2016-10-01

    Colonic diverticular disease is a frequent finding in daily clinical practice. However, its pathophysiological mechanisms are largely unknown. This condition is likely the result of several concomitant factors occurring together to cause anatomic and functional abnormalities, leading as a result to the outpouching of the colonic mucosa. A pivotal role seems to be played by an abnormal colonic neuromuscular function, as shown repeatedly in these patients, and by an altered visceral perception. There is recent evidence that these abnormalities might be related to the derangement of the enteric innervation, to an abnormal distribution of mucosal neuropeptides, and to low-grade mucosal inflammation. The latter might be responsible for the development of visceral hypersensitivity, often causing abdominal pain in a subset of these patients. PMID:27622368

  3. Cytogenetic abnormalities in Tunisian women with premature ovarian failure.

    PubMed

    Ayed, Wiem; Amouri, Ahlem; Hammami, Wajih; Kilani, Olfa; Turki, Zinet; Harzallah, Fatma; Bouayed-Abdelmoula, Nouha; Chemkhi, Imen; Zhioua, Fethi; Slama, Claude Ben

    2014-12-01

    To identify the distribution of chromosome abnormalities among Tunisian women with premature ovarian failure (POF) referred to the department of Cytogenetic at the Pasteur Institute of Tunis (Tunisia), standard cytogenetic analysis was carried out in a total of 100 women younger than 40 affected with premature ovarian failure. We identified 18 chromosomal abnormalities, including seven X-numerical anomalies in mosaic and non-mosaic state (45,X; 47,XXX), four sex reversal, three X-structural abnormalities (terminal deletion and isochromosomes), one autosomal translocation and one supernumerary marker. The overall prevalence of chromosomal abnormalities was 18% in our cohort. X chromosome aneuploidy was the most frequent aberration. This finding confirms the essential role of X chromosome in ovarian function and underlies the importance of cytogenetic investigations in the routine management of POF. PMID:25433561

  4. Mutations in FBXL4 Cause Mitochondrial Encephalopathy and a Disorder of Mitochondrial DNA Maintenance

    PubMed Central

    Bonnen, Penelope E.; Yarham, John W.; Besse, Arnaud; Wu, Ping; Faqeih, Eissa A.; Al-Asmari, Ali Mohammad; Saleh, Mohammad A.M.; Eyaid, Wafaa; Hadeel, Alrukban; He, Langping; Smith, Frances; Yau, Shu; Simcox, Eve M.; Miwa, Satomi; Donti, Taraka; Abu-Amero, Khaled K.; Wong, Lee-Jun; Craigen, William J.; Graham, Brett H.; Scott, Kenneth L.; McFarland, Robert; Taylor, Robert W.

    2013-01-01

    Nuclear genetic disorders causing mitochondrial DNA (mtDNA) depletion are clinically and genetically heterogeneous, and the molecular etiology remains undiagnosed in the majority of cases. Through whole-exome sequencing, we identified recessive nonsense and splicing mutations in FBXL4 segregating in three unrelated consanguineous kindreds in which affected children present with a fatal encephalopathy, lactic acidosis, and severe mtDNA depletion in muscle. We show that FBXL4 is an F-box protein that colocalizes with mitochondria and that loss-of-function and splice mutations in this protein result in a severe respiratory chain deficiency, loss of mitochondrial membrane potential, and a disturbance of the dynamic mitochondrial network and nucleoid distribution in fibroblasts from affected individuals. Expression of the wild-type FBXL4 transcript in cell lines from two subjects fully rescued the levels of mtDNA copy number, leading to a correction of the mitochondrial biochemical deficit. Together our data demonstrate that mutations in FBXL4 are disease causing and establish FBXL4 as a mitochondrial protein with a possible role in maintaining mtDNA integrity and stability. PMID:23993193

  5. Data for mitochondrial proteomic alterations in the developing rat brain.

    PubMed

    Villeneuve, Lance M; Stauch, Kelly L; Fox, Howard S

    2014-12-01

    Mitochondria are a critical organelle involved in many cellular processes, and due to the nature of the brain, neuronal cells are almost completely reliant on these organelles for energy generation. Due to the fact that biomedical research tends to investigate disease state pathogenesis, one area of mitochondrial research commonly overlooked is homeostatic responses to energy demands. Therefore, to elucidate mitochondrial alterations occurring during the developmentally important phase of E18 to P7 in the brain, we quantified the proteins in the mitochondrial proteome as well as proteins interacting with the mitochondria. We identified a large number of significantly altered proteins involved in a variety of pathways including glycolysis, mitochondrial trafficking, mitophagy, and the unfolded protein response. These results are important because we identified alterations thought to be homeostatic in nature occurring within mitochondria, and these results may be used to identify any abnormal deviations in the mitochondrial proteome occurring during this period of brain development. A more comprehensive analysis of this data may be obtained from the article "Proteomic analysis of mitochondria from embryonic and postnatal rat brains reveals response to developmental changes in energy demands" in the Journal of Proteomics. PMID:26217684

  6. Mitochondrial Factors and VACTERL Association-Related Congenital Malformations

    PubMed Central

    Siebel, S.; Solomon, B.D.

    2013-01-01

    VACTERL/VATER association is a group of congenital malformations characterized by at least 3 of the following findings: vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities. To date, no unifying etiology for VACTERL/VATER association has been established, and there is strong evidence for causal heterogeneity. VACTERL/VATER association has many overlapping characteristics with other congenital disorders that involve multiple malformations. In addition to these other conditions, some of which have known molecular causes, certain aspects of VACTERL/VATER association have similarities with the manifestations of disorders caused by mitochondrial dysfunction. Mitochondrial dysfunction can result from a number of distinct causes and can clinically manifest in diverse presentations; accurate diagnosis can be challenging. Case reports of individuals with VACTERL association and confirmed mitochondrial dysfunction allude to the possibility of mitochondrial involvement in the pathogenesis of VACTERL/VATER association. Further, there is biological plausibility involving mitochondrial dysfunction as a possible etiology related to a diverse group of congenital malformations, including those seen in at least a subset of individuals with VACTERL association. PMID:23653577

  7. Borrowing nuclear DNA helicases to protect mitochondrial DNA.

    PubMed

    Ding, Lin; Liu, Yilun

    2015-01-01

    In normal cells, mitochondria are the primary organelles that generate energy, which is critical for cellular metabolism. Mitochondrial dysfunction, caused by mitochondrial DNA (mtDNA) mutations or an abnormal mtDNA copy number, is linked to a range of human diseases, including Alzheimer's disease, premature aging‎ and cancer. mtDNA resides in the mitochondrial lumen, and its duplication requires the mtDNA replicative helicase, Twinkle. In addition to Twinkle, many DNA helicases, which are encoded by the nuclear genome and are crucial for nuclear genome integrity, are transported into the mitochondrion to also function in mtDNA replication and repair. To date, these helicases include RecQ-like helicase 4 (RECQ4), petite integration frequency 1 (PIF1), DNA replication helicase/nuclease 2 (DNA2) and suppressor of var1 3-like protein 1 (SUV3). Although the nuclear functions of some of these DNA helicases have been extensively studied, the regulation of their mitochondrial transport and the mechanisms by which they contribute to mtDNA synthesis and maintenance remain largely unknown. In this review, we attempt to summarize recent research progress on the role of mammalian DNA helicases in mitochondrial genome maintenance and the effects on mitochondria-associated diseases. PMID:25984607

  8. Dopamine Coupling to Mitochondrial Signaling: Implications for Transplantation.

    PubMed

    Stefano, George B; Ramin, Rohina; Kream, Richard M

    2016-01-01

    The persistence of major medical disorders afflicting millions of humans worldwide involves a functional pathophysiological coupling of systemic pro-inflammatory processes and tissue hypoxia. Mechanistically, reciprocal triggering of multiple ischemic/hypoxic and pro-inflammatory events, if not corrected, will promote pathophysiological amplification leading to a deleterious cascade of bio-senescent cellular and molecular signaling pathways that converge to markedly impair mitochondrial energy production. Given the level of energy production and utilization that can vary in and between cells and regionally in the same type of cells found in the body, e.g., dopamine neurons, the metabolic energy regulator, the mitochondrion, assumes a high position in the potential to maintain normal health and develop abnormal activities, resulting in chronic pathologies. The intra-mitochondrial availability of molecular oxygen as the ultimate electron acceptor drives the evolutionarily fashioned chemiosmotic production of ATP as a high-efficiency biological proton pump process. The mechanistic evolutionary bases of diabetes have demonstrated the profound alteration of normative mitochondrial function, notably deregulated respiratory processes. This same phenomenon provides evidence of mitochondrial linkages to neurological disorders, such as Parkinson's disease. To date, and despite considerable research efforts, the practical realization of advanced mitochondrial targeted therapies has not been forthcoming. PMID:26790458

  9. Data for mitochondrial proteomic alterations in the developing rat brain

    PubMed Central

    Villeneuve, Lance M.; Stauch, Kelly L.; Fox, Howard S.

    2014-01-01

    Mitochondria are a critical organelle involved in many cellular processes, and due to the nature of the brain, neuronal cells are almost completely reliant on these organelles for energy generation. Due to the fact that biomedical research tends to investigate disease state pathogenesis, one area of mitochondrial research commonly overlooked is homeostatic responses to energy demands. Therefore, to elucidate mitochondrial alterations occurring during the developmentally important phase of E18 to P7 in the brain, we quantified the proteins in the mitochondrial proteome as well as proteins interacting with the mitochondria. We identified a large number of significantly altered proteins involved in a variety of pathways including glycolysis, mitochondrial trafficking, mitophagy, and the unfolded protein response. These results are important because we identified alterations thought to be homeostatic in nature occurring within mitochondria, and these results may be used to identify any abnormal deviations in the mitochondrial proteome occurring during this period of brain development. A more comprehensive analysis of this data may be obtained from the article “Proteomic analysis of mitochondria from embryonic and postnatal rat brains reveals response to developmental changes in energy demands” in the Journal of Proteomics. PMID:26217684

  10. Evaluating mitochondrial DNA variation in autism spectrum disorders

    PubMed Central

    HADJIXENOFONTOS, ATHENA; SCHMIDT, MICHAEL A.; WHITEHEAD, PATRICE L.; KONIDARI, IOANNA; HEDGES, DALE J.; WRIGHT, HARRY H.; ABRAMSON, RUTH K.; MENON, RAMKUMAR; WILLIAMS, SCOTT M.; CUCCARO, MICHAEL L.; HAINES, JONATHAN L.; GILBERT, JOHN R.; PERICAK-VANCE, MARGARET A.; MARTIN, EDEN R.; MCCAULEY, JACOB L.

    2012-01-01

    SUMMARY Despite the increasing speculation that oxidative stress and abnormal energy metabolism may play a role in Autism Spectrum Disorders (ASD), and the observation that patients with mitochondrial defects have symptoms consistent with ASD, there are no comprehensive published studies examining the role of mitochondrial variation in autism. Therefore, we have sought to comprehensively examine the role of mitochondrial DNA (mtDNA) variation with regard to ASD risk, employing a multi-phase approach. In phase 1 of our experiment, we examined 132 mtDNA single-nucleotide polymorphisms (SNPs) genotyped as part of our genome-wide association studies of ASD. In phase 2 we genotyped the major European mitochondrial haplogroup-defining variants within an expanded set of autism probands and controls. Finally in phase 3, we resequenced the entire mtDNA in a subset of our Caucasian samples (~400 proband-father pairs). In each phase we tested whether mitochondrial variation showed evidence of association to ASD. Despite a thorough interrogation of mtDNA variation, we found no evidence to suggest a major role for mtDNA variation in ASD susceptibility. Accordingly, while there may be attractive biological hints suggesting the role of mitochondria in ASD our data indicate that mtDNA variation is not a major contributing factor to the development of ASD. PMID:23130936

  11. Elastocapillary Instability in Mitochondrial Fission

    NASA Astrophysics Data System (ADS)

    Gonzalez-Rodriguez, David; Sart, Sébastien; Babataheri, Avin; Tareste, David; Barakat, Abdul I.; Clanet, Christophe; Husson, Julien

    2015-08-01

    Mitochondria are dynamic cell organelles that constantly undergo fission and fusion events. These dynamical processes, which tightly regulate mitochondrial morphology, are essential for cell physiology. Here we propose an elastocapillary mechanical instability as a mechanism for mitochondrial fission. We experimentally induce mitochondrial fission by rupturing the cell's plasma membrane. We present a stability analysis that successfully explains the observed fission wavelength and the role of mitochondrial morphology in the occurrence of fission events. Our results show that the laws of fluid mechanics can describe mitochondrial morphology and dynamics.

  12. ENERGETICS, EPIGENETICS, MITOCHONDRIAL GENETICS

    PubMed Central

    Wallace, Douglas C.; Fan, Weiwei

    2011-01-01

    The epigenome has been hypothesized to provide the interface between the environment and the nuclear DNA (nDNA) genes. Key factors in the environment are the availability of calories and demands on the organism’s energetic capacity. Energy is funneled through glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), the cellular bioenergetic systems. Since there are thousands of bioenergetic genes dispersed across the chromosomes and mitochondrial DNA (mtDNA), both cis and trans regulation of the nDNA genes is required. The bioenergetic systems convert environmental calories into ATP, acetyl-Coenzyme A (acetyl-CoA), S-adenosyl-methionine (SAM), and reduced NAD+. When calories are abundant, ATP and acetyl-CoA phosphorylate and acetylate chromatin, opening the nDNA for transcription and replication. When calories are limiting, chromatin phosphorylation and acetylation are lost and gene expression is suppressed. DNA methylaton via SAM can also be modulated by mitochondrial function. Phosphorylation and acetylation are also pivotal to regulating cellular signal transduction pathways. Therefore, bioenergetics provides the interface between the environment and the epigenome. Consistent with this conclusion, the clinical phenotypes of bioenergetic diseases are strikingly similar to those observed in epigenetic diseases (Angelman, Rett, Fragile X Syndromes, the laminopathies, cancer, etc.), and an increasing number of epigenetic diseases are being associated with mitochondrial dysfunction. This bioenergetic-epigenomic hypothesis has broad implications for the etiology, pathophysiology, and treatment of a wide range of common diseases. PMID:19796712

  13. Mitochondrial Ion Channels

    PubMed Central

    O’Rourke, Brian

    2009-01-01

    In work spanning more than a century, mitochondria have been recognized for their multifunctional roles in metabolism, energy transduction, ion transport, inheritance, signaling, and cell death. Foremost among these tasks is the continuous production of ATP through oxidative phosphorylation, which requires a large electrochemical driving force for protons across the mitochondrial inner membrane. This process requires a membrane with relatively low permeability to ions to minimize energy dissipation. However, a wealth of evidence now indicates that both selective and nonselective ion channels are present in the mitochondrial inner membrane, along with several known channels on the outer membrane. Some of these channels are active under physiological conditions, and others may be activated under pathophysiological conditions to act as the major determinants of cell life and death. This review summarizes research on mitochondrial ion channels and efforts to identify their molecular correlates. Except in a few cases, our understanding of the structure of mitochondrial ion channels is limited, indicating the need for focused discovery in this area. PMID:17059356

  14. Protons Trigger Mitochondrial Flashes.

    PubMed

    Wang, Xianhua; Zhang, Xing; Huang, Zhanglong; Wu, Di; Liu, Beibei; Zhang, Rufeng; Yin, Rongkang; Hou, Tingting; Jian, Chongshu; Xu, Jiejia; Zhao, Yan; Wang, Yanru; Gao, Feng; Cheng, Heping

    2016-07-26

    Emerging evidence indicates that mitochondrial flashes (mitoflashes) are highly conserved elemental mitochondrial signaling events. However, which signal controls their ignition and how they are integrated with other mitochondrial signals and functions remain elusive. In this study, we aimed to further delineate the signal components of the mitoflash and determine the mitoflash trigger mechanism. Using multiple biosensors and chemical probes as well as label-free autofluorescence, we found that the mitoflash reflects chemical and electrical excitation at the single-organelle level, comprising bursting superoxide production, oxidative redox shift, and matrix alkalinization as well as transient membrane depolarization. Both electroneutral H(+)/K(+) or H(+)/Na(+) antiport and matrix proton uncaging elicited immediate and robust mitoflash responses over a broad dynamic range in cardiomyocytes and HeLa cells. However, charge-uncompensated proton transport, which depolarizes mitochondria, caused the opposite effect, and steady matrix acidification mildly inhibited mitoflashes. Based on a numerical simulation, we estimated a mean proton lifetime of 1.42 ns and diffusion distance of 2.06 nm in the matrix. We conclude that nanodomain protons act as a novel, to our knowledge, trigger of mitoflashes in energized mitochondria. This finding suggests that mitoflash genesis is functionally and mechanistically integrated with mitochondrial energy metabolism. PMID:27463140

  15. Cardiolipin and electron transport chain abnormalities in mouse brain tumor mitochondria: lipidomic evidence supporting the Warburg theory of cancer*

    PubMed Central

    Kiebish, Michael A.; Han, Xianlin; Cheng, Hua; Chuang, Jeffrey H.; Seyfried, Thomas N.

    2008-01-01

    Otto Warburg first proposed that cancer originated from irreversible injury to mitochondrial respiration, but the structural basis for this injury has remained elusive. Cardiolipin (CL) is a complex phospholipid found almost exclusively in the inner mitochondrial membrane and is intimately involved in maintaining mitochondrial functionality and membrane integrity. Abnormalities in CL can impair mitochondrial function and bioenergetics. We used shotgun lipidomics to analyze CL content and composition in highly purified brain mitochondria from the C57BL/6J (B6) and VM/Dk (VM) inbred strains and from subcutaneously grown brain tumors derived from these strains to include an astrocytoma and ependymoblastoma (B6 tumors), a stem cell tumor, and two microgliomas (VM tumors). Major abnormalities in CL content or composition were found in all tumors. The compositional abnormalities involved an abundance of immature molecular species and deficiencies of mature molecular species, suggesting major defects in CL synthesis and remodeling. The tumor CL abnormalities were also associated with significant reductions in both individual and linked electron transport chain activities. A mathematical model was developed to facilitate data interpretation. The implications of our findings to the Warburg cancer theory are discussed. PMID:18703489

  16. Mitochondrial Turnover in the Heart

    PubMed Central

    Gustafsson, Åsa B.

    2010-01-01

    Mitochondrial quality control is increasingly recognized as an essential element in maintaining optimally functioning tissues. Mitochondrial quality control depends upon a balance between biogenesis and autophagic destruction. Mitochondrial dynamics (fusion and fission) allows for the redistribution of mitochondrial components. We speculate that this permits sorting of highly functional components into one end of a mitochondrion, while damaged components are segregated at the other end, to be jettisoned by asymmetric fission followed by selective mitophagy. Ischemic preconditioning requires autophagy/mitophagy, resulting in selective elimination of damaged mitochondria, leaving behind a population of robust mitochondria with a higher threshold for opening of the mitochondrial permeability transition pore. In this review we will consider the factors that regulate mitochondrial biogenesis and destruction, the machinery involved in both processes, and the biomedical consequences associated with altered mitochondrial turnover. PMID:21147177

  17. Mitochondrial trafficking in neurons and the role of the Miro family of GTPase proteins.

    PubMed

    Birsa, Nicol; Norkett, Rosalind; Higgs, Nathalie; Lopez-Domenech, Guillermo; Kittler, Josef T

    2013-12-01

    Correct mitochondrial dynamics are essential to neuronal function. These dynamics include mitochondrial trafficking and quality-control systems that maintain a precisely distributed and healthy mitochondrial network, so that local energy demands or Ca2+-buffering requirements within the intricate architecture of the neuron can be met. Mitochondria make use of molecular machinery that couples these organelles to microtubule-based transport via kinesin and dynein motors, facilitating the required long-range movements. These motors in turn are associated with a variety of adaptor proteins allowing additional regulation of the complex dynamics demonstrated by these organelles. Over recent years, a number of new motor and adaptor proteins have been added to a growing list of components implicated in mitochondrial trafficking and distribution. Yet, there are major questions that remain to be addressed about the regulation of mitochondrial transport complexes. One of the core components of this machinery, the mitochondrial Rho GTPases Miro1 (mitochondrial Rho 1) and Miro2 have received special attention due to their Ca2+-sensing and GTPase abilities, marking Miro an exceptional candidate for co-ordinating mitochondrial dynamics and intracellular signalling pathways. In the present paper, we discuss the wealth of literature regarding Miro-mediated mitochondrial transport in neurons and recently highlighted involvement of Miro proteins in mitochondrial turnover, emerging as a key process affected in neurodegeneration. PMID:24256248

  18. Extracellular Matrix Abnormalities in Schizophrenia

    PubMed Central

    Berretta, Sabina

    2011-01-01

    Emerging evidence points to the involvement of the brain extracellular matrix (ECM) in the pathophysiology of schizophrenia (SZ). Abnormalities affecting several ECM components, including Reelin and chondroitin sulfate proteoglycans (CSPGs), have been described in subjects with this disease. Solid evidence supports the involvement of Reelin, an ECM glycoprotein involved in corticogenesis, synaptic functions and glutamate NMDA receptor regulation, expressed prevalently in distinct populations of GABAergic neurons, which secrete it into the ECM. Marked changes of Reelin expression in SZ have typically been reported in association with GABA-related abnormalities in subjects with SZ and bipolar disorder. Recent findings from our group point to substantial abnormalities affecting CSPGs, a main ECM component, in the amygdala and entorhinal cortex of subjects with schizophrenia, but not bipolar disorder. Striking increases of glial cells expressing CSPGs were accompanied by reductions of perineuronal nets, CSPG- and Reelin-enriched ECM aggregates enveloping distinct neuronal populations. CSPGs developmental and adult functions, including neuronal migration, axon guidance, synaptic and neurotransmission regulation are highly relevant to the pathophysiology of SZ. Together with reports of anomalies affecting several other ECM components, these findings point to the ECM as a key component of the pathology of SZ. We propose that ECM abnormalities may contribute to several aspects of the pathophysiology of this disease, including disrupted connectivity and neuronal migration, synaptic anomalies and altered GABAergic, glutamatergic and dopaminergic neurotransmission. PMID:21856318

  19. HIV alters neuronal mitochondrial fission/fusion in the brain during HIV-Associated Neurocognitive Disorders

    PubMed Central

    Fields, Jerel Adam; Serger, Elisabeth; Campos, Sofia; Divakaruni, Ajit S.; Kim, Changyoun; Smith, Kendall; Trejo, Margarita; Adame, Anthony; Spencer, Brian; Rockenstein, Edward; Murphy, Anne N.; Ellis, Ronald J.; Letendre, Scott; Grant, Igor; Masliah, Eliezer

    2015-01-01

    HIV-associated neurocognitive disorders (HAND) still occur in approximately 50% of HIV patients, and therapies to combat HAND progression are urgently needed. HIV proteins are released from infected cells and cause neuronal damage, possibly through mitochondrial abnormalities. Altered mitochondrial fission and fusion is implicated in several neurodegenerative disorders. Here, we hypothesized that mitochondrial fission/fusion may be dysregulated in neurons during HAND. We have identified decreased mitochondrial fission protein (dynamin 1-like; DNM1L) in frontal cortex tissues of HAND donors, along with enlarged and elongated mitochondria localized to the soma of damaged neurons. Similar pathology was observed in the brains of GFAP-gp120 tg mice. In vitro, recombinant gp120 decreased total and active DNM1L levels, reduced the level of Mitotracker staining, and increased extracellular acidification rate (ECAR) in primary neurons. DNM1L knockdown enhanced the effects of gp120 as measured by reduced Mitotracker signal in the treated cells. Interestingly, overexpression of DNM1L increased the level of Mitotracker staining in primary rat neurons and reduced neuroinflammation and neurodegeneration in the GFAP-gp120-tg mice. These data suggest that mitochondrial biogenesis dynamics are shifted towards mitochondrial fusion in brains of HAND patients and this may be due to gp120-induced reduction in DNM1L activity. Promoting mitochondrial fission during HIV infection of the CNS may restore mitochondrial biogenesis and prevent neurodegeneration. PMID:26611103

  20. Mitochondrial Dysfunction Contributes to Hypertensive Target Organ Damage: Lessons from an Animal Model of Human Disease

    PubMed Central

    Stanzione, Rosita; Volpe, Massimo

    2016-01-01

    Mechanisms underlying hypertensive target organ damage (TOD) are not completely understood. The pathophysiological role of mitochondrial oxidative stress, resulting from mitochondrial dysfunction, in development of TOD is unclear. The stroke-prone spontaneously hypertensive rat (SHRSP) is a suitable model of human hypertension and of its vascular consequences. Pathogenesis of TOD in SHRSP is multifactorial, being determined by high blood pressure levels, high salt/low potassium diet, and genetic factors. Accumulating evidence points to a key role of mitochondrial dysfunction in increased susceptibility to TOD development of SHRSP. Mitochondrial abnormalities were described in both heart and brain of SHRSP. Pharmacological compounds able to protect mitochondrial function exerted a significant protective effect on TOD development, independently of blood pressure levels. Through our research efforts, we discovered that two genes encoding mitochondrial proteins, one (Ndufc2) involved in OXPHOS complex I assembly and activity and the second one (UCP2) involved in clearance of mitochondrial ROS, are responsible, when dysregulated, for vascular damage in SHRSP. The suitability of SHRSP as a model of human disease represents a promising background for future translation of the experimental findings to human hypertension. Novel therapeutic strategies toward mitochondrial molecular targets may become a valuable tool for prevention and treatment of TOD in human hypertension. PMID:27594970

  1. Mitochondrial Dysfunction Contributes to Hypertensive Target Organ Damage: Lessons from an Animal Model of Human Disease.

    PubMed

    Rubattu, Speranza; Stanzione, Rosita; Volpe, Massimo

    2016-01-01

    Mechanisms underlying hypertensive target organ damage (TOD) are not completely understood. The pathophysiological role of mitochondrial oxidative stress, resulting from mitochondrial dysfunction, in development of TOD is unclear. The stroke-prone spontaneously hypertensive rat (SHRSP) is a suitable model of human hypertension and of its vascular consequences. Pathogenesis of TOD in SHRSP is multifactorial, being determined by high blood pressure levels, high salt/low potassium diet, and genetic factors. Accumulating evidence points to a key role of mitochondrial dysfunction in increased susceptibility to TOD development of SHRSP. Mitochondrial abnormalities were described in both heart and brain of SHRSP. Pharmacological compounds able to protect mitochondrial function exerted a significant protective effect on TOD development, independently of blood pressure levels. Through our research efforts, we discovered that two genes encoding mitochondrial proteins, one (Ndufc2) involved in OXPHOS complex I assembly and activity and the second one (UCP2) involved in clearance of mitochondrial ROS, are responsible, when dysregulated, for vascular damage in SHRSP. The suitability of SHRSP as a model of human disease represents a promising background for future translation of the experimental findings to human hypertension. Novel therapeutic strategies toward mitochondrial molecular targets may become a valuable tool for prevention and treatment of TOD in human hypertension. PMID:27594970

  2. The HIV Protein gp120 Alters Mitochondrial Dynamics in Neurons.

    PubMed

    Avdoshina, Valeria; Fields, Jerel Adam; Castellano, Paul; Dedoni, Simona; Palchik, Guillermo; Trejo, Margarita; Adame, Anthony; Rockenstein, Edward; Eugenin, Eliseo; Masliah, Eliezer; Mocchetti, Italo

    2016-05-01

    Neurotoxicity of human immunodeficiency virus-1 (HIV) includes synaptic simplification and neuronal apoptosis. However, the mechanisms of HIV-associated neurotoxicity remain unclear, thus precluding an effective treatment of the neurological complications. The present study was undertaken to characterize novel mechanisms of HIV neurotoxicity that may explain how HIV subjects develop neuronal degeneration. Several neurodegenerative disorders are characterized by mitochondrial dysfunction; therefore, we hypothesized that HIV promotes mitochondrial damage. We first analyzed brains from HIV encephalitis (HIVE) by electron microscopy. Several sections of HIVE subjects contained enlarged and damaged mitochondria compared to brains from HIV subjects with no neurological complications. Similar pathologies were observed in mice overexpressing the HIV protein gp120, suggesting that this viral protein may be responsible for mitochondrial pathology found in HIVE. To gain more information about the cellular mechanisms of gp120 neurotoxicity, we exposed rat cortical neurons to gp120 and we determined cellular oxygen consumption rate, mitochondrial distribution, and trafficking. Our data show that gp120 evokes impairment in mitochondrial function and distribution. These data suggest that one of the mechanisms of HIV neurotoxicity includes altered mitochondrial dynamics in neurons. PMID:26936603

  3. Mitochondrial function in skeletal muscle in type 2 diabetes.

    PubMed

    Rabøl, Rasmus

    2011-04-01

    Reduced skeletal muscle mitochondrial function has been proposed to lead to insulin resistance and type 2 diabetes. It has been known for several years that oxidative capacity of skeletal muscle is reduced in patients with type 2 diabetes compared to weight matched controls. The reduction in oxidative capacity supposedly leads to the accumulation of intramyocellular lipid which inhibits insulin signalling and causes insulin resistance. It is not known whether this reduction in mitochondrial capacity is the cause or the effect of type 2 diabetes. This PhD-thesis describes the effect of different pharmacological interventions on mitochondrial function in type 2 diabetes and describe whether mitochondrial function is uniformly distributed to both upper and lower extremities. Furthermore, a hypothesis on the molecular mechanism for weight gain observed with anthyperglycaemic treatment will be presented. PMID:21466770

  4. Mitochondrial nucleoid interacting proteins support mitochondrial protein synthesis

    PubMed Central

    He, J.; Cooper, H. M.; Reyes, A.; Di Re, M.; Sembongi, H.; Litwin, T. R.; Gao, J.; Neuman, K. C.; Fearnley, I. M.; Spinazzola, A.; Walker, J. E.; Holt, I. J.

    2012-01-01

    Mitochondrial ribosomes and translation factors co-purify with mitochondrial nucleoids of human cells, based on affinity protein purification of tagged mitochondrial DNA binding proteins. Among the most frequently identified proteins were ATAD3 and prohibitin, which have been identified previously as nucleoid components, using a variety of methods. Both proteins are demonstrated to be required for mitochondrial protein synthesis in human cultured cells, and the major binding partner of ATAD3 is the mitochondrial ribosome. Altered ATAD3 expression also perturbs mtDNA maintenance and replication. These findings suggest an intimate association between nucleoids and the machinery of protein synthesis in mitochondria. ATAD3 and prohibitin are tightly associated with the mitochondrial membranes and so we propose that they support nucleic acid complexes at the inner membrane of the mitochondrion. PMID:22453275

  5. Mitochondrial flashes: new insights into mitochondrial ROS signalling and beyond.

    PubMed

    Hou, Tingting; Wang, Xianhua; Ma, Qi; Cheng, Heping

    2014-09-01

    Respiratory mitochondria undergo stochastic, intermittent bursts of superoxide production accompanied by transient depolarization of the mitochondrial membrane potential and reversible opening of the membrane permeability transition pore. These discrete events were named 'superoxide flashes' for the reactive oxygen species (ROS) signal involved, and 'mitochondrial flashes' (mitoflashes) for the entirety of the multifaceted and intertwined mitochondrial processes. In contrast to the flashless basal ROS production of 'homeostatic ROS' for redox regulation, bursting ROS production during mitoflashes may provide 'signalling ROS' at the organelle level, fulfilling distinctly different cell functions. Mounting evidence indicates that mitoflash frequency is richly regulated over a broad range, and represents a novel, universal, and 'digital' readout of mitochondrial functional status and of the mitochondrial stress response. An emerging view is that mitoflashes participate in vital processes including metabolism, cell differentiation, the stress response and ageing. These recent advances shed new light on the role of mitochondrial functional dynamics in health and disease. PMID:25038239

  6. Fetal MR Imaging of Gastrointestinal Abnormalities.

    PubMed

    Furey, Elizabeth A; Bailey, April A; Twickler, Diane M

    2016-01-01

    Fetal magnetic resonance (MR) imaging plays an increasing and valuable role in antenatal diagnosis and perinatal management of fetal gastrointestinal (GI) abnormalities. Advances in MR imaging data acquisition and use of motion-insensitive techniques have established MR imaging as an important adjunct to obstetric ultrasonography (US) for fetal diagnosis. In this regard, MR imaging provides high diagnostic accuracy for antenatal diagnosis of common and uncommon GI pathologic conditions. In the setting of fetal GI disease, T1-weighted images demonstrate the amount and distribution of meconium, which is crucial to the diagnostic capability of fetal MR imaging. Specifically, knowledge of the T1 signal intensity characteristics of fetal meconium, the normal pattern of meconium with advancing gestational age, and the expected caliber of small and large bowel in the fetus is key to diagnosis of abnormalities of the GI tract. Use of ultrafast T2-weighted sequences for evaluation of the expected location and morphology of fluid-containing structures, including the stomach and small bowel, in the fetal abdomen further aids in diagnostic confidence. Uncommonly encountered fetal GI pathologic conditions, especially cloacal dysmorphology, may demonstrate characteristic MR imaging patterns, which may add additional information to that from fetal US, allowing improved fetal and neonatal management. This article discusses common indications for fetal MR imaging of the GI tract, imaging protocols for fetal GI MR imaging, the normal appearance of the fetal GI tract with advancing gestational age, and the imaging appearances of common fetal GI abnormalities, as well as uncommon fetal GI conditions with characteristic appearances. (©)RSNA, 2016. PMID:27163598

  7. Mitochondrial cholesterol: mechanisms of import and effects on mitochondrial function.

    PubMed

    Martin, Laura A; Kennedy, Barry E; Karten, Barbara

    2016-04-01

    Mitochondria require cholesterol for biogenesis and membrane maintenance, and for the synthesis of steroids, oxysterols and hepatic bile acids. Multiple pathways mediate the transport of cholesterol from different subcellular pools to mitochondria. In steroidogenic cells, the steroidogenic acute regulatory protein (StAR) interacts with a mitochondrial protein complex to mediate cholesterol delivery to the inner mitochondrial membrane for conversion to pregnenolone. In non-steroidogenic cells, several members of a protein family defined by the presence of a StAR-related lipid transfer (START) domain play key roles in the delivery of cholesterol to mitochondrial membranes. Subdomains of the endoplasmic reticulum (ER), termed mitochondria-associated ER membranes (MAM), form membrane contact sites with mitochondria and may contribute to the transport of ER cholesterol to mitochondria, either independently or in conjunction with lipid-transfer proteins. Model systems of mitochondria enriched with cholesterol in vitro and mitochondria isolated from cells with (patho)physiological mitochondrial cholesterol accumulation clearly demonstrate that mitochondrial cholesterol levels affect mitochondrial function. Increased mitochondrial cholesterol levels have been observed in several diseases, including cancer, ischemia, steatohepatitis and neurodegenerative diseases, and influence disease pathology. Hence, a deeper understanding of the mechanisms maintaining mitochondrial cholesterol homeostasis may reveal additional targets for therapeutic intervention. Here we give a brief overview of mitochondrial cholesterol import in steroidogenic cells, and then focus on cholesterol trafficking pathways that deliver cholesterol to mitochondrial membranes in non-steroidogenic cells. We also briefly discuss the consequences of increased mitochondrial cholesterol levels on mitochondrial function and their potential role in disease pathology. PMID:25425472

  8. Brain abnormality segmentation based on l1-norm minimization

    NASA Astrophysics Data System (ADS)

    Zeng, Ke; Erus, Guray; Tanwar, Manoj; Davatzikos, Christos

    2014-03-01

    We present a method that uses sparse representations to model the inter-individual variability of healthy anatomy from a limited number of normal medical images. Abnormalities in MR images are then defined as deviations from the normal variation. More precisely, we model an abnormal (pathological) signal y as the superposition of a normal part ~y that can be sparsely represented under an example-based dictionary, and an abnormal part r. Motivated by a dense error correction scheme recently proposed for sparse signal recovery, we use l1- norm minimization to separate ~y and r. We extend the existing framework, which was mainly used on robust face recognition in a discriminative setting, to address challenges of brain image analysis, particularly the high dimensionality and low sample size problem. The dictionary is constructed from local image patches extracted from training images aligned using smooth transformations, together with minor perturbations of those patches. A multi-scale sliding-window scheme is applied to capture anatomical variations ranging from fine and localized to coarser and more global. The statistical significance of the abnormality term r is obtained by comparison to its empirical distribution through cross-validation, and is used to assign an abnormality score to each voxel. In our validation experiments the method is applied for segmenting abnormalities on 2-D slices of FLAIR images, and we obtain segmentation results consistent with the expert-defined masks.

  9. Mitochondrial phylogeny and systematics of baboons (Papio).

    PubMed

    Newman, Timothy K; Jolly, Clifford J; Rogers, Jeffrey

    2004-05-01

    Baboons (Papio, s.s.) comprise a series of parapatric allotaxa (subspecies or closely related species) widely distributed in sub-Saharan Africa. Despite extensive studies of their ecology, morphology, and behavior, disagreement about their phylogenetic relationships continues, as expressed in the current coexistence of at least three major, competing taxonomic treatments. To help resolve this situation, we sequenced approximately 900 bases of mitochondrial DNA of 40 individuals from five of the widely recognized "major" allotaxa. Total sequence diversity (>5%) is high compared to most primate species. Major mitochondrial clades correspond to recognized allotaxa, with the important exception that haplotypes from yellow and olive baboons form a single, monophyletic clade within which the two allotaxa do not comprise mutually exclusive clusters. The major clades fall unambiguously into the pattern: (chacma (Guinea (hamadryas (yellow + olive)))). This phylogeny does not support taxonomies that oppose hamadryas to all other baboons ("desert" vs. "savanna"), but is compatible with the view that all definable allotaxa should be recognized as coordinates, either as "phylogenetic" species or "biological" subspecies. The close relationship and unsegregated distribution of haplotypes from Kenyan and Tanzanian yellow and olive baboons are unexplained, but may reflect introgression across the documented hybrid zone. The overall phylogeny, when combined with paleontological data, suggests a southern African origin for extant Papio baboons, with all extant lineages sharing a common mitochondrial ancestor at approximately 1.8 Ma. PMID:15085544

  10. Unique acyl-carnitine profiles are potential biomarkers for acquired mitochondrial disease in autism spectrum disorder

    PubMed Central

    Frye, R E; Melnyk, S; MacFabe, D F

    2013-01-01

    Autism spectrum disorder (ASD) has been associated with mitochondrial disease (MD). Interestingly, most individuals with ASD and MD do not have a specific genetic mutation to explain the MD, raising the possibility of that MD may be acquired, at least in a subgroup of children with ASD. Acquired MD has been demonstrated in a rodent ASD model in which propionic acid (PPA), an enteric bacterial fermentation product of ASD-associated gut bacteria, is infused intracerebroventricularly. This animal model shows validity as it demonstrates many behavioral, metabolic, neuropathologic and neurophysiologic abnormalities associated with ASD. This animal model also demonstrates a unique pattern of elevations in short-chain and long-chain acyl-carnitines suggesting abnormalities in fatty-acid metabolism. To determine if the same pattern of biomarkers of abnormal fatty-acid metabolism are present in children with ASD, the laboratory results from a large cohort of children with ASD (n=213) who underwent screening for metabolic disorders, including mitochondrial and fatty-acid oxidation disorders, in a medically based autism clinic were reviewed. Acyl-carnitine panels were determined to be abnormal if three or more individual acyl-carnitine species were abnormal in the panel and these abnormalities were verified by repeated testing. Overall, 17% of individuals with ASD demonstrated consistently abnormal acyl-carnitine panels. Next, it was determined if specific acyl-carnitine species were consistently elevated across the individuals with consistently abnormal acyl-carnitine panels. Significant elevations in short-chain and long-chain, but not medium-chain, acyl-carnitines were found in the ASD individuals with consistently abnormal acyl-carnitine panels—a pattern consistent with the PPA rodent ASD model. Examination of electron transport chain function in muscle and fibroblast culture, histological and electron microscopy examination of muscle and other biomarkers of

  11. Mitochondrial DNA deletion mutations are concomitant with ragged red regions of individual, aged muscle fibers: analysis by laser-capture microdissection

    PubMed Central

    Cao, Zhengjin; Wanagat, Jonathan; McKiernan, Susan H.; Aiken, Judd M.

    2001-01-01

    Laser-capture microdissection was coupled with PCR to define the mitochondrial genotype of aged muscle fibers exhibiting mitochondrial enzymatic abnormalities. These electron transport system (ETS) abnormalities accumulate with age, are localized segmentally along muscle fibers, are associated with fiber atrophy and may contribute to age-related fiber loss. DNA extracted from single, 10 µm thick, ETS abnormal muscle fibers, as well as sections from normal fibers, served as templates for PCR-based deletion analysis. Large mitochondrial (mt) DNA deletion mutations (4.4–9.7 kb) were detected in all 29 ETS abnormal fibers analyzed. Deleted mtDNA genomes were detected only in the regions of the fibers with ETS abnormalities; adjacent phenotypically normal portions of the same fiber contained wild-type mtDNA. In addition, identical mtDNA deletion mutations were found within different sections of the same abnormal region. These findings demonstrate that large deletion mutations are associated with ETS abnormalities in aged rat muscle and that, within a fiber, deletion mutations are clonal. The displacement of wild-type mtDNAs with mutant mtDNAs results in concomitant mitochondrial enzymatic abnormalities, fiber atrophy and fiber breakage. PMID:11691938

  12. Platyzoan mitochondrial genomes.

    PubMed

    Wey-Fabrizius, Alexandra R; Podsiadlowski, Lars; Herlyn, Holger; Hankeln, Thomas

    2013-11-01

    Platyzoa is a putative lophotrochozoan (spiralian) subtaxon within the protostome clade of Metazoa, comprising a range of biologically diverse, mostly small worm-shaped animals. The monophyly of Platyzoa, the relationships between the putative subgroups Platyhelminthes, Gastrotricha and Gnathifera (the latter comprising at least Gnathostomulida, "Rotifera" and Acanthocephala) as well as some aspects of the internal phylogenies of these subgroups are highly debated. Here we review how complete mitochondrial (mt) genome data contribute to these debates. We highlight special features of the mt genomes and discuss problems in mtDNA phylogenies of the clade. Mitochondrial genome data seem to be insufficient to resolve the position of the platyzoan clade within the Spiralia but can help to address internal phylogenetic questions. The present review includes a tabular survey of all published platyzoan mt genomes. PMID:23274056

  13. GLIAL ABNORMALITIES IN MOOD DISORDERS

    PubMed Central

    Öngür, Dost; Bechtholt, Anita J.; Carlezon, William A.; Cohen, Bruce M.

    2015-01-01

    Multiple lines of evidence indicate that mood disorders are associated with abnormalities in the brain's cellular composition, especially in glial cells. Considered inert support cells in the past, glial cells are now known to be important for brain function. Treatments for mood disorders enhance glial cell proliferation, and experimental stimulation of cell growth has antidepressant effects in animal models of mood disorders. These findings suggest that the proliferation and survival of glial cells may be important in the pathogenesis of mood disorders and may be possible targets for the development of new treatments. In this chapter, we will review the evidence for glial abnormalities in mood disorders. We will discuss glial cell biology and evidence from postmortem studies of mood disorders. This is not carry out a comprehensive review; rather we selectively discuss existing evidence in building an argument for the role of glial cells in mood disorders. PMID:25377605

  14. Mitochondrial Functional Impairment in Response to Environmental Toxins in the Cardiorenal Metabolic Syndrome

    PubMed Central

    Jia, Guanghong; Aroor, Annayya R.; Martinez-Lemus, Luis A.; Sowers, James R.

    2015-01-01

    Environmental toxins can promote cardiovascular, metabolic and renal abnormalities, which characterize the cardiorenal metabolic syndrome (CRS). Heavy metals, such as mercury and arsenic, represent two of the most toxic pollutants. Exposure to these toxins is increasing due to increased industrialization throughout much of the world. Studies conducted to understand the impact of environmental toxins have shown a major impact on mitochondrial structure and function. The maladaptive adaptive stress products caused by these toxins, including aggregated proteins, damaged organelles, and intracellular pathogens, can be removed through autophagy, which is also known as mitophagy in mitochondria. Although the underlying mechanisms involved in the regulation of mitophagy in response to pollution are not well understood, accumulating evidence supports a role for maladaptive mitochondrial responses to environmental pollution in the pathogenesis of the CRS. In this review, we discuss ongoing research, which explores the mechanisms by which these toxins promote abnormalities in mitophagy and associated mitochondrial dysfunction and the CRS. PMID:25559775

  15. Endosymbionts and mitochondrial origins

    NASA Technical Reports Server (NTRS)

    Woese, C. R.

    1977-01-01

    The possibility is put forth that the mitochondrion did not originate from an endosymbiosis 1-2 billion years ago involving an aerobic bacterium. Rather, it arose by endosymbiosis in a much earlier anaerobic period and was initially a photosynthetic organelle analogous to the modern chloroplast. This suggestion arises from a reconsideration of the nature of endosymbiosis. It explains the remarkable diversity in mitochondrial information storage and processing systems.

  16. Modifying the Mitochondrial Genome.

    PubMed

    Patananan, Alexander N; Wu, Ting-Hsiang; Chiou, Pei-Yu; Teitell, Michael A

    2016-05-10

    Human mitochondria produce ATP and metabolites to support development and maintain cellular homeostasis. Mitochondria harbor multiple copies of a maternally inherited, non-nuclear genome (mtDNA) that encodes for 13 subunit proteins of the respiratory chain. Mutations in mtDNA occur mainly in the 24 non-coding genes, with specific mutations implicated in early death, neuromuscular and neurodegenerative diseases, cancer, and diabetes. A significant barrier to new insights in mitochondrial biology and clinical applications for mtDNA disorders is our general inability to manipulate the mtDNA sequence. Microinjection, cytoplasmic fusion, nucleic acid import strategies, targeted endonucleases, and newer approaches, which include the transfer of genomic DNA, somatic cell reprogramming, and a photothermal nanoblade, attempt to change the mtDNA sequence in target cells with varying efficiencies and limitations. Here, we discuss the current state of manipulating mammalian mtDNA and provide an outlook for mitochondrial reverse genetics, which could further enable mitochondrial research and therapies for mtDNA diseases. PMID:27166943

  17. Mitochondrial sirtuins and metabolic homeostasis

    PubMed Central

    Pirinen, Eija; Sasso, Giuseppe Lo; Auwerx, Johan

    2013-01-01

    The maintenance of metabolic homeostasis requires the well-orchestrated network of several pathways of glucose, lipid and amino acid metabolism. Mitochondria integrate these pathways and serve not only as the prime site of cellular energy harvesting but also as the producer of many key metabolic intermediates. The sirtuins are a family of NAD+-dependent enzymes, which have a crucial role in the cellular adaptation to metabolic stress. The mitochondrial sirtuins SIRT3, SIRT4 and SIRT5 together with the nuclear SIRT1 regulate several aspects of mitochondrial physiology by controlling posttranslational modifications of mitochondrial protein and transcription of mitochondrial genes. Here we discuss current knowledge how mitochondrial sirtuins and SIRT1 govern mitochondrial processes involved in different metabolic pathways. PMID:23168278

  18. Mitochondrial Dynamics in Heart Disease

    PubMed Central

    Dorn, Gerald W

    2012-01-01

    Mitochondrial fission and fusion have been observed, and their importance revealed, in almost every tissue and cell type except adult cardiac myocytes. As each human heart is uniquely dependent upon mitochondria to generate massive amounts of ATP that fuel its approximately 38 million contractions per year, it seems odd that cardiac myocytes are the sole exception to the general rule that mitochondrial dynamism is important to function. Here, I briefly review the mechanisms for mitochondrial fusion and fission and examine current data that dispel the previous notion that mitochondrial fusion is dispensable in the heart. Rare and generally overlooked examples of cardiomyopathies linked either to naturally-occurring mutations or to experimentally-induced mutagenesis of mitochondrial fusion/fission genes are described. New findings from genetically targeted Drosophila and mouse models wherein mitochondrial fusion deficiency has specifically been induced in cardiac myocytes are discussed. PMID:22450031

  19. Drug-Induced Mitochondrial Toxicity.

    PubMed

    Hargreaves, Iain P; Al Shahrani, Mesfer; Wainwright, Luke; Heales, Simon J R

    2016-07-01

    The mitochondrial respiratory chain (MRC) and ATP synthase (complex V) play an essential role in cellular energy production by the process of oxidative phosphorylation. In addition to inborn errors of metabolism, as well as secondary causes from disease pathophysiology, an impairment of oxidative phosphorylation can result from drug toxicity. These 'off-target' pharmacological effects can occur from a direct inhibition of MRC enzyme activity, an induction of mitochondrial oxidative stress, an uncoupling of oxidative phosphorylation, an impairment of mitochondrial membrane structure or a disruption in the replication of mitochondrial DNA. The purpose of this review is to focus on the off-target mitochondrial toxicity associated with both commonly used pharmacotherapies and a topical 'weight loss' agent. The mechanisms of drug-induced mitochondrial impairment will be discussed together with putative therapeutic strategies to counteract the adverse effects of the pharmacotherapy. PMID:26992920

  20. Early abnormalities in transgenic mouse models of amyotrophic lateral sclerosis.

    PubMed

    Durand, Jacques; Amendola, Julien; Bories, Cyril; Lamotte d'Incamps, Boris

    2006-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative and fatal human disorder characterized by progressive loss of motor neurons. Transgenic mouse models of ALS are very useful to study the initial mechanisms underlying this neurodegenerative disease. We will focus here on the earlier abnormalities observed in superoxide dismutase 1 (SOD1) mutant mice. Several hypotheses have been advanced to explain the selective loss of motor neurons such as apoptosis, neurofilament disorganisation, oxidative stress, mitochondrial dysfunction, astrogliosis and excitotoxicity. Although disease onset appears at adulthood, recent studies have detected abnormalities during embryonic and postnatal maturation in animal models of ALS. We reported that SOD1(G85R) mutant mice exhibit specific delays in acquiring sensory-motor skills during the first week after birth. In addition, physiological measurements on in vitro spinal cord preparations reveal defects in evoking rhythmic activity with N-methyl-DL-aspartate and serotonin at lumbar, but not sacral roots. This is potentially significant, as functions involving sacral roots are spared at late stages of the disease. Moreover, electrical properties of SOD1 lumbar motoneurons are altered as early as the second postnatal week when mice begin to walk. Alterations concern the input resistance and the gain of SOD1 motoneurons which are lower than in control motoneurons. Whether or not the early changes in discharge firing are responsible for the uncoupling between motor axon terminals and muscles is still an open question. A link between these early electrical abnormalities and the late degeneration of motoneurons is proposed in this short review. Our data suggest that ALS, as other neurodegenerative diseases, could be a consequence of an abnormal development of neurons and network properties. We hypothesize that the SOD1 mutation could induce early changes during the period of maturation of motor systems and that compensatory mechanisms

  1. Extensive mitochondrial gene rearrangement in a genus of plant parasitic nematodes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The nematodes Globodera pallida and G. rostochiensis are two of the only animals known to have multipartite mitochondrial genomes. In such genomes, mitochondrial genes are distributed on multiple circles. The entire sequence of a nematode (Radopholus similis) that belongs to the same superfamily (...

  2. Automated detection of whole-cell mitochondrial motility and its dependence on cytoarchitectural integrity.

    PubMed

    Kandel, Judith; Chou, Philip; Eckmann, David M

    2015-07-01

    Current methodologies used for mitochondrial motility analysis tend to either overlook individual mitochondrial tracks or analyze only peripheral mitochondria instead of mitochondria in all regions of the cell. Furthermore, motility analysis of an individual mitochondrion is usually quantified by establishing an arbitrary threshold for "directed" motion. In this work, we created a custom, publicly available computational algorithm based on a previously published approach (Giedt et al., 2012. Ann Biomed Eng 40:1903-1916) in order to characterize the distribution of mitochondrial movements at the whole-cell level, while still preserving information about single mitochondria. Our technique is easy to use, robust, and computationally inexpensive. Images are first pre-processed for increased resolution, and then individual mitochondria are tracked based on object connectivity in space and time. When our method is applied to microscopy fields encompassing entire cells, we reveal that the mitochondrial net distances in fibroblasts follow a lognormal distribution within a given cell or group of cells. The ability to model whole-cell mitochondrial motility as a lognormal distribution provides a new quantitative paradigm for comparing mitochondrial motility in naïve and treated cells. We further demonstrate that microtubule and microfilament depolymerization shift the lognormal distribution in directions which indicate decreased and increased mitochondrial movement, respectively. These findings advance earlier work on neuronal axons (Morris and Hollenbeck, 1993. J Cell Sci 104:917-927) by relating them to a different cell type, applying them on a global scale, and automating measurement of mitochondrial motility in general. PMID:25678368

  3. Oxidative stress induces mitochondrial dysfunction in a subset of autistic lymphoblastoid cell lines.

    PubMed

    Rose, S; Frye, R E; Slattery, J; Wynne, R; Tippett, M; Melnyk, S; James, S J

    2014-01-01

    There is an increasing recognition that mitochondrial dysfunction is associated with autism spectrum disorders. However, little attention has been given to the etiology of mitochondrial dysfunction and how mitochondrial abnormalities might interact with other physiological disturbances such as oxidative stress. Reserve capacity is a measure of the ability of the mitochondria to respond to physiological stress. In this study, we demonstrate, for the first time, that lymphoblastoid cell lines (LCLs) derived from children with autistic disorder (AD) have an abnormal mitochondrial reserve capacity before and after exposure to reactive oxygen species (ROS). Ten (44%) of 22 AD LCLs exhibited abnormally high reserve capacity at baseline and a sharp depletion of reserve capacity when challenged with ROS. This depletion of reserve capacity was found to be directly related to an atypical simultaneous increase in both proton-leak respiration and adenosine triphosphate-linked respiration in response to increased ROS in this AD LCL subgroup. In this AD LCL subgroup, 48-hour pretreatment with N-acetylcysteine, a glutathione precursor, prevented these abnormalities and improved glutathione metabolism, suggesting a role for altered glutathione metabolism associated with this type of mitochondrial dysfunction. The results of this study suggest that a significant subgroup of AD children may have alterations in mitochondrial function, which could render them more vulnerable to a pro-oxidant microenvironment as well as intrinsic and extrinsic sources of ROS such as immune activation and pro-oxidant environmental toxins. These findings are consistent with the notion that AD is caused by a combination of genetic and environmental factors. PMID:24690598

  4. Detection of heteroplasmy in individual mitochondrial particles.

    PubMed

    Poe, Bobby G; Duffy, Ciarán F; Greminger, Michael A; Nelson, Bradley J; Arriaga, Edgar A

    2010-08-01

    Mitochondrial DNA (mtDNA) mutations have been associated with disease and aging. Since each cell has thousands of mtDNA copies, clustered into nucleoids of five to ten mtDNA molecules each, determining the effects of a given mtDNA mutation and their connection with disease phenotype is not straightforward. It has been postulated that heteroplasmy (coexistence of mutated and wild-type DNA) follows simple probability rules dictated by the random distribution of mtDNA molecules at the nucleoid level. This model has been used to explain how mutation levels correlate with the onset of disease phenotype and loss of cellular function. Nonetheless, experimental evidence of heteroplasmy at the nucleoid level is scarce. Here, we report a new method to determine heteroplasmy of individual mitochondrial particles containing one or more nucleoids. The method uses capillary cytometry with laser-induced fluorescence detection to detect individual mitochondrial particles stained with PicoGreen, which makes it possible to quantify the mtDNA copy number of each particle. After detection, one or more particles are collected into polymerase chain reaction (PCR) wells and then subjected to real-time multiplexed PCR amplification. This PCR strategy is suitable to obtain the relative abundance of mutated and wild-type mtDNA. The results obtained here indicate that individual mitochondrial particles and nucleoids contained within these particles are not heteroplasmic. The results presented here suggest that current models of mtDNA segregation and distribution (i.e., heteroplasmic nucleoids) need further consideration. PMID:20467729

  5. Metabolic abnormalities of the heart in type II diabetes.

    PubMed

    Amaral, Nelson; Okonko, Darlington O

    2015-07-01

    Type 2 diabetes mellitus escalates the risk of heart failure partly via its ability to induce a cardiomyopathic state that is independent of coronary artery disease and hypertension. Although the pathogenesis of diabetic cardiomyopathy has yet to be fully elucidated, aberrations in cardiac substrate metabolism and energetics are thought to be key drivers. These aberrations include excessive fatty acid utilisation and storage, suppressed glucose oxidation and impaired mitochondrial oxidative phosphorylation. An appreciation of how these abnormalities arise and synergise to promote adverse cardiac remodelling is critical to their effective amelioration. This review focuses on disturbances in myocardial fuel (fatty acids and glucose) flux and energetics in type 2 diabetes, how these disturbances relate to the development of diabetic cardiomyopathy and the potential therapeutic agents that could be used to correct them. PMID:25941161

  6. Mitochondrial impairment observed in fibroblasts from South African Parkinson’s disease patients with parkin mutations

    SciTech Connect

    Merwe, Celia van der; Loos, Ben; Swart, Chrisna; Kinnear, Craig; Merwe, Lize van der; Pillay, Komala; Muller, Nolan; Zaharie, Dan; Engelbrecht, Lize; Carr, Jonathan; and others

    2014-05-02

    Highlights: • Mitochondrial dysfunction observed in patients with parkin-null mutations. • Mitochondrial ATP levels were decreased. • Electron-dense vacuoles were observed in the patients. • Mitochondria from muscle biopsies appeared within normal limits. • One patient did not show these defects possibly due to compensatory mechanisms. - Abstract: Parkinson’s disease (PD), defined as a neurodegenerative disorder, is characterized by the loss of dopaminergic neurons in the substantia nigra in the midbrain. Loss-of-function mutations in the parkin gene are a major cause of autosomal recessive, early-onset PD. Parkin has been implicated in the maintenance of healthy mitochondria, although previous studies show conflicting findings regarding mitochondrial abnormalities in fibroblasts from patients harboring parkin-null mutations. The aim of the present study was to determine whether South African PD patients with parkin mutations exhibit evidence for mitochondrial dysfunction. Fibroblasts were cultured from skin biopsies obtained from three patients with homozygous parkin-null mutations, two heterozygous mutation carriers and two wild-type controls. Muscle biopsies were obtained from two of the patients. The muscle fibers showed subtle abnormalities such as slightly swollen mitochondria in focal areas of the fibers and some folding of the sarcolemma. Although no differences in the degree of mitochondrial network branching were found in the fibroblasts, ultrastructural abnormalities were observed including the presence of electron-dense vacuoles. Moreover, decreased ATP levels which are consistent with mitochondrial dysfunction were observed in the patients’ fibroblasts compared to controls. Remarkably, these defects did not manifest in one patient, which may be due to possible compensatory mechanisms. These results suggest that parkin-null patients exhibit features of mitochondrial dysfunction. Involvement of mitochondria as a key role player in PD

  7. Mitochondrial Fusion in Yeast Requires the Transmembrane GTPase Fzo1p

    PubMed Central

    Hermann, Greg J.; Thatcher, John W.; Mills, John P.; Hales, Karen G.; Fuller, Margaret T.; Nunnari, Jodi; Shaw, Janet M.

    1998-01-01

    Membrane fusion is required to establish the morphology and cellular distribution of the mitochondrial compartment. In Drosophila, mutations in the fuzzy onions (fzo) GTPase block a developmentally regulated mitochondrial fusion event during spermatogenesis. Here we report that the yeast orthologue of fuzzy onions, Fzo1p, plays a direct and conserved role in mitochondrial fusion. A conditional fzo1 mutation causes the mitochondrial reticulum to fragment and blocks mitochondrial fusion during yeast mating. Fzo1p is a mitochondrial integral membrane protein with its GTPase domain exposed to the cytoplasm. Point mutations that alter conserved residues in the GTPase domain do not affect Fzo1p localization but disrupt mitochondrial fusion. Suborganellar fractionation suggests that Fzo1p spans the outer and is tightly associated with the inner mitochondrial membrane. This topology may be required to coordinate the behavior of the two mitochondrial membranes during the fusion reaction. We propose that the fuzzy onions family of transmembrane GTPases act as molecular switches to regulate a key step in mitochondrial membrane docking and/or fusion. PMID:9786948

  8. The regulation of neuronal mitochondrial metabolism by calcium.

    PubMed

    Llorente-Folch, I; Rueda, C B; Pardo, B; Szabadkai, G; Duchen, M R; Satrustegui, J

    2015-08-15

    Calcium signalling is fundamental to the function of the nervous system, in association with changes in ionic gradients across the membrane. Although restoring ionic gradients is energetically costly, a rise in intracellular Ca(2+) acts through multiple pathways to increase ATP synthesis, matching energy supply to demand. Increasing cytosolic Ca(2+) stimulates metabolite transfer across the inner mitochondrial membrane through activation of Ca(2+) -regulated mitochondrial carriers, whereas an increase in matrix Ca(2+) stimulates the citric acid cycle and ATP synthase. The aspartate-glutamate exchanger Aralar/AGC1 (Slc25a12), a component of the malate-aspartate shuttle (MAS), is stimulated by modest increases in cytosolic Ca(2+) and upregulates respiration in cortical neurons by enhancing pyruvate supply into mitochondria. Failure to increase respiration in response to small (carbachol) and moderate (K(+) -depolarization) workloads and blunted stimulation of respiration in response to high workloads (veratridine) in Aralar/AGC1 knockout neurons reflect impaired MAS activity and limited mitochondrial pyruvate supply. In response to large workloads (veratridine), acute stimulation of respiration occurs in the absence of MAS through Ca(2+) influx through the mitochondrial calcium uniporter (MCU) and a rise in matrix [Ca(2+) ]. Although the physiological importance of the MCU complex in work-induced stimulation of respiration of CNS neurons is not yet clarified, abnormal mitochondrial Ca(2+) signalling causes pathology. Indeed, loss of function mutations in MICU1, a regulator of MCU complex, are associated with neuromuscular disease. In patient-derived MICU1 deficient fibroblasts, resting matrix Ca(2+) is increased and mitochondria fragmented. Thus, the fine tuning of Ca(2+) signals plays a key role in shaping mitochondrial bioenergetics. PMID:25809592

  9. The regulation of neuronal mitochondrial metabolism by calcium

    PubMed Central

    Llorente-Folch, I; Rueda, C B; Pardo, B; Szabadkai, G; Duchen, M R; Satrustegui, J

    2015-01-01

    Calcium signalling is fundamental to the function of the nervous system, in association with changes in ionic gradients across the membrane. Although restoring ionic gradients is energetically costly, a rise in intracellular Ca2+ acts through multiple pathways to increase ATP synthesis, matching energy supply to demand. Increasing cytosolic Ca2+ stimulates metabolite transfer across the inner mitochondrial membrane through activation of Ca2+-regulated mitochondrial carriers, whereas an increase in matrix Ca2+ stimulates the citric acid cycle and ATP synthase. The aspartate–glutamate exchanger Aralar/AGC1 (Slc25a12), a component of the malate–aspartate shuttle (MAS), is stimulated by modest increases in cytosolic Ca2+ and upregulates respiration in cortical neurons by enhancing pyruvate supply into mitochondria. Failure to increase respiration in response to small (carbachol) and moderate (K+-depolarization) workloads and blunted stimulation of respiration in response to high workloads (veratridine) in Aralar/AGC1 knockout neurons reflect impaired MAS activity and limited mitochondrial pyruvate supply. In response to large workloads (veratridine), acute stimulation of respiration occurs in the absence of MAS through Ca2+ influx through the mitochondrial calcium uniporter (MCU) and a rise in matrix [Ca2+]. Although the physiological importance of the MCU complex in work-induced stimulation of respiration of CNS neurons is not yet clarified, abnormal mitochondrial Ca2+ signalling causes pathology. Indeed, loss of function mutations in MICU1, a regulator of MCU complex, are associated with neuromuscular disease. In patient-derived MICU1 deficient fibroblasts, resting matrix Ca2+ is increased and mitochondria fragmented. Thus, the fine tuning of Ca2+ signals plays a key role in shaping mitochondrial bioenergetics. PMID:25809592

  10. Constitutive Reprogramming of Fibroblast Mitochondrial Metabolism in Pulmonary Hypertension.

    PubMed

    Plecitá-Hlavatá, Lydie; Tauber, Jan; Li, Min; Zhang, Hui; Flockton, Amanda R; Pullamsetti, Soni Savai; Chelladurai, Prakash; D'Alessandro, Angelo; El Kasmi, Karim C; Ježek, Petr; Stenmark, Kurt R

    2016-07-01

    Remodeling of the distal pulmonary artery wall is a characteristic feature of pulmonary hypertension (PH). In hypoxic PH, the most substantial pathologic changes occur in the adventitia. Here, there is marked fibroblast proliferation and profound macrophage accumulation. These PH fibroblasts (PH-Fibs) maintain a hyperproliferative, apoptotic-resistant, and proinflammatory phenotype in ex vivo culture. Considering that a similar phenotype is observed in cancer cells, where it has been associated, at least in part, with specific alterations in mitochondrial metabolism, we sought to define the state of mitochondrial metabolism in PH-Fibs. In PH-Fibs, pyruvate dehydrogenase was markedly inhibited, resulting in metabolism of pyruvate to lactate, thus consistent with a Warburg-like phenotype. In addition, mitochondrial bioenergetics were suppressed and mitochondrial fragmentation was increased in PH-Fibs. Most importantly, complex I activity was substantially decreased, which was associated with down-regulation of the accessory subunit nicotinamide adenine dinucleotide reduced dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4). Owing to less-efficient ATP synthesis, mitochondria were hyperpolarized and mitochondrial superoxide production was increased. This pro-oxidative status was further augmented by simultaneous induction of cytosolic nicotinamide adenine dinucleotide phosphate reduced oxidase 4. Although acute and chronic exposure to hypoxia of adventitial fibroblasts from healthy control vessels induced increased glycolysis, it did not induce complex I deficiency as observed in PH-Fibs. This suggests that hypoxia alone is insufficient to induce NDUFS4 down-regulation and constitutive abnormalities in complex I. In conclusion, our study provides evidence that, in the pathogenesis of vascular remodeling in PH, alterations in fibroblast mitochondrial metabolism drive distinct changes in cellular behavior, which potentially occur independently of hypoxia. PMID:26699943

  11. NLRP3 inflammasome activation by mitochondrial ROS in bronchial epithelial cells is required for allergic inflammation

    PubMed Central

    Kim, S R; Kim, D I; Kim, S H; Lee, H; Lee, K S; Cho, S H; Lee, Y C

    2014-01-01

    Abnormality in mitochondria has been suggested to be associated with development of allergic airway disorders. In this study, to evaluate the relationship between mitochondrial reactive oxygen species (ROS) and NLRP3 inflammasome activation in allergic asthma, we used a newly developed mitochondrial ROS inhibitor, NecroX-5. NecroX-5 reduced the increase of mitochondrial ROS generation in airway inflammatory cells, as well as bronchial epithelial cells, NLRP3 inflammasome activation, the nuclear translocation of nuclear factor-κB, increased expression of various inflammatory mediators and pathophysiological features of allergic asthma in mice. Finally, blockade of IL-1β substantially reduced airway inflammation and hyperresponsiveness in the asthmatic mice. These findings suggest that mitochondrial ROS have a critical role in the pathogenesis of allergic airway inflammation through the modulation of NLRP3 inflammasome activation, providing a novel role of airway epithelial cells expressing NLRP3 inflammasome as an immune responder. PMID:25356867

  12. Cyclosporine A Suppressed Glucose Oxidase Induced P53 Mitochondrial Translocation and Hepatic Cell Apoptosis through Blocking Mitochondrial Permeability Transition

    PubMed Central

    Yu, Weihua; Zhang, Xiaodi; Liu, Jiangzheng; Wang, Xin; Li, Shuang; Liu, Rui; Liao, Nai; Zhang, Tao; Hai, Chunxu

    2016-01-01

    P53 is known as a transcription factor to control apoptotic cell death through regulating a series of target genes in nucleus. There is accumulating evidences show that p53 can directly induce cell apoptosis through transcription independent way at mitochondria. However, the mechanism by which p53 translocation into mitochondria in response to oxidative stress remains unclear. Here, glucose oxidase (GOX) was used to induce ROS generation in HepG2 cells and liver tissues of mice. The results showed that p53 was stabilized and translocated to mitochondria in a time and dose dependent manner after GOX exposure. Interestingly, as an inhibitor of mitochondrial permeability transition, cyclosporine A (CsA) was able to effectively reduce GOX mediated mitochondrial p53 distribution without influencing on the expression of p53 target genes including Bcl-2 and Bax. These indicated that CsA could just block p53 entering into mitochondria, but not affect p53-dependent transcription. Meanwhile, CsA failed to inhibit the ROS generation induced by GOX, which indicated that CsA had no antioxidant function. Moreover, GOX induced typical apoptosis characteristics including, mitochondrial dysfunction, accumulation of Bax and release of cytochrome C in mitochondria, accompanied with activation of caspase-9 and caspase-3. These processions were suppressed after pretreatment with CsA and pifithrin-μ (PFT-μ, a specific inhibitor of p53 mitochondrial translocation). In vivo, CsA was able to attenuate p53 mitochondrial distribution and protect mice liver against from GOX mediated apoptotic cell death. Taken together, these suggested that CsA could suppress ROS-mediated p53 mitochondrial distribution and cell apoptosis depended on its inhibition effect to mitochondrial permeability transition. It might be used to rescue the hepatic cell apoptosis in the patients with acute liver injury. PMID:26884717

  13. Cyclosporine A Suppressed Glucose Oxidase Induced P53 Mitochondrial Translocation and Hepatic Cell Apoptosis through Blocking Mitochondrial Permeability Transition.

    PubMed

    Yu, Weihua; Zhang, Xiaodi; Liu, Jiangzheng; Wang, Xin; Li, Shuang; Liu, Rui; Liao, Nai; Zhang, Tao; Hai, Chunxu

    2016-01-01

    P53 is known as a transcription factor to control apoptotic cell death through regulating a series of target genes in nucleus. There is accumulating evidences show that p53 can directly induce cell apoptosis through transcription independent way at mitochondria. However, the mechanism by which p53 translocation into mitochondria in response to oxidative stress remains unclear. Here, glucose oxidase (GOX) was used to induce ROS generation in HepG2 cells and liver tissues of mice. The results showed that p53 was stabilized and translocated to mitochondria in a time and dose dependent manner after GOX exposure. Interestingly, as an inhibitor of mitochondrial permeability transition, cyclosporine A (CsA) was able to effectively reduce GOX mediated mitochondrial p53 distribution without influencing on the expression of p53 target genes including Bcl-2 and Bax. These indicated that CsA could just block p53 entering into mitochondria, but not affect p53-dependent transcription. Meanwhile, CsA failed to inhibit the ROS generation induced by GOX, which indicated that CsA had no antioxidant function. Moreover, GOX induced typical apoptosis characteristics including, mitochondrial dysfunction, accumulation of Bax and release of cytochrome C in mitochondria, accompanied with activation of caspase-9 and caspase-3. These processions were suppressed after pretreatment with CsA and pifithrin-μ (PFT-μ, a specific inhibitor of p53 mitochondrial translocation). In vivo, CsA was able to attenuate p53 mitochondrial distribution and protect mice liver against from GOX mediated apoptotic cell death. Taken together, these suggested that CsA could suppress ROS-mediated p53 mitochondrial distribution and cell apoptosis depended on its inhibition effect to mitochondrial permeability transition. It might be used to rescue the hepatic cell apoptosis in the patients with acute liver injury. PMID:26884717

  14. Mitochondrial cereblon functions as a Lon-type protease

    PubMed Central

    Kataoka, Kosuke; Nakamura, China; Asahi, Toru; Sawamura, Naoya

    2016-01-01

    Lon protease plays a major role in the protein quality control system in mammalian cell mitochondria. It is present in the mitochondrial matrix, and degrades oxidized and misfolded proteins, thereby protecting the cell from various extracellular stresses, including oxidative stress. The intellectual disability-associated and thalidomide-binding protein cereblon (CRBN) contains a large, highly conserved Lon domain. However, whether CRBN has Lon protease-like function remains unknown. Here, we determined if CRBN has a protective function against oxidative stress, similar to Lon protease. We report that CRBN partially distributes in mitochondria, suggesting it has a mitochondrial function. To specify the mitochondrial role of CRBN, we mitochondrially expressed CRBN in human neuroblastoma SH-SY5Y cells. The resulting stable SH-SY5Y cell line showed no apparent effect on the mitochondrial functions of fusion, fission, and membrane potential. However, mitochondrially expressed CRBN exhibited protease activity, and was induced by oxidative stress. In addition, stably expressed cells exhibited suppressed neuronal cell death induced by hydrogen peroxide. These results suggest that CRBN functions specifically as a Lon-type protease in mitochondria. PMID:27417535

  15. Mitochondrial Mutations in Adenoid Cystic Carcinoma of the Salivary Glands

    PubMed Central

    Tan, Marietta; Smith, Ian M.; Califano, Joseph A.; El-Naggar, Adel K.; Ha, Patrick K.

    2009-01-01

    Background The MitoChip v2.0 resequencing array is an array-based technique allowing for accurate and complete sequencing of the mitochondrial genome. No studies have investigated mitochondrial mutation in salivary gland adenoid cystic carcinomas. Methodology The entire mitochondrial genome of 22 salivary gland adenoid cystic carcinomas (ACC) of salivary glands and matched leukocyte DNA was sequenced to determine the frequency and distribution of mitochondrial mutations in ACC tumors. Principal Findings Seventeen of 22 ACCs (77%) carried mitochondrial mutations, ranging in number from 1 to 37 mutations. A disproportionate number of mutations occurred in the D-loop. Twelve of 17 tumors (70.6%) carried mutations resulting in amino acid changes of translated proteins. Nine of 17 tumors (52.9%) with a mutation carried an amino acid changing mutation in the nicotinamide adenine dinucleotide dehydrogenase (NADH) complex. Conclusions/Significance Mitochondrial mutation is frequent in salivary ACCs. The high incidence of amino acid changing mutations implicates alterations in aerobic respiration in ACC carcinogenesis. D-loop mutations are of unclear significance, but may be associated with alterations in transcription or replication. PMID:20041111

  16. Mitochondrial fission protein Drp1 regulates mitochondrial transport and dendritic arborization in cerebellar Purkinje cells.

    PubMed

    Fukumitsu, Kansai; Hatsukano, Tetsu; Yoshimura, Azumi; Heuser, John; Fujishima, Kazuto; Kengaku, Mineko

    2016-03-01

    Mitochondria dynamically change their shape by repeated fission and fusion in response to physiological and pathological conditions. Recent studies have uncovered significant roles of mitochondrial fission and fusion in neuronal functions, such as neurotransmission and spine formation. However, the contribution of mitochondrial fission to the development of dendrites remains controversial. We analyzed the function of the mitochondrial fission GTPase Drp1 in dendritic arborization in cerebellar Purkinje cells. Overexpression of a dominant-negative mutant of Drp1 in postmitotic Purkinje cells enlarged and clustered mitochondria, which failed to exit from the soma into the dendrites. The emerging dendrites lacking mitochondrial transport remained short and unstable in culture and in vivo. The dominant-negative Drp1 affected neither the basal respiratory function of mitochondria nor the survival of Purkinje cells. Enhanced ATP supply by creatine treatment, but not reduced ROS production by antioxidant treatment, restored the hypomorphic dendrites caused by inhibition of Drp1 function. Collectively, our results suggest that Drp1 is required for dendritic distribution of mitochondria and thereby regulates energy supply in growing dendritic branches in developing Purkinje cells. PMID:26689905

  17. Mitochondrial Peroxiredoxin III is a Potential Target for Cancer Therapy

    PubMed Central

    Song, In-Sung; Kim, Hyoung-Kyu; Jeong, Seung-Hun; Lee, Sung-Ryul; Kim, Nari; Rhee, Byoung Doo; Ko, Kyung Soo; Han, Jin

    2011-01-01

    Mitochondria are involved either directly or indirectly in oncogenesis and the alteration of metabolism in cancer cells. Cancer cells contain large numbers of abnormal mitochondria and produce large amounts of reactive oxygen species (ROS). Oxidative stress is caused by an imbalance between the production of ROS and the antioxidant capacity of the cell. Several cancer therapies, such as chemotherapeutic drugs and radiation, disrupt mitochondrial homeostasis and release cytochrome c, leading to apoptosome formation, which activates the intrinsic pathway. This is modulated by the extent of mitochondrial oxidative stress. The peroxiredoxin (Prx) system is a cellular defense system against oxidative stress, and mitochondria in cancer cells are known to contain high levels of Prx III. Here, we review accumulating evidence suggesting that mitochondrial oxidative stress is involved in cancer, and discuss the role of the mitochondrial Prx III antioxidant system as a potential target for cancer therapy. We hope that this review will provide the basis for new strategic approaches in the development of effective cancer treatments. PMID:22072940

  18. Cardiac mitochondrial calcium content during fatal doxorubicin toxicity

    SciTech Connect

    Eckenhoff, R.G.; Somlyo, A.P.

    1989-01-01

    The purpose of this study was to determine whether abnormalities of mitochondrial divalent cation metabolism are early, causative events in doxorubicin (DXR, Adriamycin) cardiotoxicity. We used electron probe microanalysis (EPMA) to examine the calcium (Ca) and magensium (Mg) content of in situ mitochondria in cryosections of rat hearts, rapidly frozen at 6 hr and 1, 3, and 5 days after a single iv injection of 20 mg/kg DXR. This dose produced 100% mortality in 7 days, with a mean survival of 5.8 days. Mean control mitochondrial Ca and Mg was 0.7 and 28 mmol/kg dry wt, respectively (+/- SEM), and did not change in the DXR-injected animals, even in severely symptomatic rats 5 days after DXR. This suggests that an alteration in mitochondrial divalent cation metabolism is unlikely to be a primary event in the pathogenesis of DXR-induced cardiotoxicity, and that the mitochondrial Ca accumulation demonstrated in previous studies represents a secondary event in cells damaged by another mechanism.

  19. Making chromosome abnormalities treatable conditions.

    PubMed

    Cody, Jannine DeMars; Hale, Daniel Esten

    2015-09-01

    Individuals affected by the classic chromosome deletion syndromes which were first identified at the beginning of the genetic age, are now positioned to benefit from genomic advances. This issue highlights five of these conditions (4p-, 5p-, 11q-, 18p-, and 18q-). It focuses on the increased in understanding of the molecular underpinnings and envisions how these can be transformed into effective treatments. While it is scientifically exciting to see the phenotypic manifestations of hemizygosity being increasingly understood at the molecular and cellular level, it is even more amazing to consider that we are now on the road to making chromosome abnormalities treatable conditions. PMID:26351122

  20. Foot abnormalities of wild birds

    USGS Publications Warehouse

    Herman, C.M.; Locke, L.N.; Clark, G.M.

    1962-01-01

    The various foot abnormalities that occur in birds, including pox, scaly-leg, bumble-foot, ergotism and freezing are reviewed. In addition, our findings at the Patuxent Wildlife Research Center include pox from dove, mockingbird, cowbird, grackle and several species of sparrows. Scaly-leg has been particularly prevalent on icterids. Bumble foot has been observed in a whistling swan and in a group of captive woodcock. Ergotism is reported from a series of captive Canada geese from North Dakota. Several drug treatments recommended by others are presented.

  1. DISC1-dependent Regulation of Mitochondrial Dynamics Controls the Morphogenesis of Complex Neuronal Dendrites*

    PubMed Central

    Norkett, Rosalind; Modi, Souvik; Birsa, Nicol; Atkin, Talia A.; Ivankovic, Davor; Pathania, Manav; Trossbach, Svenja V.; Korth, Carsten; Hirst, Warren D.; Kittler, Josef T.

    2016-01-01

    The DISC1 protein is implicated in major mental illnesses including schizophrenia, depression, bipolar disorder, and autism. Aberrant mitochondrial dynamics are also associated with major mental illness. DISC1 plays a role in mitochondrial transport in neuronal axons, but its effects in dendrites have yet to be studied. Further, the mechanisms of this regulation and its role in neuronal development and brain function are poorly understood. Here we have demonstrated that DISC1 couples to the mitochondrial transport and fusion machinery via interaction with the outer mitochondrial membrane GTPase proteins Miro1 and Miro2, the TRAK1 and TRAK2 mitochondrial trafficking adaptors, and the mitochondrial fusion proteins (mitofusins). Using live cell imaging, we show that disruption of the DISC1-Miro-TRAK complex inhibits mitochondrial transport in neurons. We also show that the fusion protein generated from the originally described DISC1 translocation (DISC1-Boymaw) localizes to the mitochondria, where it similarly disrupts mitochondrial dynamics. We also show by super resolution microscopy that DISC1 is localized to endoplasmic reticulum contact sites and that the DISC1-Boymaw fusion protein decreases the endoplasmic reticulum-mitochondria contact area. Moreover, disruption of mitochondrial dynamics by targeting the DISC1-Miro-TRAK complex or upon expression of the DISC1-Boymaw fusion protein impairs the correct development of neuronal dendrites. Thus, DISC1 acts as an important regulator of mitochondrial dynamics in both axons and dendrites to mediate the transport, fusion, and cross-talk of these organelles, and pathological DISC1 isoforms disrupt this critical function leading to abnormal neuronal development. PMID:26553875

  2. Sulfur Dioxide Contributes to the Cardiac and Mitochondrial Dysfunction in Rats.

    PubMed

    Qin, Guohua; Wu, Meiqiong; Wang, Jiaoxia; Xu, Zhifang; Xia, Jin; Sang, Nan

    2016-06-01

    Epidemiological studies have demonstrated an association between sulfur dioxide (SO2) and an increase of morbidity and mortality of cardiovascular diseases, such as ischemic heart disease, heart failure, and arrhythmia. Mitochondrion is the most sensitive organelle in myocardium of animals exposed to SO2 Here we study the molecular characterization of mitochondrial dysfunction in cardiac muscles of rat after SO2 exposure. We found that the cytochrome c oxidase (COX) activity, mitochondrial membrane potential (ΔΨm), ATP contents, mitochondrial DNA (mtDNA) contents, and mRNA expression of complexes IV and V subunits encoded by mtDNA were decreased after NaHSO3 treatment in vitro or SO2 inhalation in vivo The mitochondrial dysfunctions were accompanied by depressions of co-activator of peroxisome proliferator activated receptor gamma (PGC-1α), nuclear respiratory factor 1, and mitochondrial transcription factor A (TFAM) mRNA and protein. We observed swollen mitochondria and lower amounts of cristae in hearts of rats after 3.5 mg/m(3) SO2 inhalation for 30 days. Interestingly, NaHSO3 induced mitochondrial dysfunctions marked by ΔΨm and ATP reduction could be inhibited by an antioxidant N-acetyl-L-cysteine (NALC), accompanied by the restoration of transcriptional factors expressions. The cardiac mitochondrial dysfunctions could also be alleviated by overexpression of TFAM. SO2 induced abnormal left ventricular function was restored by NALC in vivo Our findings demonstrate that SO2 induces cardiac and mitochondrial dysfunction. And inhibition of reactive oxygen species and enhancing the transcriptional network controlling mitochondrial biogenesis can mitigate the SO2-induced mitochondrial dysfunction. PMID:26980303

  3. DISC1-dependent Regulation of Mitochondrial Dynamics Controls the Morphogenesis of Complex Neuronal Dendrites.

    PubMed

    Norkett, Rosalind; Modi, Souvik; Birsa, Nicol; Atkin, Talia A; Ivankovic, Davor; Pathania, Manav; Trossbach, Svenja V; Korth, Carsten; Hirst, Warren D; Kittler, Josef T

    2016-01-01

    The DISC1 protein is implicated in major mental illnesses including schizophrenia, depression, bipolar disorder, and autism. Aberrant mitochondrial dynamics are also associated with major mental illness. DISC1 plays a role in mitochondrial transport in neuronal axons, but its effects in dendrites have yet to be studied. Further, the mechanisms of this regulation and its role in neuronal development and brain function are poorly understood. Here we have demonstrated that DISC1 couples to the mitochondrial transport and fusion machinery via interaction with the outer mitochondrial membrane GTPase proteins Miro1 and Miro2, the TRAK1 and TRAK2 mitochondrial trafficking adaptors, and the mitochondrial fusion proteins (mitofusins). Using live cell imaging, we show that disruption of the DISC1-Miro-TRAK complex inhibits mitochondrial transport in neurons. We also show that the fusion protein generated from the originally described DISC1 translocation (DISC1-Boymaw) localizes to the mitochondria, where it similarly disrupts mitochondrial dynamics. We also show by super resolution microscopy that DISC1 is localized to endoplasmic reticulum contact sites and that the DISC1-Boymaw fusion protein decreases the endoplasmic reticulum-mitochondria contact area. Moreover, disruption of mitochondrial dynamics by targeting the DISC1-Miro-TRAK complex or upon expression of the DISC1-Boymaw fusion protein impairs the correct development of neuronal dendrites. Thus, DISC1 acts as an important regulator of mitochondrial dynamics in both axons and dendrites to mediate the transport, fusion, and cross-talk of these organelles, and pathological DISC1 isoforms disrupt this critical function leading to abnormal neuronal development. PMID:26553875

  4. Thermal adaptation and clinal mitochondrial DNA variation of European anchovy.

    PubMed

    Silva, Gonçalo; Lima, Fernando P; Martel, Paulo; Castilho, Rita

    2014-10-01

    Natural populations of widely distributed organisms often exhibit genetic clinal variation over their geographical ranges. The European anchovy, Engraulis encrasicolus, illustrates this by displaying a two-clade mitochondrial structure clinally arranged along the eastern Atlantic. One clade has low frequencies at higher latitudes, whereas the other has an anti-tropical distribution, with frequencies decreasing towards the tropics. The distribution pattern of these clades has been explained as a consequence of secondary contact after an ancient geographical isolation. However, it is not unlikely that selection acts on mitochondria whose genes are involved in relevant oxidative phosphorylation processes. In this study, we performed selection tests on a fragment of 1044 bp of the mitochondrial cytochrome b gene using 455 individuals from 18 locations. We also tested correlations of six environmental features: temperature, salinity, apparent oxygen utilization and nutrient concentrations of phosphate, nitrate and silicate, on a compilation of mitochondrial clade frequencies from 66 sampling sites comprising 2776 specimens from previously published studies. Positive selection in a single codon was detected predominantly (99%) in the anti-tropical clade and temperature was the most relevant environmental predictor, contributing with 59% of the variance in the geographical distribution of clade frequencies. These findings strongly suggest that temperature is shaping the contemporary distribution of mitochondrial DNA clade frequencies in the European anchovy. PMID:25143035

  5. Dynamics of morphological changes for mitochondrial fission and fusion

    NASA Astrophysics Data System (ADS)

    Wang, Shiqi; Fu, Changliang; Zhang, Yan; Chen, Quan; Long, Mian

    2010-04-01

    Mitochondria experience continuous fusion and fission in a living cell, but their dynamics remains poorly quantified. Here a theoretical model was developed, upon a simplified population balance equation (PBE), to predict the morphological changes induced by mitochondrial fission and fusion. Assuming that both fission and fusion events are statistically independent, the survival probability of mitochondria staying in the fission or fusion state was formulated as an exponentially-decayed function with time, which depended on the time-dependent distribution of the mitochondrial volume and the fission and fusion rates. Parametric analysis was done for two typical volume distributions. One was Gamma distribution and the other was Gaussian distribution, derived from the measurements of volume distribution for individual mitochondria in a living cell and purified mitochondria in vitro. The predictions indicated that the survival probability strongly depended on morphological changes of individual mitochondria and was inversely correlated to the fission and fusion rates. This work provided a new insight into quantifying the mitochondrial dynamics via monitoring the evolution of the mitochondrial volume.

  6. Thermal adaptation and clinal mitochondrial DNA variation of European anchovy

    PubMed Central

    Silva, Gonçalo; Lima, Fernando P.; Martel, Paulo; Castilho, Rita

    2014-01-01

    Natural populations of widely distributed organisms often exhibit genetic clinal variation over their geographical ranges. The European anchovy, Engraulis encrasicolus, illustrates this by displaying a two-clade mitochondrial structure clinally arranged along the eastern Atlantic. One clade has low frequencies at higher latitudes, whereas the other has an anti-tropical distribution, with frequencies decreasing towards the tropics. The distribution pattern of these clades has been explained as a consequence of secondary contact after an ancient geographical isolation. However, it is not unlikely that selection acts on mitochondria whose genes are involved in relevant oxidative phosphorylation processes. In this study, we performed selection tests on a fragment of 1044 bp of the mitochondrial cytochrome b gene using 455 individuals from 18 locations. We also tested correlations of six environmental features: temperature, salinity, apparent oxygen utilization and nutrient concentrations of phosphate, nitrate and silicate, on a compilation of mitochondrial clade frequencies from 66 sampling sites comprising 2776 specimens from previously published studies. Positive selection in a single codon was detected predominantly (99%) in the anti-tropical clade and temperature was the most relevant environmental predictor, contributing with 59% of the variance in the geographical distribution of clade frequencies. These findings strongly suggest that temperature is shaping the contemporary distribution of mitochondrial DNA clade frequencies in the European anchovy. PMID:25143035

  7. Aldose Reductase-Mediated Phosphorylation of p53 Leads to Mitochondrial Dysfunction, and Damage in Diabetic Platelets

    PubMed Central

    Tang, Wai Ho; Stitham, Jeremiah; Jin, Yu; Liu, Renjing; Lee, Seung Hee; Du, Jing; Atteya, Gourg; Gleim, Scott; Spollett, Geralyn; Martin, Kathleen; Hwa, John

    2014-01-01

    Background Platelet abnormalities are well-recognized complications of diabetes mellitus (DM). Mitochondria play a central role in platelet metabolism and activation. Mitochondrial dysfunction is evident in DM. The molecular pathway for hyperglycemia-induced mitochondrial dysfunction in DM platelets is unknown. Methods and Results Using both human and humanized mouse models, we report that hyperglycemia-induced aldose reductase (AR) activation, and subsequent reactive oxygen species (ROS) production, leads to increased p53 phosphorylation (Ser15), which promotes mitochondrial dysfunction, damage and rupture by sequestration of the anti-apoptotic protein Bcl-xL. In a glucose dose dependent manner, severe mitochondrial damage leads to loss of mitochondrial membrane potential and platelet apoptosis (cytochrome c release, caspase 3 activation and phosphatidylserine exposure). Although platelet hyperactivation, mitochondrial dysfunction, AR activation, ROS production and p53 phosphorylation are all induced by hyperglycemia, we demonstrate that platelet apoptosis and hyperactivation are two distinct states, dependent upon the severity of the hyperglycemia and mitochondrial damage. Combined, both lead to increased thrombus formation in a mouse blood stasis model. Conclusions AR contributes to diabetes-mediated mitochondrial dysfunction and damage through the activation of p53. The degree of mitochondrial dysfunction and damage determines whether hyperactivity (mild damage) or apoptosis (severe damage) will ensue. These signaling components provide novel therapeutic targets for DM thrombotic complications. PMID:24474649

  8. Mitochondrial Contagion Induced by Parkin Deficiency in Drosophila Hearts and Its Containment by Suppressing Mitofusin

    PubMed Central

    Bhandari, Poonam; Song, Moshi; Chen, Yun; Burelle, Yan; Dorn, Gerald W.

    2015-01-01

    Rationale Dysfunctional Parkin-mediated mitophagic culling of senescent or damaged mitochondria is a major pathological process underlying Parkinson disease and a potential genetic mechanism of cardiomyopathy. Despite epidemiological associations between Parkinson disease and heart failure, the role of Parkin and mitophagic quality control in maintaining normal cardiac homeostasis is poorly understood. Objective We used germline mutants and cardiac-specific RNA interference to interrogate Parkin regulation of cardiomyocyte mitochondria and examine functional crosstalk between mitophagy and mitochondrial dynamics in Drosophila heart tubes. Methods and Results Transcriptional profiling of Parkin knockout mouse hearts revealed compensatory upregulation of multiple related E3 ubiquitin ligases. Because Drosophila lack most of these redundant genes, we examined heart tubes of parkin knockout flies and observed accumulation of enlarged hollow donut mitochondria with dilated cardiomyopathy, which could be rescued by cardiomyocyte-specific Parkin expression. Identical abnormalities were induced by cardiomyocyte-specific Parkin suppression using 2 different inhibitory RNAs. Parkin-deficient cardiomyocyte mitochondria exhibited dysmorphology, depolarization, and reactive oxygen species generation without calcium cycling abnormalities, pointing to a primary mitochondrial defect. Suppressing cardiomyocyte mitochondrial fusion in Parkin-deficient fly heart tubes completely prevented the cardiomyopathy and corrected mitochondrial dysfunction without normalizing mitochondrial dysmorphology, demonstrating a central role for mitochondrial fusion in the cardiomyopathy provoked by impaired mitophagy. Conclusions Parkin deficiency and resulting mitophagic disruption produces cardiomyopathy in part by contamination of the cardiomyocyte mitochondrial pool through fusion between improperly retained dysfunctional/senescent and normal mitochondria. Limiting mitochondrial contagion by

  9. The mitochondrial calcium uniporter is involved in mitochondrial calcium cycle dysfunction: Underlying mechanism of hypertension associated with mitochondrial tRNA(Ile) A4263G mutation.

    PubMed

    Chen, Xi; Zhang, Yu; Xu, Bin; Cai, Zhongqi; Wang, Lin; Tian, Jinwen; Liu, Yuqi; Li, Yang

    2016-09-01

    Recent studies have shown that the mitochondrial DNA mutations are involved in the pathogenesis of hypertension. Our previous study identified mitochondrial tRNA(Ile) A4263G mutation in a large Chinese Han family with maternally-inherited hypertension. This mutation may contribute to mitochondrial Ca(2+) cycling dysfuntion, but the mechanism is unclear. Lymphoblastoid cell lines were derived from hypertensive and normotensive individuals, either with or without tRNA(Ile) A4263G mutation. The mitochondrial calcium ([Ca(2+)]m) in cells from hypertensive subjects with the tRNA(Ile) A4263G mutation, was lower than in cells from normotension or hypertension without mutation, or normotension with mutation (P<0.05). Meanwhile, cytosolic calcium ([Ca(2+)]c) in hypertensive with mutation cells was higher than another three groups. After exposure to caffeine, which could increase the [Ca(2+)]c by activating ryanodine receptor on endoplasmic reticulum, [Ca(2+)]c/[Ca(2+)]m increased higher than in hypertensive with mutation cells from another three groups. Moreover, MCU expression was decreased in hypertensive with mutation cells compared with in another three groups (P<0.05). [Ca(2+)]c increased and [Ca(2+)]m decreased after treatment with Ru360 (an inhibitor of MCU) or an siRNA against MCU. In this study we found decreased MCU expression in hypertensive with mutation cells contributed to dysregulated Ca(2+) uptake into the mitochondria, and cytoplasmic Ca(2+) overload. This abnormality might be involved in the underlying mechanisms of maternally inherited hypertension in subjects carrying the mitochondrial tRNA(Ile) A4263G mutation. PMID:27471128

  10. Cutaneous mitochondrial respirometry: non-invasive monitoring of mitochondrial function.

    PubMed

    Harms, Floor A; Bodmer, Sander I A; Raat, Nicolaas J H; Mik, Egbert G

    2015-08-01

    The recently developed technique for measuring cutaneous mitochondrial oxygen tension (mitoPO2) by means of the Protoporphyrin IX-Triplet State Lifetime Technique (PpIX-TSLT) provides new opportunities for assessing mitochondrial function in vivo. The aims of this work were to study whether cutaneous mitochondrial measurements reflect mitochondrial status in other parts of the body and to demonstrate the feasibility of the technique for potential clinical use. The first part of this paper demonstrates a correlation between alterations in mitochondrial parameters in skin and other tissues during endotoxemia. Experiments were performed in rats in which mitochondrial dysfunction was induced by a lipopolysaccharide-induced sepsis (n = 5) and a time control group (n = 5). MitoPO2 and mitochondrial oxygen consumption (mitoVO2) were measured using PpIX-TSLT in skin, liver and buccal mucosa of the mouth. Both skin and buccal mucosa show a significant mitoPO2-independent decrease (P < 0.05) in mitoVO2 after LPS infusion (a decrease of 37 and 39% respectively). In liver both mitoPO2 and mitoVO2 decreased significantly (33 and 27% respectively). The second part of this paper describes the clinical concept of monitoring cutaneous mitochondrial respiration in man. A first prototype of a clinical PpIX-TSLT monitor is described and its usability is demonstrated on human skin. We expect that clinical implementation of this device will greatly contribute to our understanding of mitochondrial oxygenation and oxygen metabolism in perioperative medicine and in critical illness. Our ultimate goal is to develop a clinical monitor for mitochondrial function and the current results are an important step forward. PMID:25388510

  11. Segregation patterns of a novel mutation in the mitochondrial tRNA glutamic acid gene associated with myopathy and diabetes mellitus

    SciTech Connect

    Hao, H.; Moraes, C.T.; Bonilla, E.; Manfredi, G.; DiMauro, S.

    1995-05-01

    We have identified a novel mtDNA mutation in a 29-year-old man with myopathy and diabetes mellitus. This T{r_arrow}C transition at mtDNA position 14709 alters an evolutionarily conserved nucleotide in the region specifying for the anticodon loop of the mitochondrial tRNA{sup Glu}. The nt-14709 mutation was heteroplasmic but present at very high levels in the patient`s muscle, white blood cells (WBCs), and hair follicles; lower proportions of mutated mtDNA were observed in WBCs and hair follicles of all examined maternal relatives. In the patient`s muscle, abnormal fibers showed mitochondrial proliferation, severe focal defects in cytochrome c oxidase activity, and absence of cross-reacting material for mitochondrially synthesized polypeptides. These fibers had higher levels of mutated mtDNA than did surrounding {open_quotes}normal{close_quotes} fibers. Although the percentage of mutated mtDNA in WBCs from family members were distributed around the percentage observed in the mothers, the pattern was different in hair follicles, where the mutated population tended to increase in subsequent generations. PCR/RFLP analysis of single hair showed that the intercellular variations in the percentage of mutated mtDNA differed among family members, with younger generations having a more homogeneous distribution of mutated mtDNA in different hair follicles. These results suggests that the intercellular distribution of the mutated and wild-type mtDNA populations may drift toward homogeneity in subsequent generations. 43 refs., 4 figs., 1 tab.

  12. Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease

    PubMed Central

    Nguyen, Tammy T.; Oh, Sang S.; Weaver, David; Lewandowska, Agnieszka; Maxfield, Dane; Schuler, Max-Hinderk; Smith, Nathan K.; Macfarlane, Jane; Saunders, Gerald; Palmer, Cheryl A.; Debattisti, Valentina; Koshiba, Takumi; Pulst, Stefan; Feldman, Eva L.; Hajnóczky, György; Shaw, Janet M.

    2014-01-01

    Defective mitochondrial distribution in neurons is proposed to cause ATP depletion and calcium-buffering deficiencies that compromise cell function. However, it is unclear whether aberrant mitochondrial motility and distribution alone are sufficient to cause neurological disease. Calcium-binding mitochondrial Rho (Miro) GTPases attach mitochondria to motor proteins for anterograde and retrograde transport in neurons. Using two new KO mouse models, we demonstrate that Miro1 is essential for development of cranial motor nuclei required for respiratory control and maintenance of upper motor neurons required for ambulation. Neuron-specific loss of Miro1 causes depletion of mitochondria from corticospinal tract axons and progressive neurological deficits mirroring human upper motor neuron disease. Although Miro1-deficient neurons exhibit defects in retrograde axonal mitochondrial transport, mitochondrial respiratory function continues. Moreover, Miro1 is not essential for calcium-mediated inhibition of mitochondrial movement or mitochondrial calcium buffering. Our findings indicate that defects in mitochondrial motility and distribution are sufficient to cause neurological disease. PMID:25136135

  13. Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease.

    PubMed

    Nguyen, Tammy T; Oh, Sang S; Weaver, David; Lewandowska, Agnieszka; Maxfield, Dane; Schuler, Max-Hinderk; Smith, Nathan K; Macfarlane, Jane; Saunders, Gerald; Palmer, Cheryl A; Debattisti, Valentina; Koshiba, Takumi; Pulst, Stefan; Feldman, Eva L; Hajnóczky, György; Shaw, Janet M

    2014-09-01

    Defective mitochondrial distribution in neurons is proposed to cause ATP depletion and calcium-buffering deficiencies that compromise cell function. However, it is unclear whether aberrant mitochondrial motility and distribution alone are sufficient to cause neurological disease. Calcium-binding mitochondrial Rho (Miro) GTPases attach mitochondria to motor proteins for anterograde and retrograde transport in neurons. Using two new KO mouse models, we demonstrate that Miro1 is essential for development of cranial motor nuclei required for respiratory control and maintenance of upper motor neurons required for ambulation. Neuron-specific loss of Miro1 causes depletion of mitochondria from corticospinal tract axons and progressive neurological deficits mirroring human upper motor neuron disease. Although Miro1-deficient neurons exhibit defects in retrograde axonal mitochondrial transport, mitochondrial respiratory function continues. Moreover, Miro1 is not essential for calcium-mediated inhibition of mitochondrial movement or mitochondrial calcium buffering. Our findings indicate that defects in mitochondrial motility and distribution are sufficient to cause neurological disease. PMID:25136135

  14. Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation

    PubMed Central

    Hartmann, Bianca; Wai, Timothy; Hu, Hao; MacVicar, Thomas; Musante, Luciana; Fischer-Zirnsak, Björn; Stenzel, Werner; Gräf, Ralph; van den Heuvel, Lambert; Ropers, Hans-Hilger; Wienker, Thomas F; Hübner, Christoph; Langer, Thomas; Kaindl, Angela M

    2016-01-01

    Mitochondriopathies often present clinically as multisystemic disorders of primarily high-energy consuming organs. Assembly, turnover, and surveillance of mitochondrial proteins are essential for mitochondrial function and a key task of AAA family members of metalloproteases. We identified a homozygous mutation in the nuclear encoded mitochondrial escape 1-like 1 gene YME1L1, member of the AAA protease family, as a cause of a novel mitochondriopathy in a consanguineous pedigree of Saudi Arabian descent. The homozygous missense mutation, located in a highly conserved region in the mitochondrial pre-sequence, inhibits cleavage of YME1L1 by the mitochondrial processing peptidase, which culminates in the rapid degradation of YME1L1 precursor protein. Impaired YME1L1 function causes a proliferation defect and mitochondrial network fragmentation due to abnormal processing of OPA1. Our results identify mutations in YME1L1 as a cause of a mitochondriopathy with optic nerve atrophy highlighting the importance of YME1L1 for mitochondrial functionality in humans. DOI: http://dx.doi.org/10.7554/eLife.16078.001 PMID:27495975

  15. Impaired ALDH2 activity decreases the mitochondrial respiration in H9C2 cardiomyocytes.

    PubMed

    Mali, Vishal R; Deshpande, Mandar; Pan, Guodong; Thandavarayan, Rajarajan A; Palaniyandi, Suresh S

    2016-02-01

    Reactive oxygen species (ROS)-mediated reactive aldehydes induce cellular stress. In cardiovascular diseases such as ischemia-reperfusion injury, lipid-peroxidation derived reactive aldehydes such as 4-hydroxy-2-nonenal (4HNE) are known to contribute to the pathogenesis. 4HNE is involved in ROS formation, abnormal calcium handling and more importantly defective mitochondrial respiration. Aldehyde dehydrogenase (ALDH) superfamily contains NAD(P)(+)-dependent isozymes which can detoxify endogenous and exogenous aldehydes into non-toxic carboxylic acids. Therefore we hypothesize that 4HNE afflicts mitochondrial respiration and leads to cell death by impairing ALDH2 activity in cultured H9C2 cardiomyocyte cell lines. H9C2 cardiomyocytes were treated with 25, 50 and 75 μM 4HNE and its vehicle, ethanol as well as 25, 50 and 75 μM disulfiram (DSF), an inhibitor of ALDH2 and its vehicle (DMSO) for 4 h. 4HNE significantly decreased ALDH2 activity, ALDH2 protein levels, mitochondrial respiration and mitochondrial respiratory reserve capacity, and increased 4HNE adduct formation and cell death in cultured H9C2 cardiomyocytes. ALDH2 inhibition by DSF and ALDH2 siRNA attenuated ALDH2 activity besides reducing ALDH2 levels, mitochondrial respiration and mitochondrial respiratory reserve capacity and increased cell death. Our results indicate that ALDH2 impairment can lead to poor mitochondrial respiration and increased cell death in cultured H9C2 cardiomyocytes. PMID:26577527

  16. Glucocorticoid-induced alterations in mitochondrial membrane properties and respiration in childhood acute lymphoblastic leukemia.

    PubMed

    Eberhart, Karin; Rainer, Johannes; Bindreither, Daniel; Ritter, Ireen; Gnaiger, Erich; Kofler, Reinhard; Oefner, Peter J; Renner, Kathrin

    2011-06-01

    Mitochondria are signal-integrating organelles involved in cell death induction. Mitochondrial alterations and reduction in energy metabolism have been previously reported in the context of glucocorticoid (GC)-triggered apoptosis, although the mechanism is not yet clarified. We analyzed mitochondrial function in a GC-sensitive precursor B-cell acute lymphoblastic leukemia (ALL) model as well as in GC-sensitive and GC-resistant T-ALL model systems. Respiratory activity was preserved in intact GC-sensitive cells up to 24h under treatment with 100 nM dexamethasone before depression of mitochondrial respiration occurred. Severe repression of mitochondrial respiratory function was observed after permeabilization of the cell membrane and provision of exogenous substrates. Several mitochondrial metabolite and protein transporters and two subunits of the ATP synthase were downregulated in the T-ALL and in the precursor B-ALL model at the gene expression level under dexamethasone treatment. These data could partly be confirmed in ALL lymphoblasts from patients, dependent on the molecular abnormality in the ALL cells. GC-resistant cell lines did not show any of these defects after dexamethasone treatment. In conclusion, in GC-sensitive ALL cells, dexamethasone induces changes in membrane properties that together with the reduced expression of mitochondrial transporters of substrates and proteins may lead to repressed mitochondrial respiratory activity and lower ATP levels that contribute to GC-induced apoptosis. PMID:21237131

  17. Homozygous YME1L1 mutation causes mitochondriopathy with optic atrophy and mitochondrial network fragmentation.

    PubMed

    Hartmann, Bianca; Wai, Timothy; Hu, Hao; MacVicar, Thomas; Musante, Luciana; Fischer-Zirnsak, Björn; Stenzel, Werner; Gräf, Ralph; van den Heuvel, Lambert; Ropers, Hans-Hilger; Wienker, Thomas F; Hübner, Christoph; Langer, Thomas; Kaindl, Angela M

    2016-01-01

    Mitochondriopathies often present clinically as multisystemic disorders of primarily high-energy consuming organs. Assembly, turnover, and surveillance of mitochondrial proteins are essential for mitochondrial function and a key task of AAA family members of metalloproteases. We identified a homozygous mutation in the nuclear encoded mitochondrial escape 1-like 1 gene YME1L1, member of the AAA protease family, as a cause of a novel mitochondriopathy in a consanguineous pedigree of Saudi Arabian descent. The homozygous missense mutation, located in a highly conserved region in the mitochondrial pre-sequence, inhibits cleavage of YME1L1 by the mitochondrial processing peptidase, which culminates in the rapid degradation of YME1L1 precursor protein. Impaired YME1L1 function causes a proliferation defect and mitochondrial network fragmentation due to abnormal processing of OPA1. Our results identify mutations in YME1L1 as a cause of a mitochondriopathy with optic nerve atrophy highlighting the importance of YME1L1 for mitochondrial functionality in humans. PMID:27495975

  18. Parkinson disease-associated mutant VPS35 causes mitochondrial dysfunction by recycling DLP1 complexes

    PubMed Central

    Fujioka, Hisashi; Hoppel, Charles; Whone, Alan L.; Caldwell, Maeve A.; Cullen, Peter J.; Liu, Jun; Zhu, Xiongwei

    2015-01-01

    Mitochondrial dysfunction represents a critical step during the pathogenesis of Parkinson disease (PD) and increasing evidence suggests abnormal mitochondrial dynamics and quality control as important underlying mechanisms. The VPS35 gene, encoding a key component of the retromer complex, is the third autosomal-dominant gene associated with PD. However, how VPS35 mutations may lead to neurodegeneration remains unclear. Here we demonstrate that PD-associated VPS35 mutations caused mitochondrial fragmentation and cell death in cultured neurons in vitro, in mouse substantia nigra neurons in vivo, and in human fibroblasts from PD patient bearing the D620N mutation. VPS35-induced mitochondrial deficits and neuronal dysfunction could be prevented by inhibition of mitochondrial fission. VPS35 mutation caused increased interactions with DLP1 which enhanced mitochondrial DLP1 complex turnover via mitochondria-derived vesicles-dependent trafficking to lysosomes for degradation. Importantly, oxidative stress increased the VPS35–DLP1 interaction which was also increased in the brains of sporadic PD cases. These results revealed a novel cellular mechanism for the involvement of VPS35 in mitochondrial fission, dysregulation of which is likely involved in the pathogenesis of familial, and possibly sporadic, PD. PMID:26618722

  19. Drosophila melanogaster LRPPRC2 is involved in coordination of mitochondrial translation

    PubMed Central

    Baggio, Francesca; Bratic, Ana; Mourier, Arnaud; Kauppila, Timo E.S.; Tain, Luke S.; Kukat, Christian; Habermann, Bianca; Partridge, Linda; Larsson, Nils-Göran

    2014-01-01

    Members of the pentatricopeptide repeat domain (PPR) protein family bind RNA and are important for post-transcriptional control of organelle gene expression in unicellular eukaryotes, metazoans and plants. They also have a role in human pathology, as mutations in the leucine-rich PPR-containing (LRPPRC) gene cause severe neurodegeneration. We have previously shown that the mammalian LRPPRC protein and its Drosophila melanogaster homolog DmLRPPRC1 (also known as bicoid stability factor) are necessary for mitochondrial translation by controlling stability and polyadenylation of mRNAs. We here report characterization of DmLRPPRC2, a second fruit fly homolog of LRPPRC, and show that it has a predominant mitochondrial localization and interacts with a stem-loop interacting RNA binding protein (DmSLIRP2). Ubiquitous downregulation of DmLrpprc2 expression causes respiratory chain dysfunction, developmental delay and shortened lifespan. Unexpectedly, decreased DmLRPPRC2 expression does not globally affect steady-state levels or polyadenylation of mitochondrial transcripts. However, some mitochondrial transcripts abnormally associate with the mitochondrial ribosomes and some products are dramatically overproduced and other ones decreased, which, in turn, results in severe deficiency of respiratory chain complexes. The function of DmLRPPRC2 thus seems to be to ensure that mitochondrial transcripts are presented to the mitochondrial ribosomes in an orderly fashion to avoid poorly coordinated translation. PMID:25428350

  20. Drosophila melanogaster LRPPRC2 is involved in coordination of mitochondrial translation.

    PubMed

    Baggio, Francesca; Bratic, Ana; Mourier, Arnaud; Kauppila, Timo E S; Tain, Luke S; Kukat, Christian; Habermann, Bianca; Partridge, Linda; Larsson, Nils-Göran

    2014-12-16

    Members of the pentatricopeptide repeat domain (PPR) protein family bind RNA and are important for post-transcriptional control of organelle gene expression in unicellular eukaryotes, metazoans and plants. They also have a role in human pathology, as mutations in the leucine-rich PPR-containing (LRPPRC) gene cause severe neurodegeneration. We have previously shown that the mammalian LRPPRC protein and its Drosophila melanogaster homolog DmLRPPRC1 (also known as bicoid stability factor) are necessary for mitochondrial translation by controlling stability and polyadenylation of mRNAs. We here report characterization of DmLRPPRC2, a second fruit fly homolog of LRPPRC, and show that it has a predominant mitochondrial localization and interacts with a stem-loop interacting RNA binding protein (DmSLIRP2). Ubiquitous downregulation of DmLrpprc2 expression causes respiratory chain dysfunction, developmental delay and shortened lifespan. Unexpectedly, decreased DmLRPPRC2 expression does not globally affect steady-state levels or polyadenylation of mitochondrial transcripts. However, some mitochondrial transcripts abnormally associate with the mitochondrial ribosomes and some products are dramatically overproduced and other ones decreased, which, in turn, results in severe deficiency of respiratory chain complexes. The function of DmLRPPRC2 thus seems to be to ensure that mitochondrial transcripts are presented to the mitochondrial ribosomes in an orderly fashion to avoid poorly coordinated translation. PMID:25428350

  1. V63 and N65 of overexpressed α-synuclein are involved in mitochondrial dysfunction.

    PubMed

    Zhang, Huilin; Liu, Jia; Wang, Xue; Duan, Chunli; Wang, Xiaomin; Yang, Hui

    2016-07-01

    Parkinson's Disease (PD) is one of the most common neurodegenerative diseases. α-Synuclein (α-Syn)-encoded by SNCA, the first-identified PD-related gene-is the main component of Lewy bodies, which are a pathological hallmark of PD. We previously reported that α-Syn accumulates in mitochondria in PD, causing mitochondrial abnormalities and disrupting mitochondrial membrane potential (Δψm) and mitochondrial potential transition pore (mPTP) opening by interacting with the voltage-dependent anion channel (VDAC) and adenine nucleotide translocator. However, the mechanistic basis of mitochondrial impairment caused by α-Syn has yet to be elucidated. It has been suggested that the amino acid residues Q62, V63, and N65 of α-Syn are important for the interaction of the protein with membranes. To investigate whether this underlies the mitochondrial dysfunction induced by α-Syn overexpression, we mutated these residues to alanine and transfected HEK293T and MN9D cells with the mutated forms of α-Syn protein. The V63A and N65A mutations prevented mitochondrial Ca(2+) overload and Δψm dysregulation as well as complex I inactivation and reactive oxygen species production while blocking mPTP opening and caspase 9 activation, possibly by reducing α-Syn accumulation in mitochondria. These results indicate that V63 and N65 are critical residues mediating mitochondrial inactivation. These findings provide novel insight into the molecular events contributing to PD pathogenesis. PMID:27048753

  2. Mitochondrial Structure, Function and Dynamics Are Temporally Controlled by c-Myc

    PubMed Central

    Graves, J. Anthony; Wang, Yudong; Sims-Lucas, Sunder; Cherok, Edward; Rothermund, Kristi; Branca, Maria F.; Elster, Jennifer; Beer-Stolz, Donna; Van Houten, Bennett; Vockley, Jerry; Prochownik, Edward V.

    2012-01-01

    Although the c-Myc (Myc) oncoprotein controls mitochondrial biogenesis and multiple enzymes involved in oxidative phosphorylation (OXPHOS), the coordination of these events and the mechanistic underpinnings of their regulation remain largely unexplored. We show here that re-expression of Myc in myc−/− fibroblasts is accompanied by a gradual accumulation of mitochondrial biomass and by increases in membrane polarization and mitochondrial fusion. A correction of OXPHOS deficiency is also seen, although structural abnormalities in electron transport chain complexes (ETC) are not entirely normalized. Conversely, the down-regulation of Myc leads to a gradual decrease in mitochondrial mass and a more rapid loss of fusion and membrane potential. Increases in the levels of proteins specifically involved in mitochondrial fission and fusion support the idea that Myc affects mitochondrial mass by influencing both of these processes, albeit favoring the latter. The ETC defects that persist following Myc restoration may represent metabolic adaptations, as mitochondrial function is re-directed away from producing ATP to providing a source of metabolic precursors demanded by the transformed cell. PMID:22629444

  3. Mitochondrial complex 1 gene analysis in keratoconus

    PubMed Central

    Pathak, Dhananjay; Nayak, Bhagabat; Singh, Manvendra; Sharma, Namrata; Tandon, Radhika; Sinha, Rajesh; Titiyal, Jeewan S.

    2011-01-01

    Purpose Keratoconus is characterized by the thinning of corneal stroma, resulting in reduced vision. The exact etiology of keratoconus (KC) is still unknown. The involvement of oxidative stress (OS) in this disease has been reported. However, the exact mechanism of OS in keratoconus is still unknown. Thus we planned this study to screen mitochondrial complex I genes for sequence changes in keratoconus patients and controls, as mitochondrial complex I is the chief source of reactive oxygen species (ROS) production. Methods A total of 20 keratoconus cases and 20 healthy controls without any ocular disorder were enrolled in this study. Mitochondrial complex I genes (ND1, 2, 3, 4, 4L, 5, and 6) were amplified in all patients and controls using 12 pairs of primers by PCR. After sequencing, DNA sequences were analyzed against the mitochondrial reference sequence NC_012920. Haplogroup frequency based Principle Component Analysis (PCA) was constructed to determine whether the gene pool of keratoconus patients is closer to major populations in India. Results DNA sequencing revealed a total 84 nucleotide variations in patients and 29 in controls. Of 84 nucleotide changes, 18 variations were non-synonymous and two novel frame-shift mutations were detected in cases. Non-synonymous mtDNA sequence variations may account for increased ROS and decreased ATP production. This ultimately leads to OS; which is a known cause for variety of corneal abnormalities. Haplotype analysis showed that most of the patients were clustered under the haplogroups: T, C4a2a, R2’TJ, M21’Q1a, M12’G2a2a, M8’CZ and M7a2a, which are present as negligible frequency in normal Indian population, whereas only few patients were found to be a part of the other haplogroups like U7 (Indo-European), R2 and R31, whose origin is contentious. Conclusions Mt complex I sequence variations are the main cause of elevated ROS production which leads oxidative stress. This oxidative stress then starts a cascade of

  4. Regulation of mitochondrial morphology and cell cycle by microRNA-214 targeting Mitofusin2.

    PubMed

    Bucha, Sudha; Mukhopadhyay, Debashis; Bhattacharyya, Nitai Pada

    2015-10-01

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by the increase in CAG repeats beyond 36 at the exon1 of the gene Huntingtin (HTT). Among the various dysfunctions of biological processes in HD, transcription deregulation due to abnormalities in actions of transcription factors has been considered to be one of the important pathological conditions. In addition, deregulation of microRNA (miRNA) expression has been described in HD. Earlier, expression of microRNA-214 (miR-214) has been shown to increase in HD cell models and target HTT gene; the expression of the later being inversely correlated to that of miR-214. In the present communication, we observed that the expressions of several HTT co-expressed genes are modulated by exogenous expression of miR-214 or by its mutant. Among several HTT co-expressed genes, MFN2 was shown to be the direct target of miR-214. Exogenous expression of miR-214, repressed the expression of MFN2, increased the distribution of fragmented mitochondria and altered the distribution of cells in different phases of cell cycle. In summary, we have shown that increased expression of miR-214 observed in HD cell model could target MFN2, altered mitochondrial morphology and deregulated cell cycle. Inhibition of miR-214 could be a possible target of intervention in HD pathogenesis. PMID:26307536

  5. Sealing the mitochondrial respirasome.

    PubMed

    Winge, Dennis R

    2012-07-01

    The mitochondrial respiratory chain is organized within an array of supercomplexes that function to minimize the generation of reactive oxygen species (ROS) during electron transfer reactions. Structural models of supercomplexes are now known. Another recent advance is the discovery of non-OXPHOS complex proteins that appear to adhere to and seal the individual respiratory complexes to form stable assemblages that prevent electron leakage. This review highlights recent advances in our understanding of the structures of supercomplexes and the factors that mediate their stability. PMID:22586278

  6. Mitochondrial form and function

    PubMed Central

    Friedman, Jonathan R.; Nunnari, Jodi

    2014-01-01

    Mitochondria are one of the major ancient endomembrane systems in eukaryotic cells. Owing to their ability to produce ATP through respiration, they became a driving force in evolution. As an essential step in the process of eukaryotic evolution, the size of the mitochondrial chromosome was drastically reduced, and the behaviour of mitochondria within eukaryotic cells radically changed. Recent advances have revealed how the organelle’s behaviour has evolved to allow the accurate transmission of its genome and to become responsive to the needs of the cell and its own dysfunction. PMID:24429632

  7. Mitochondrial anomalies in a Swiss family with autosomal dominant myoglobinuria

    SciTech Connect

    Martin-du Pan, R.C.; Favre, H.; Junod, A.

    1997-04-14

    We report on a Swiss family in which 10 individuals of both sexes in 4 successive generations suffered from myoglobinuria, precipitated by febrile illness. It is the second family described with autosomal dominant inheritance of myoglobinuria. Four individuals suffered acute renal failure, which in two was reversible only after dialysis. In a recent case, a mitochondrial disorder was suspected because of an abnormal increase in lactate levels during an exercise test and because of a subsarcolemmal accumulation of mitochondria in a muscle biopsy, associated with a lack of cytochrome C oxidase in some muscle fibers. No mutation in the mitochondrial DNA was identified. Along with the inheritance pattern, these findings suggest that the myoglobinuria in this family is caused by a nuclear-encoded mutation affecting the respiratory chain. 22 refs., 2 figs.

  8. CCN6 regulates mitochondrial function.

    PubMed

    Patra, Milan; Mahata, Sushil K; Padhan, Deepesh K; Sen, Malini

    2016-07-15

    Despite established links of CCN6, or Wnt induced signaling protein-3 (WISP3), with progressive pseudo rheumatoid dysplasia, functional characterization of CCN6 remains incomplete. In light of the documented negative correlation between accumulation of reactive oxygen species (ROS) and CCN6 expression, we investigated whether CCN6 regulates ROS accumulation through its influence on mitochondrial function. We found that CCN6 localizes to mitochondria, and depletion of CCN6 in the chondrocyte cell line C-28/I2 by using siRNA results in altered mitochondrial electron transport and respiration. Enhanced electron transport chain (ETC) activity of CCN6-depleted cells was reflected by increased mitochondrial ROS levels in association with augmented mitochondrial ATP synthesis, mitochondrial membrane potential and Ca(2+) Additionally, CCN6-depleted cells display ROS-dependent PGC1α (also known as PPARGC1A) induction, which correlates with increased mitochondrial mass and volume density, together with altered mitochondrial morphology. Interestingly, transcription factor Nrf2 (also known as NFE2L2) repressed CCN6 expression. Taken together, our results suggest that CCN6 acts as a molecular brake, which is appropriately balanced by Nrf2, in regulating mitochondrial function. PMID:27252383

  9. Molecular Genetics of Mitochondrial Disorders

    ERIC Educational Resources Information Center

    Wong, Lee-Jun C.

    2010-01-01

    Mitochondrial respiratory chain (RC) disorders (RCDs) are a group of genetically and clinically heterogeneous diseases because of the fact that protein components of the RC are encoded by both mitochondrial and nuclear genomes and are essential in all cells. In addition, the biogenesis, structure, and function of mitochondria, including DNA…

  10. Abnormality on Liver Function Test

    PubMed Central

    2013-01-01

    Children with abnormal liver function can often be seen in outpatient clinics or inpatients wards. Most of them have respiratory disease, or gastroenteritis by virus infection, accompanying fever. Occasionally, hepatitis by the viruses causing systemic infection may occur, and screening tests are required. In patients with jaundice, the tests for differential diagnosis and appropriate treatment are important. In the case of a child with hepatitis B virus infection vertically from a hepatitis B surface antigen positive mother, the importance of the recognition of immune clearance can't be overstressed, for the decision of time to begin treatment. Early diagnosis changes the fate of a child with Wilson disease. So, screening test for the disease should not be omitted. Non-alcoholic fatty liver disease, which is mainly discovered in obese children, is a new strong candidate triggering abnormal liver function. Muscular dystrophy is a representative disease mimicking liver dysfunction. Although muscular dystrophy is a progressive disorder, and early diagnosis can't change the fate of patients, it will be better to avoid parent's blame for delayed diagnosis. PMID:24511518

  11. Medical management of abnormal pregnancy.

    PubMed

    Ratnam, S S; Prasad, R N

    1990-06-01

    Medical termination of abnormal pregnancy requires specific techniques since some conditions make therapy more effective, e.g., missed abortion intrauterine death and molar pregnancy, and others less so, e.g. anencephalic pregnancy. In all cases it is best to terminate the pregnancy as soon as possible to reduce anguish and risks of complications such as consumptive coagulopathy. Oxytocin is not consistently effective, but intraamniotic rivanol has oxytocic properties, and prostaglandins (PGs) are effective by several routes. Surgical methods are more popular in Japan and the US. A diagnostic flow chart is included and described. For missed abortion and fetal death vacuum aspiration or dilatation and evacuation are appropriate for early pregnancy, or PGs are used for later pregnancy, unless there are medical contraindications. Anencephalic pregnancy, usually diagnoses in 2nd or 3rd trimester, is resistant to medical therapy and must often be terminated by cesarean section. Molar pregnancy can be managed with vacuum aspiration at any length of gestation, but must be completed by curettage. Intraamniotic PGs are not advised for mole or fetal death. PG analogs can be administered intramuscularly, or vaginally in gel form. Other types of abnormal pregnancy that can be managed with PGs are spina bifida, hydrocephalus, hydrops fetalis, Dandy-Walker syndrome and Down's syndrome. Tubal pregnancy can be evacuated with intratubally administered PGs under laparoscopic control, thereby preserving tubal integrity. PMID:2225605

  12. Mitochondrial calcium uptake capacity modulates neocortical excitability

    PubMed Central

    Sanganahalli, Basavaraju G; Herman, Peter; Hyder, Fahmeed; Kannurpatti, Sridhar S

    2013-01-01

    Local calcium (Ca2+) changes regulate central nervous system metabolism and communication integrated by subcellular processes including mitochondrial Ca2+ uptake. Mitochondria take up Ca2+ through the calcium uniporter (mCU) aided by cytoplasmic microdomains of high Ca2+. Known only in vitro, the in vivo impact of mCU activity may reveal Ca2+-mediated roles of mitochondria in brain signaling and metabolism. From in vitro studies of mitochondrial Ca2+ sequestration and cycling in various cell types of the central nervous system, we evaluated ranges of spontaneous and activity-induced Ca2+ distributions in multiple subcellular compartments in vivo. We hypothesized that inhibiting (or enhancing) mCU activity would attenuate (or augment) cortical neuronal activity as well as activity-induced hemodynamic responses in an overall cytoplasmic and mitochondrial Ca2+-dependent manner. Spontaneous and sensory-evoked cortical activities were measured by extracellular electrophysiology complemented with dynamic mapping of blood oxygen level dependence and cerebral blood flow. Calcium uniporter activity was inhibited and enhanced pharmacologically, and its impact on the multimodal measures were analyzed in an integrated manner. Ru360, an mCU inhibitor, reduced all stimulus-evoked responses, whereas Kaempferol, an mCU enhancer, augmented all evoked responses. Collectively, the results confirm aforementioned hypotheses and support the Ca2+ uptake-mediated integrative role of in vivo mitochondria on neocortical activity. PMID:23591650

  13. Comparative mitochondrial genomics within and among species of killifish

    PubMed Central

    Whitehead, Andrew

    2009-01-01

    Background This study was motivated by the observation of unusual mitochondrial haplotype distributions and associated physiological differences between populations of the killifish Fundulus heteroclitus distributed along the Atlantic coast of North America. A distinct "northern" haplotype is fixed in all populations north of New Jersey, and does not appear south of New Jersey except in extreme upper-estuary fresh water habitats, and northern individuals are known to be more tolerant of hyposmotic conditions than southern individuals. Complete mitochondrial genomes were sequenced from individuals from northern coastal, southern coastal, and fresh water populations (and from out-groups). Comparative genomics approaches were used to test multiple evolutionary hypotheses proposed to explain among-population genome variation including directional selection and hybridization. Results Structure and organization of the Fundulus mitochondrial genome is typical of animals, yet subtle differences in substitution patterns exist among populations. No signals of directional selection or hybridization were detected. Mitochondrial genes evolve at variable rates, but all genes exhibit very low dN/dS ratios across all lineages, and the southern population harbors more synonymous polymorphism than other populations. Conclusion Evolution of mitochondrial genomes within Fundulus is primarily governed by interaction between strong purifying selection and demographic influences, including larger historical population size in the south. Though directional selection and hybridization hypotheses were not supported, adaptive processes may indirectly contribute to partitioning of variation between populations. PMID:19144111

  14. Miro sculpts mitochondrial dynamics in neuronal health and disease.

    PubMed

    Devine, Michael J; Birsa, Nicol; Kittler, Josef T

    2016-06-01

    Neurons are highly polarised cells with an elaborate and diverse cytoarchitecture. But this complex architecture presents a major problem: how to appropriately distribute metabolic resources where they are most needed within the cell. The solution comes in the form of mitochondria: highly dynamic organelles subject to a repertoire of trafficking, fission/fusion and quality control systems which work in concert to orchestrate a precisely distributed and healthy mitochondrial network. Mitochondria are critical for maintaining local energy supply and buffering Ca(2+) flux within neurons, and are increasingly recognised as being essential for healthy neuronal function. Mitochondrial movements are facilitated by their coupling to microtubule-based transport via kinesin and dynein motors. Adaptor proteins are required for this coupling and the mitochondrial Rho GTPases Miro1 and Miro2 are core components of this machinery. Both Miros have Ca(2+)-sensing and GTPase domains, and are therefore ideally suited to coordinating mitochondrial dynamics with intracellular signalling pathways and local energy turnover. In this review, we focus on Miro's role in mediating mitochondrial transport in neurons, and the relevance of these mechanisms to neuronal health and disease. PMID:26707701

  15. Mitochondrial Morphology in Metabolic Diseases

    PubMed Central

    Galloway, Chad A.

    2013-01-01

    Abstract Significance: Mitochondria are the cellular energy-producing organelles and are at the crossroad of determining cell life and death. As such, the function of mitochondria has been intensely studied in metabolic disorders, including diabetes and associated maladies commonly grouped under all-inclusive pathological condition of metabolic syndrome. More recently, the altered metabolic profiles and function of mitochondria in these ailments have been correlated with their aberrant morphologies. This review describes an overview of mitochondrial fission and fusion machineries, and discusses implications of mitochondrial morphology and function in these metabolic maladies. Recent Advances: Mitochondria undergo frequent morphological changes, altering the mitochondrial network organization in response to environmental cues, termed mitochondrial dynamics. Mitochondrial fission and fusion mediate morphological plasticity of mitochondria and are controlled by membrane-remodeling mechanochemical enzymes and accessory proteins. Growing evidence suggests that mitochondrial dynamics play an important role in diabetes establishment and progression as well as associated ailments, including, but not limited to, metabolism–secretion coupling in the pancreas, nonalcoholic fatty liver disease progression, and diabetic cardiomyopathy. Critical Issues: While mitochondrial dynamics are intimately associated with mitochondrial bioenergetics, their cause-and-effect correlation remains undefined in metabolic diseases. Future Directions: The involvement of mitochondrial dynamics in metabolic diseases is in its relatively early stages. Elucidating the role of mitochondrial dynamics in pathological metabolic conditions will aid in defining the intricate form–function correlation of mitochondria in metabolic pathologies and should provide not only important clues to metabolic disease progression, but also new therapeutic targets. Antioxid. Redox Signal. 19, 415–430. PMID:22793999

  16. MITOCHONDRIAL FUNCTION IN SEPSIS.

    PubMed

    Arulkumaran, Nishkantha; Deutschman, Clifford S; Pinsky, Michael R; Zuckerbraun, Brian; Schumacker, Paul T; Gomez, Hernando; Gomez, Alonso; Murray, Patrick; Kellum, John A

    2016-03-01

    Mitochondria are an essential part of the cellular infrastructure, being the primary site for high-energy adenosine triphosphate production through oxidative phosphorylation. Clearly, in severe systemic inflammatory states, like sepsis, cellular metabolism is usually altered, and end organ dysfunction is not only common, but also predictive of long-term morbidity and mortality. Clearly, interest is mitochondrial function both as a target for intracellular injury and response to extrinsic stress have been a major focus of basic science and clinical research into the pathophysiology of acute illness. However, mitochondria have multiple metabolic and signaling functions that may be central in both the expression of sepsis and its ultimate outcome. In this review, the authors address five primary questions centered on the role of mitochondria in sepsis. This review should be used both as a summary source in placing mitochondrial physiology within the context of acute illness and as a focal point for addressing new research into diagnostic and treatment opportunities these insights provide. PMID:26871665

  17. ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells.

    PubMed

    Lewis, Samantha C; Uchiyama, Lauren F; Nunnari, Jodi

    2016-07-15

    Mitochondrial DNA (mtDNA) encodes RNAs and proteins critical for cell function. In human cells, hundreds to thousands of mtDNA copies are replicated asynchronously, packaged into protein-DNA nucleoids, and distributed within a dynamic mitochondrial network. The mechanisms that govern how nucleoids are chosen for replication and distribution are not understood. Mitochondrial distribution depends on division, which occurs at endoplasmic reticulum (ER)-mitochondria contact sites. These sites were spatially linked to a subset of nucleoids selectively marked by mtDNA polymerase and engaged in mtDNA synthesis--events that occurred upstream of mitochondrial constriction and division machine assembly. Our data suggest that ER tubules proximal to nucleoids are necessary but not sufficient for mtDNA synthesis. Thus, ER-mitochondria contacts coordinate licensing of mtDNA synthesis with division to distribute newly replicated nucleoids to daughter mitochondria. PMID:27418514

  18. Mitochondrial DNA divergence in Lygus lineolaris (Hemiptera: Miridae)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The genus Lygus is widely distributed in North America and Eurasia. The tarnished plant bug, Lygus lineolaris, is one of the most serious pest species within this genus having >300 different plant hosts. The intra-specific genetic diversity of L. lineolaris is being examined by employing mitochondri...

  19. Abnormalities of the Erythrocyte Membrane

    PubMed Central

    Gallagher, Patrick G.

    2014-01-01

    Synopsis Primary abnormalities of the erythrocyte membrane, including the hereditary spherocytosis and hereditary elliptocytosis syndromes, are an important group of inherited hemolytic anemias. Classified by distinctive morphology on peripheral blood smear, these disorders are characterized by clinical, laboratory, and genetic heterogeneity. Among this group, hereditary spherocytosis patients are more likely to experience symptomatic anemia. Treatment of hereditary spherocytosis with splenectomy is curative in most patients. Once considered routine, growing recognition of the longterm risks of splenectomy, including cardiovascular disease, thrombotic disorders, and pulmonary hypertension, as well as the emergence of penicillin-resistant pneumococci, a concern for infection in overwhelming postsplenectomy infection, have led to re-evaluation of the role of splenectomy. Current management guidelines acknowledge these important considerations when entertaining splenectomy and recommend detailed discussion between health care providers, patient, and family. The hereditary elliptocytosis syndromes are the most common primary disorders of erythrocyte membrane proteins. However, most elliptocytosis patients are asymptomatic and do not require therapy. PMID:24237975

  20. Adults with Chromosome 18 Abnormalities.

    PubMed

    Soileau, Bridgette; Hasi, Minire; Sebold, Courtney; Hill, Annice; O'Donnell, Louise; Hale, Daniel E; Cody, Jannine D

    2015-08-01

    The identification of an underlying chromosome abnormality frequently marks the endpoint of a diagnostic odyssey. However, families are frequently left with more questions than answers as they consider their child's future. In the case of rare chromosome conditions, a lack of longitudinal data often makes it difficult to provide anticipatory guidance to these families. The objective of this study is to describe the lifespan, educational attainment, living situation, and behavioral phenotype of adults with chromosome 18 abnormalities. The Chromosome 18 Clinical Research Center has enrolled 483 individuals with one of the following conditions: 18q-, 18p-, Tetrasomy 18p, and Ring 18. As a part of the ongoing longitudinal study, we collect data on living arrangements, educational level attained, and employment status as well as data on executive functioning and behavioral skills on an annual basis. Within our cohort, 28 of the 483 participants have died, the majority of whom have deletions encompassing the TCF4 gene or who have unbalanced rearrangement involving other chromosomes. Data regarding the cause of and age at death are presented. We also report on the living situation, educational attainment, and behavioral phenotype of the 151 participants over the age of 18. In general, educational level is higher for people with all these conditions than implied by the early literature, including some that received post-high school education. In addition, some individuals are able to live independently, though at this point they represent a minority of patients. Data on executive function and behavioral phenotype are also presented. Taken together, these data provide insight into the long-term outcome for individuals with a chromosome 18 condition. This information is critical in counseling families on the range of potential outcomes for their child. PMID:25403900

  1. S-Nitrosylation of Critical Protein Thiols Mediates Protein Misfolding and Mitochondrial Dysfunction in Neurodegenerative Diseases

    PubMed Central

    Nakamura, Tomohiro

    2011-01-01

    Abstract Excessive nitrosative and oxidative stress is thought to trigger cellular signaling pathways leading to neurodegenerative conditions. Such redox dysregulation can result from many cellular events, including hyperactivation of the N-methyl-d-aspartate-type glutamate receptor, mitochondrial dysfunction, and cellular aging. Recently, we and our colleagues have shown that excessive generation of free radicals and related molecules, in particular nitric oxide species (NO), can trigger pathological production of misfolded proteins, abnormal mitochondrial dynamics (comprised of mitochondrial fission and fusion events), and apoptotic pathways in neuronal cells. Emerging evidence suggests that excessive NO production can contribute to these pathological processes, specifically by S-nitrosylation of specific target proteins. Here, we highlight examples of S-nitrosylated proteins that regulate misfolded protein accumulation and mitochondrial dynamics. For instance, in models of Parkinson's disease, these S-nitrosylation targets include parkin, a ubiquitin E3 ligase and neuroprotective molecule, and protein-disulfide isomerase, a chaperone enzyme for nascent protein folding. S-Nitrosylation of protein-disulfide isomerase may also be associated with mutant Cu/Zn superoxide dismutase toxicity in amyotrophic lateral sclerosis. Additionally, in models of Alzheimer's disease, excessive NO generation leads to the formation of S-nitrosylated dynamin-related protein 1 (forming SNO-Drp1), which contributes to abnormal mitochondrial fragmentation and resultant synaptic damage. Antioxid. Redox Signal. 14, 1479–1492. PMID:20812868

  2. Mitochondrial organization and motility probed by two-photon microscopy in cultured mouse brainstem neurons

    SciTech Connect

    Mueller, Michael . E-mail: mike@neuro-physiol.med.uni-goettingen.de; Mironov, Sergej L.; Ivannikov, Maxim V.; Schmidt, Joerg; Richter, Diethelm W.

    2005-02-01

    Two-photon microscopy of rhodamine 123-labeled mitochondria revealed that mitochondria of neurons cultured from mouse respiratory center form functionally coupled, dynamically organized aggregates such as chains and clusters, while single mitochondria were rarely seen. Mitochondrial chain structures predominate in dendrites, while irregularly shaped mitochondrial clusters are mostly found in the soma. Both types of mitochondrial structures showed chaotic Brownian motions and the mitochondrial chains also revealed well-directed movements. The latter dislocations were arrested upon mitochondrial depolarization or blockade of mitochondrial ATP synthesis. Depolymerization of microtubules by colchicine or nocodazole or inhibition of protein phosphatases by calyculin A disrupted mitochondrial chains and the mitochondria accumulated in the soma. Forskolin and IBMX reversibly blocked directed movements of mitochondria, but did not affect their overall spatial distribution. Thus, protein phosphorylation seems to control both mitochondrial transport and organization. Protein phosphorylation downstream of enhanced cytosolic cAMP levels apparently regulates the transition from motile to non-motile mitochondria, while phosphorylation resulting from inhibition of types 1 and 2A protein phosphatases massively disturbs mitochondrial organization. The complex phosphorylation processes seem to control the close interaction of mitochondria and cytoskeleton which may guarantee that mitochondria are immobilized at energetic hot spots and rearranged in response to changes in local energy demands.

  3. Role and Treatment of Mitochondrial DNA-Related Mitochondrial Dysfunction in Sporadic Neurodegenerative Diseases

    PubMed Central

    Swerdlow, Russell H.

    2012-01-01

    Several sporadic neurodegenerative diseases display phenomena that directly or indirectly relate to mitochondrial function. Data suggesting altered mitochondrial function in these diseases could arise from mitochondrial DNA (mtDNA) are reviewed. Approaches for manipulating mitochondrial function and minimizing the downstream consequences of mitochondrial dysfunction are discussed. PMID:21902672

  4. Role of mitochondrial dysfunction in cancer progression.

    PubMed

    Hsu, Chia-Chi; Tseng, Ling-Ming; Lee, Hsin-Chen

    2016-06-01

    Deregulated cellular energetics was one of the cancer hallmarks. Several underlying mechanisms of deregulated cellular energetics are associated with mitochondrial dysfunction caused by mitochondrial DNA mutations, mitochondrial enzyme defects, or altered oncogenes/tumor suppressors. In this review, we summarize the current understanding about the role of mitochondrial dysfunction in cancer progression. Point mutations and copy number changes are the two most common mitochondrial DNA alterations in cancers, and mitochondrial dysfunction induced by chemical depletion of mitochondrial DNA or impairment of mitochondrial respiratory chain in cancer cells promotes cancer progression to a chemoresistance or invasive phenotype. Moreover, defects in mitochondrial enzymes, such as succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase, are associated with both familial and sporadic forms of cancer. Deregulated mitochondrial deacetylase sirtuin 3 might modulate cancer progression by regulating cellular metabolism and oxidative stress. These mitochondrial defects during oncogenesis and tumor progression activate cytosolic signaling pathways that ultimately alter nuclear gene expression, a process called retrograde signaling. Changes in the intracellular level of reactive oxygen species, Ca(2+), or oncometabolites are important in the mitochondrial retrograde signaling for neoplastic transformation and cancer progression. In addition, altered oncogenes/tumor suppressors including hypoxia-inducible factor 1 and tumor suppressor p53 regulate mitochondrial respiration and cellular metabolism by modulating the expression of their target genes. We thus suggest that mitochondrial dysfunction plays a critical role in cancer progression and that targeting mitochondrial alterations and mitochondrial retrograde signaling might be a promising strategy for the development of selective anticancer therapy. PMID:27022139

  5. Mitochondrial dysfunction in heart failure

    PubMed Central

    Rosca, Mariana G.; Hoppel, Charles L.

    2013-01-01

    Heart failure (HF) is a complex chronic clinical syndrome. Energy deficit is considered to be a key contributor to the development of both cardiac and skeletal myopathy. In HF several components of cardiac and skeletal muscle bioenergetics are altered, such as oxygen availability, substrate oxidation, mitochondrial ATP production, and ATP transfer to the contractile apparatus via the creatine kinase shuttle. This review focuses on alterations in mitochondrial biogenesis and respirasome organization, substrate oxidation coupled with ATP synthesis in the context of their contribution to the chronic energy deficit, and mechanical dysfunction of the cardiac and skeletal muscle in HF. We conclude that HF is associated with decreased mitochondrial biogenesis and function in both heart and skeletal muscle, supporting the concept of a systemic mitochondrial cytopathy. The sites of mitochondrial defects are located within the electron transport and phosphorylation apparatus, and differ with the etiology and progression of HF in the two mitochondrial populations (subsarcolemmal and interfibrillar) of cardiac and skeletal muscle. The roles of adrenergic stimulation, the renin-angiotensin system, and cytokines are evaluated as factors responsible for the systemic energy deficit. We propose a cylic AMP-mediated mechanism by which increased adrenergic stimulation contributes to the mitochondrial dysfunction. PMID:22948484

  6. Ubisol-Q10 Prevents Glutamate-Induced Cell Death by Blocking Mitochondrial Fragmentation and Permeability Transition Pore Opening

    PubMed Central

    Kumari, Santosh; Mehta, Suresh L; Milledge, Gaolin Z.; Huang, Xinyu; Li, Haining; Li, P. Andy

    2016-01-01

    Mitochondrial dysfunction and oxidative stress are the major events that lead to the formation of mitochondrial permeability transition pore (mPTP) during glutamate-induced cytotoxicity and cell death. Coenzyme Q10 (CoQ10) has widely been used for the treatment of mitochondrial disorders and neurodegenerative diseases. Comparing to traditional lipid-soluble CoQ10, water soluble CoQ10 (Ubisol-Q10) has high intracellular and intra-mitochondrial distribution. The aims of the present study are to determine the neuroprotective effects of Ubisol-Q10 on glutamate-induced cell death and to explore its functional mechanisms. HT22 neuronal cells were exposed to glutamate. Cell viability was measured and mitochondrial fragmentation was assessed by mitochondrial imaging. The mPTP opening was determined by mitochondrial membrane potential and calcium retention capacity. The results revealed that the anti-glutamate toxicity effects of Ubisol-Q10 was associated with its ability to block mitochondrial fragmentation, to maintain calcium retention capacity and mitochondrial membrane potential, and to prevent mPTP formation, AIF release, and DNA fragmentation. We concluded that Ubisol-Q10 protects cells from glutamate toxicity by preserving the integrity of mitochondrial structure and function. Therefore, adequate CoQ10 supplementation may be beneficial in preventing cerebral stroke and other disorders that involve mitochondrial dysfunction. PMID:27194946

  7. Modulation of mitochondrial function and morphology by interaction of Omi/HtrA2 with the mitochondrial fusion factor OPA1

    SciTech Connect

    Kieper, Nicole; Holmstroem, Kira M.; Ciceri, Dalila; Fiesel, Fabienne C.; Wolburg, Hartwig; Ziviani, Elena; Whitworth, Alexander J.; Martins, L. Miguel; Kahle, Philipp J.; Krueger, Rejko

    2010-04-15

    Loss of Omi/HtrA2 function leads to nerve cell loss in mouse models and has been linked to neurodegeneration in Parkinson's and Huntington's disease. Omi/HtrA2 is a serine protease released as a pro-apoptotic factor from the mitochondrial intermembrane space into the cytosol. Under physiological conditions, Omi/HtrA2 is thought to be involved in protection against cellular stress, but the cytological and molecular mechanisms are not clear. Omi/HtrA2 deficiency caused an accumulation of reactive oxygen species and reduced mitochondrial membrane potential. In Omi/HtrA2 knockout mouse embryonic fibroblasts, as well as in Omi/HtrA2 silenced human HeLa cells and Drosophila S2R+ cells, we found elongated mitochondria by live cell imaging. Electron microscopy confirmed the mitochondrial morphology alterations and showed abnormal cristae structure. Examining the levels of proteins involved in mitochondrial fusion, we found a selective up-regulation of more soluble OPA1 protein. Complementation of knockout cells with wild-type Omi/HtrA2 but not with the protease mutant [S306A]Omi/HtrA2 reversed the mitochondrial elongation phenotype and OPA1 alterations. Finally, co-immunoprecipitation showed direct interaction of Omi/HtrA2 with endogenous OPA1. Thus, we show for the first time a direct effect of loss of Omi/HtrA2 on mitochondrial morphology and demonstrate a novel role of this mitochondrial serine protease in the modulation of OPA1. Our results underscore a critical role of impaired mitochondrial dynamics in neurodegenerative disorders.

  8. Degree of Glutathione Deficiency and Redox Imbalance Depend on Subtype of Mitochondrial Disease and Clinical Status

    PubMed Central

    Enns, Gregory M.; Moore, Tereza; Le, Anthony; Atkuri, Kondala; Shah, Monisha K.; Cusmano-Ozog, Kristina; Niemi, Anna-Kaisa; Cowan, Tina M.

    2014-01-01

    Mitochondrial disorders are associated with decreased energy production and redox imbalance. Glutathione plays a central role in redox signaling and protecting cells from oxidative damage. In order to understand the consequences of mitochondrial dysfunction on in vivo redox status, and to determine how this varies by mitochondrial disease subtype and clinical severity, we used a sensitive tandem mass spectrometry assay to precisely quantify whole blood reduced (GSH) and oxidized (GSSG) glutathione levels in a large cohort of mitochondrial disorder patients. Glutathione redox potential was calculated using the Nernst equation. Compared to healthy controls (n = 59), mitochondrial disease patients (n = 58) as a group showed significant redox imbalance (redox potential −251 mV±9.7, p<0.0001) with an increased level of oxidation by ∼9 mV compared to controls (−260 mV±6.4). Underlying this abnormality were significantly lower whole blood GSH levels (p = 0.0008) and GSH/GSSG ratio (p = 0.0002), and significantly higher GSSG levels (p<0.0001) in mitochondrial disease patients compared to controls. Redox potential was significantly more oxidized in all mitochondrial disease subgroups including Leigh syndrome (n = 15), electron transport chain abnormalities (n = 10), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (n = 8), mtDNA deletion syndrome (n = 7), mtDNA depletion syndrome (n = 7), and miscellaneous other mitochondrial disorders (n = 11). Patients hospitalized in metabolic crisis (n = 7) showed the greatest degree of redox imbalance at −242 mV±7. Peripheral whole blood GSH and GSSG levels are promising biomarkers of mitochondrial dysfunction, and may give insights into the contribution of oxidative stress to the pathophysiology of the various mitochondrial disorders. In particular, evaluation of redox potential may be useful in monitoring of clinical status or response to redox

  9. Breathing abnormalities in sleep in achondroplasia.

    PubMed Central

    Waters, K A; Everett, F; Sillence, D; Fagan, E; Sullivan, C E

    1993-01-01

    Overnight sleep studies were performed in 20 subjects with achondroplasia to document further the respiratory abnormalities present in this group. Somatosensory evoked potentials (SEPs) were recorded in 19 of the subjects to screen for the presence of brainstem abnormalities, which are one of the potential aetiological mechanisms. Fifteen children aged 1 to 14 years, and five young adults, aged 20 to 31 years were included. All had upper airway obstruction and 15 (75%) had a pathological apnoea index (greater than five per hour). Other sleep associated respiratory abnormalities, including partial obstruction, central apnoea, and abnormal electromyographic activity of accessory muscles of respiration, also showed a high prevalence. SEPs were abnormal in eight (42%), but there was no correlation between abnormal SEPs and apnoea during sleep, either qualitatively or quantitatively. A high prevalence of both sleep related respiratory abnormalities and abnormal SEPs in young subjects with achondroplasia was demonstrated. However, the sleep related respiratory abnormalities do not always result in significant blood gas disturbances or correlate with abnormal SEPs in this group. PMID:8215519

  10. Cognitive dysfunction in mitochondrial disorders.

    PubMed

    Finsterer, J

    2012-07-01

    Among the various central nervous system (CNS) manifestations of mitochondrial disorders (MIDs), cognitive impairment is increasingly recognized and diagnosed (mitochondrial cognitive dysfunction). Aim of the review was to summarize recent findings concerning the aetiology, pathogenesis, diagnosis and treatment of cognitive decline in MIDs. Among syndromic MIDs due to mitochondrial DNA (mtDNA) mutations, cognitive impairment occurs in patients with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome, myoclonus epilepsy with ragged-red fibres syndrome, mitochondrial chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, neuropathy, ataxia and retinitis pigmentosa syndrome and maternally inherited diabetes and deafness. Among syndromic MIDs due to nuclear DNA (nDNA) mutations, cognitive decline has been reported in myo-neuro-gastro-intestinal encephalopathy, mitochondrial recessive ataxia syndrome, spinocerebellar ataxia with encephalopathy, Mohr-Tranebjaerg syndrome, leuko-encephalopathy; brain and spinal cord involvement and lactic acidosis, CMT2, Wolfram syndrome, Wolf-Hirschhorn syndrome and Leigh syndrome. In addition to syndromic MIDs, a large number of non-syndromic MIDs due to mtDNA as well as nDNA mutations have been reported, which present with cognitive impairment as the sole or one among several other CNS manifestations of a MID. Delineation of mitochondrial cognitive impairment from other types of cognitive impairment is essential to guide the optimal management of these patients. Treatment of mitochondrial cognitive impairment is largely limited to symptomatic and supportive measures. Cognitive impairment may be a CNS manifestation of syndromic as well as non-syndromic MIDs. Correct diagnosis of mitochondrial cognitive impairment is a prerequisite for the optimal management of these patients. PMID:22335339

  11. Towards germline gene therapy of inherited mitochondrial diseases

    PubMed Central

    Tachibana, Masahito; Amato, Paula; Sparman, Michelle; Woodward, Joy; Sanchis, Dario Melguizo; Ma, Hong; Gutierrez, Nuria Marti; Tippner-Hedges, Rebecca; Kang, Eunju; Lee, Hyo-Sang; Ramsey, Cathy; Masterson, Keith; Battaglia, David; Lee, David; Wu, Diana; Jensen, Jeffrey; Patton, Phillip; Gokhale, Sumita; Stouffer, Richard; Mitalipov, Shoukhrat

    2012-01-01

    Mutations in mitochondrial DNA (mtDNA) are associated with serious human diseases and inherited from mother's eggs. Here we investigated the feasibility of mtDNA replacement in human oocytes by spindle transfer (ST). Of 106 human oocytes donated for research, 65 were subjected to reciprocal ST and 33 served as controls. Fertilization rate in ST oocytes (73%) was similar to controls (75%). However, a significant portion of ST zygotes (52%) displayed abnormal fertilization as determined by irregular number of pronuclei. Among normally fertilized ST zygotes, blastocyst development (62%) and embryonic stem cell (ESC) isolation (38%) rates were comparable to controls. All ESC lines derived from ST zygotes displayed normal euploid karyotypes and contained exclusively donor mtDNA. The mtDNA can be efficiently replaced in human oocytes. Although some ST oocytes displayed abnormal fertilization, remaining embryos were capable of developing to blastocysts and producing ESCs similar to controls. PMID:23103867

  12. Mitochondrial dysfunction leads to impairment of insulin sensitivity and adiponectin secretion in adipocytes.

    PubMed

    Wang, Chih-Hao; Wang, Ching-Chu; Huang, Hsin-Chang; Wei, Yau-Huei

    2013-02-01

    Adipocytes play an integrative role in the regulation of energy metabolism and glucose homeostasis in the human body. Functional defects in adipocytes may cause systemic disturbance of glucose homeostasis. Recent studies revealed mitochondrial abnormalities in the adipose tissue of patients with type 2 diabetes. In addition, patients with mitochondrial diseases usually manifest systemic metabolic disorder. However, it is unclear how mitochondrial dysfunction in adipocytes affects the regulation of glucose homeostasis. In this study, we induced mitochondrial dysfunction and overproduction of reactive oxygen species (ROS) by addition of respiratory inhibitors oligomycin A and antimycin A and by knockdown of mitochondrial transcription factor A (mtTFA), respectively. We found an attenuation of the insulin response as indicated by lower glucose uptake and decreased phosphorylation of Akt upon insulin stimulation of adipocytes with mitochondrial dysfunction. Furthermore, the expression of glucose transporter 4 (Glut4) and secretion of adiponectin were decreased in adipocytes with increased ROS generated by defective mitochondria. Moreover, the severity of insulin insensitivity was correlated with the extent of mitochondrial dysfunction. These results suggest that higher intracellular ROS levels elicited by mitochondrial dysfunction resulted in impairment of the function of adipocytes in the maintenance of glucose homeostasis through attenuation of insulin signaling, downregulation of Glut4 expression, and decrease in adiponectin secretion. Our findings substantiate the important role of mitochondria in the regulation of glucose homeostasis in adipocytes and also provide a molecular basis for the explanation of the manifestation of diabetes mellitus or insulin insensitivity in a portion of patients with mitochondrial diseases such as MELAS or MERRF syndrome. PMID:23253816

  13. RECG Maintains Plastid and Mitochondrial Genome Stability by Suppressing Extensive Recombination between Short Dispersed Repeats

    PubMed Central

    Odahara, Masaki; Masuda, Yuichi; Sato, Mayuko; Wakazaki, Mayumi; Harada, Chizuru; Toyooka, Kiminori; Sekine, Yasuhiko

    2015-01-01

    Maintenance of plastid and mitochondrial genome stability is crucial for photosynthesis and respiration, respectively. Recently, we have reported that RECA1 maintains mitochondrial genome stability by suppressing gross rearrangements induced by aberrant recombination between short dispersed repeats in the moss Physcomitrella patens. In this study, we studied a newly identified P. patens homolog of bacterial RecG helicase, RECG, some of which is localized in both plastid and mitochondrial nucleoids. RECG partially complements recG deficiency in Escherichia coli cells. A knockout (KO) mutation of RECG caused characteristic phenotypes including growth delay and developmental and mitochondrial defects, which are similar to those of the RECA1 KO mutant. The RECG KO cells showed heterogeneity in these phenotypes. Analyses of RECG KO plants showed that mitochondrial genome was destabilized due to a recombination between 8–79 bp repeats and the pattern of the recombination partly differed from that observed in the RECA1 KO mutants. The mitochondrial DNA (mtDNA) instability was greater in severe phenotypic RECG KO cells than that in mild phenotypic ones. This result suggests that mitochondrial genomic instability is responsible for the defective phenotypes of RECG KO plants. Some of the induced recombination caused efficient genomic rearrangements in RECG KO mitochondria. Such loci were sometimes associated with a decrease in the levels of normal mtDNA and significant decrease in the number of transcripts derived from the loci. In addition, the RECG KO mutation caused remarkable plastid abnormalities and induced recombination between short repeats (12–63 bp) in the plastid DNA. These results suggest that RECG plays a role in the maintenance of both plastid and mitochondrial genome stability by suppressing aberrant recombination between dispersed short repeats; this role is crucial for plastid and mitochondrial functions. PMID:25769081

  14. Mitochondrial Membrane Studies Using Impedance Spectroscopy with Parallel pH Monitoring

    PubMed Central

    Padmaraj, Divya; Pande, Rohit; Miller, John H.; Wosik, Jarek; Zagozdzon-Wosik, Wanda

    2014-01-01

    A biological microelectromechanical system (BioMEMS) device was designed to study complementary mitochondrial parameters important in mitochondrial dysfunction studies. Mitochondrial dysfunction has been linked to many diseases, including diabetes, obesity, heart failure and aging, as these organelles play a critical role in energy generation, cell signaling and apoptosis. The synthesis of ATP is driven by the electrical potential across the inner mitochondrial membrane and by the pH difference due to proton flux across it. We have developed a tool to study the ionic activity of the mitochondria in parallel with dielectric measurements (impedance spectroscopy) to gain a better understanding of the properties of the mitochondrial membrane. This BioMEMS chip includes: 1) electrodes for impedance studies of mitochondria designed as two- and four-probe structures for optimized operation over a wide frequency range and 2) ion-sensitive field effect transistors for proton studies of the electron transport chain and for possible monitoring other ions such as sodium, potassium and calcium. We have used uncouplers to depolarize the mitochondrial membrane and disrupt the ionic balance. Dielectric spectroscopy responded with a corresponding increase in impedance values pointing at changes in mitochondrial membrane potential. An electrical model was used to describe mitochondrial sample’s complex impedance frequency dependencies and the contribution of the membrane to overall impedance changes. The results prove that dielectric spectroscopy can be used as a tool for membrane potential studies. It can be concluded that studies of the electrochemical parameters associated with mitochondrial bioenergetics may render significant information on various abnormalities attributable to these organelles. PMID:25010497

  15. Lipopolysaccharide Disrupts Mitochondrial Physiology in Skeletal Muscle via Disparate Effects on Sphingolipid Metabolism

    PubMed Central

    Hansen, Melissa E.; Simmons, Kurtis J.; Tippetts, Trevor S.; Thatcher, Mikayla O.; Saito, Rex R.; Hubbard, Sheryl T.; Trumbull, Annie M.; Parker, Brian A.; Taylor, Oliver J.; Bikman, Benjamin T.

    2015-01-01

    ABSTRACT Lipopolysaccharides (LPS) are prevalent pathogenic molecules that are found within tissues and blood. Elevated circulating LPS is a feature of obesity and sepsis, both of which are associated with mitochondrial abnormalities that are key pathological features of LPS excess. However, the mechanism of LPS-induced mitochondrial alterations remains poorly understood. Herein we demonstrate the necessity of sphingolipid accrual in mediating altered mitochondrial physiology in skeletal muscle following LPS exposure. In particular, we found LPS elicited disparate effects on the sphingolipids dihydroceramides (DhCer) and ceramides (Cer) in both cultured myotubes and in muscle of LPS-injected mice. Although LPS-treated myotubes had reduced DhCer and increased Cer as well as increased mitochondrial respiration, muscle from LPS-injected mice manifested a reverse trend, namely elevated DhCer, but reduced Cer as well as reduced mitochondrial respiration. In addition, we found that LPS treatment caused mitochondrial fission, likely via dynamin-related protein 1, and increased oxidative stress. However, inhibition of de novo sphingolipid biosynthesis via myriocin protected normal mitochondrial function in spite of LPS, but inhibition of DhCer desaturase 1, which increases DhCer, but not Cer, exacerbated mitochondrial respiration with LPS. In an attempt to reconcile the incongruent effects of LPS in isolated muscle cells and whole muscle tissue, we incubated myotubes with conditioned medium from treated macrophages. In contrast to direct myotube LPS treatment, conditioned medium from LPS-treated macrophages reduced myotube respiration, but this was again mitigated with sphingolipid inhibition. Thus, macrophage sphingolipid production appears to be necessary for LPS-induced mitochondrial alterations in skeletal muscle tissue. PMID:26529656

  16. Historical Perspective on Mitochondrial Medicine

    PubMed Central

    DiMauro, Salvatore; Garone, Caterina

    2010-01-01

    In this review, we trace the origins and follow the development of mitochondrial medicine from the pre-molecular era (1962-1988) based on clinical clues, muscle morphology, and biochemistry into the molecular era that started in 1988 and is still advancing at a brisk pace. We have tried to stress conceptual advances, such as endosymbiosis, uniparental inheritance, intergenomic signaling and its defects, and mitochondrial dynamics. We hope that this historical review also provides an update on mitochondrial medicine, although we fully realize that the speed of progress in this area makes any such endeavor akin to writing on water. PMID:20818724

  17. Novel targets for mitochondrial medicine.

    PubMed

    Wang, Wang; Karamanlidis, Georgios; Tian, Rong

    2016-02-17

    Mitochondria-classically viewed as the powerhouses of the cell-have taken center stage in disease pathogenesis and resolution. Mitochondrial dysfunction, which originates from primary defects within the organelle or is induced by environmental stresses, plays a critical role in human disease. Despite their central role in human health and disease, there are no approved drugs that directly target mitochondria. We present possible new druggable targets in mitochondrial biology, including protein modification, calcium ion (Ca(2+)) transport, and dynamics, as we move into a new era of mitochondrial medicine. PMID:26888432

  18. Lophotrochozoan mitochondrial genomes

    SciTech Connect

    Valles, Yvonne; Boore, Jeffrey L.

    2005-10-01

    Progress in both molecular techniques and phylogeneticmethods has challenged many of the interpretations of traditionaltaxonomy. One example is in the recognition of the animal superphylumLophotrochozoa (annelids, mollusks, echiurans, platyhelminthes,brachiopods, and other phyla), although the relationships within thisgroup and the inclusion of some phyla remain uncertain. While much ofthis progress in phylogenetic reconstruction has been based on comparingsingle gene sequences, we are beginning to see the potential of comparinglarge-scale features of genomes, such as the relative order of genes.Even though tremendous progress is being made on the sequencedetermination of whole nuclear genomes, the dataset of choice forgenome-level characters for many animals across a broad taxonomic rangeremains mitochondrial genomes. We review here what is known aboutmitochondrial genomes of the lophotrochozoans and discuss the promisethat this dataset will enable insight into theirrelationships.

  19. Mitochondrial Energetics and Therapeutics

    PubMed Central

    Wallace, Douglas C.; Fan, Weiwei; Procaccio, Vincent

    2011-01-01

    Mitochondrial dysfunction has been linked to a wide range of degenerative and metabolic diseases, cancer, and aging. All these clinical manifestations arise from the central role of bioenergetics in cell biology. Although genetic therapies are maturing as the rules of bioenergetic genetics are clarified, metabolic therapies have been ineffectual. This failure results from our limited appreciation of the role of bioenergetics as the interface between the environment and the cell. A systems approach, which, ironically, was first successfully applied over 80 years ago with the introduction of the ketogenic diet, is required. Analysis of the many ways that a shift from carbohydrate glycolytic metabolism to fatty acid and ketone oxidative metabolism may modulate metabolism, signal transduction pathways, and the epigenome gives us an appreciation of the ketogenic diet and the potential for bioenergetic therapeutics. PMID:20078222

  20. A novel ECGF1 mutation in a Thai patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).

    PubMed

    Kintarak, Jutatip; Liewluck, Teerin; Sangruchi, Tumtip; Hirano, Michio; Kulkantrakorn, Kongkiat; Muengtaweepongsa, Sombat

    2007-09-01

    Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive, multisystem disorder, which is clinically defined by ptosis, ophthalmoparesis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and leukoencephalopathy. MNGIE is caused by mutations in the nuclear gene, endothelial cell growth factor 1 (ECGF1), encoding thymidine phosphorylase (TP). ECGF1 mutations cause severe loss of TP activity, abnormal accumulations of thymidine and deoxyuridine in plasma, and alterations of mitochondrial DNA. Here, we report the first Thai patient with MNGIE confirmed genetically by the identification of a homozygous novel ECGF1 gene mutation, c.100insC, which causes a frameshift and premature truncation of TP protein. PMID:17544574

  1. Experimental studies of mitochondrial function in CADASIL vascular smooth muscle cells

    SciTech Connect

    Viitanen, Matti; Sundström, Erik; Baumann, Marc; Tikka, Saara

    2013-02-01

    Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a familiar fatal progressive degenerative disorder characterized by cognitive decline, and recurrent stroke in young adults. Pathological features include a dramatic reduction of brain vascular smooth muscle cells and severe arteriopathy with the presence of granular osmophilic material in the arterial walls. Here we have investigated the cellular and mitochondrial function in vascular smooth muscle cell lines (VSMCs) established from CADASIL mutation carriers (R133C) and healthy controls. We found significantly lower proliferation rates in CADASIL VSMC as compared to VSMC from controls. Cultured CADASIL VSMCs were not more vulnerable than control cells to a number of toxic substances. Morphological studies showed reduced mitochondrial connectivity and increased number of mitochondria in CADASIL VSMCs. Transmission electron microscopy analysis demonstrated increased irregular and abnormal mitochondria in CADASIL VSMCs. Measurements of mitochondrial membrane potential (Δψ{sub m}) showed a lower percentage of fully functional mitochondria in CADASIL VSMCs. For a number of genes previously reported to be changed in CADASIL VSMCs, immunoblotting analysis demonstrated a significantly reduced SOD1 expression. These findings suggest that alteration of proliferation and mitochondrial function in CADASIL VSMCs might have an effect on vital cellular functions important for CADASIL pathology. -- Highlights: ► CADASIL is an inherited disease of cerebral vascular cells. ► Mitochondrial dysfunction has been implicated in the pathogenesis of CADASIL. ► Lower proliferation rates in CADASIL VSMC. ► Increased irregular and abnormal mitochondria and lower mitochondrial membrane potential in CADASIL VSMCs. ► Reduced mitochondrial connectivity and increased number of mitochondria in CADASIL VSMCs.

  2. 'Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich's ataxia'.

    PubMed

    Abeti, R; Parkinson, M H; Hargreaves, I P; Angelova, P R; Sandi, C; Pook, M A; Giunti, P; Abramov, A Y

    2016-01-01

    Friedreich's ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a GAA repeat expansion within the FXN gene, which downregulates frataxin, leading to abnormal mitochondrial iron accumulation, which may in turn cause changes in mitochondrial function. Although, many studies of FRDA patients and mouse models have been conducted in the past two decades, the role of frataxin in mitochondrial pathophysiology remains elusive. Are the mitochondrial abnormalities only a side effect of the increased accumulation of reactive iron, generating oxidative stress? Or does the progressive lack of iron-sulphur clusters (ISCs), induced by reduced frataxin, cause an inhibition of the electron transport chain complexes (CI, II and III) leading to reactive oxygen species escaping from oxidative phosphorylation reactions? To answer these crucial questions, we have characterised the mitochondrial pathophysiology of a group of disease-relevant and readily accessible neurons, cerebellar granule cells, from a validated FRDA mouse model. By using live cell imaging and biochemical techniques we were able to demonstrate that mitochondria are deregulated in neurons from the YG8R FRDA mouse model, causing a decrease in mitochondrial membrane potential (▵Ψm) due to an inhibition of Complex I, which is partially compensated by an overactivation of Complex II. This complex activity imbalance leads to ROS generation in both mitochondrial matrix and cytosol, which results in glutathione depletion and increased lipid peroxidation. Preventing this increase in lipid peroxidation, in neurons, protects against in cell death. This work describes the pathophysiological properties of the mitochondria in neurons from a FRDA mouse model and shows that lipid peroxidation could be an important target for novel therapeutic strategies in FRDA, which still lacks a cure. PMID:27228352

  3. 'Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich's ataxia'

    PubMed Central

    Abeti, R; Parkinson, M H; Hargreaves, I P; Angelova, P R; Sandi, C; Pook, M A; Giunti, P; Abramov, A Y

    2016-01-01

    Friedreich's ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a GAA repeat expansion within the FXN gene, which downregulates frataxin, leading to abnormal mitochondrial iron accumulation, which may in turn cause changes in mitochondrial function. Although, many studies of FRDA patients and mouse models have been conducted in the past two decades, the role of frataxin in mitochondrial pathophysiology remains elusive. Are the mitochondrial abnormalities only a side effect of the increased accumulation of reactive iron, generating oxidative stress? Or does the progressive lack of iron-sulphur clusters (ISCs), induced by reduced frataxin, cause an inhibition of the electron transport chain complexes (CI, II and III) leading to reactive oxygen species escaping from oxidative phosphorylation reactions? To answer these crucial questions, we have characterised the mitochondrial pathophysiology of a group of disease-relevant and readily accessible neurons, cerebellar granule cells, from a validated FRDA mouse model. By using live cell imaging and biochemical techniques we were able to demonstrate that mitochondria are deregulated in neurons from the YG8R FRDA mouse model, causing a decrease in mitochondrial membrane potential (▵Ψm) due to an inhibition of Complex I, which is partially compensated by an overactivation of Complex II. This complex activity imbalance leads to ROS generation in both mitochondrial matrix and cytosol, which results in glutathione depletion and increased lipid peroxidation. Preventing this increase in lipid peroxidation, in neurons, protects against in cell death. This work describes the pathophysiological properties of the mitochondria in neurons from a FRDA mouse model and shows that lipid peroxidation could be an important target for novel therapeutic strategies in FRDA, which still lacks a cure. PMID:27228352

  4. CR6-interacting factor 1 is a key regulator in Aβ-induced mitochondrial disruption and pathogenesis of Alzheimer's disease

    PubMed Central

    Byun, J; Son, S M; Cha, M-Y; Shong, M; Hwang, Y J; Kim, Y; Ryu, H; Moon, M; Kim, K-S; Mook-Jung, I

    2015-01-01

    Mitochondrial dysfunction, often characterized by massive fission and other morphological abnormalities, is a well-known risk factor for Alzheimer's disease (AD). One causative mechanism underlying AD-associated mitochondrial dysfunction is thought to be amyloid-β (Aβ), yet the pathways between Aβ and mitochondrial dysfunction remain elusive. In this study, we report that CR6-interacting factor 1 (Crif1), a mitochondrial inner membrane protein, is a key player in Aβ-induced mitochondrial dysfunction. Specifically, we found that Crif1 levels were downregulated in the pathological regions of Tg6799 mice brains, wherein overexpressed Aβ undergoes self-aggregation. Downregulation of Crif1 was similarly observed in human AD brains as well as in SH-SY5Y cells treated with Aβ. In addition, knockdown of Crif1, using RNA interference, induced mitochondrial dysfunction with phenotypes similar to those observed in Aβ-treated cells. Conversely, Crif1 overexpression prevented Aβ-induced mitochondrial dysfunction and cell death. Finally, we show that Aβ-induced downregulation of Crif1 is mediated by enhanced reactive oxygen species (ROS) and ROS-dependent sumoylation of the transcription factor specificity protein 1 (Sp1). These results identify the ROS-Sp1-Crif1 pathway to be a new mechanism underlying Aβ-induced mitochondrial dysfunction and suggest that ROS-mediated downregulation of Crif1 is a crucial event in AD pathology. We propose that Crif1 may serve as a novel therapeutic target in the treatment of AD. PMID:25361083

  5. The clinical maze of mitochondrial neurology

    PubMed Central

    DiMauro, Salvatore; Schon, Eric A.; Carelli, Valerio; Hirano, Michio

    2014-01-01

    Mitochondrial diseases involve the respiratory chain, which is under the dual control of nuclear and mitochondrial DNA (mtDNA). The complexity of mitochondrial genetics provides one explanation for the clinical heterogeneity of mitochondrial diseases, but our understanding of disease pathogenesis remains limited. Classification of Mendelian mitochondrial encephalomyopathies has been laborious, but whole-exome sequencing studies have revealed unexpected molecular aetiologies for both typical and atypical mitochondrial disease phenotypes. Mendelian mitochondrial defects can affect five components of mitochondrial biology: subunits of respiratory chain complexes (direct hits); mitochondrial assembly proteins; mtDNA translation; phospholipid composition of the inner mitochondrial membrane; or mitochondrial dynamics. A sixth category—defects of mtDNA maintenance—combines features of Mendelian and mitochondrial genetics. Genetic defects in mitochondrial dynamics are especially important in neurology as they cause optic atrophy, hereditary spastic paraplegia, and Charcot–Marie–Tooth disease. Therapy is inadequate and mostly palliative, but promising new avenues are being identified. Here, we review current knowledge on the genetics and pathogenesis of the six categories of mitochondrial disorders outlined above, focusing on their salient clinical manifestations and highlighting novel clinical entities. An outline of diagnostic clues for the various forms of mitochondrial disease, as well as potential therapeutic strategies, is also discussed. PMID:23835535

  6. The complete mitochondrial genome of Glaucidium brodiei (Strigiformes: Strigidae).

    PubMed

    Sun, Xiaonan; Zhou, Wenliang; Sun, Zhonglou; Qian, Lifu; Zhang, Yanan; Pan, Tao; Zhang, Baowei

    2016-07-01

    In this paper, the complete mitochondrial genome of Glaucidium brodiei is sequenced and reported for the first time. The mitochondrial genome is a circular molecule of 17,318 bp in length, consisting of 13 protein-coding genes (PCGs), 22 transfer RNA genes, 2 ribosomal RNA genes and a control region. Overall base composition of the complete mitochondrial DNA is A (29.9%), G (14.1%), C (32.1%) and T (23.9%), the percentage of A and T (53.8%) is slightly higher than G and C (46.2%). All the genes in G. brodiei are distributed on the H-strand, except for the ND6 subunit gene and nine tRNA genes, which are encoded on the L-strand. PMID:26075474

  7. Link between Cancer and Alzheimer Disease via Oxidative Stress Induced by Nitric Oxide-Dependent Mitochondrial DNA Overproliferation and Deletion

    PubMed Central

    Obrenovich, Mark E.; Tabrez, Shams; Jabir, Nasimudeen R.; Reddy, V. Prakash; Li, Yi; Burnstock, Geoffrey; Cacabelos, Ramon; Kamal, Mohammad Amjad

    2013-01-01

    Nitric oxide- (NO-) dependent oxidative stress results in mitochondrial ultrastructural alterations and DNA damage in cases of Alzheimer disease (AD). However, little is known about these pathways in human cancers, especially during the development as well as the progression of primary brain tumors and metastatic colorectal cancer. One of the key features of tumors is the deficiency in tissue energy that accompanies mitochondrial lesions and formation of the hypoxic smaller sized mitochondria with ultrastructural abnormalities. We speculate that mitochondrial involvement may play a significant role in the etiopathogenesis of cancer. Recent studies also demonstrate a potential link between AD and cancer, and anticancer drugs are being explored for the inhibition of AD-like pathology in transgenic mice. Severity of the cancer growth, metastasis, and brain pathology in AD (in animal models that mimic human AD) correlate with the degree of mitochondrial ultrastructural abnormalities. Recent advances in the cell-cycle reentry of the terminally differentiated neuronal cells indicate that NO-dependent mitochondrial abnormal activities and mitotic cell division are not the only important pathogenic factors in pathogenesis of cancer and AD, but open a new window for the development of novel treatment strategies for these devastating diseases. PMID:23691268

  8. Bioenergetic roles of mitochondrial fusion.

    PubMed

    Silva Ramos, Eduardo; Larsson, Nils-Göran; Mourier, Arnaud

    2016-08-01

    Mitochondria are bioenergetic hotspots, producing the bulk of ATP by the oxidative phosphorylation process. Mitochondria are also structurally dynamic and undergo coordinated fusion and fission to maintain their function. Recent studies of the mitochondrial fusion machinery have provided new evidence in detailing their role in mitochondrial metabolism. Remarkably, mitofusin 2, in addition to its role in fusion, is important for maintaining coenzyme Q levels and may be an integral player in the mevalonate synthesis pathway. Here, we review the bioenergetic roles of mitochondrial dynamics and emphasize the importance of the in vitro growth conditions when evaluating mitochondrial respiration. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016,' edited by Prof. Paolo Bernardi. PMID:27060252

  9. Pathological Significance of Mitochondrial Glycation

    PubMed Central

    Pun, Pamela Boon Li; Murphy, Michael P.

    2012-01-01

    Glycation, the nonenzymatic glycosylation of biomolecules, is commonly observed in diabetes and ageing. Reactive dicarbonyl species such as methylglyoxal and glyoxal are thought to be major physiological precursors of glycation. Because these dicarbonyls tend to be formed intracellularly, the levels of advanced glycation end products on cellular proteins are higher than on extracellular ones. The formation of glycation adducts within cells can have severe functional consequences such as inhibition of protein activity and promotion of DNA mutations. Although several lines of evidence suggest that there are specific mitochondrial targets of glycation, and mitochondrial dysfunction itself has been implicated in disease and ageing, it is unclear if glycation of biomolecules specifically within mitochondria induces dysfunction and contributes to disease pathology. We discuss here the possibility that mitochondrial glycation contributes to disease, focussing on diabetes, ageing, cancer, and neurodegeneration, and highlight the current limitations in our understanding of the pathological significance of mitochondrial glycation. PMID:22778743

  10. Semen abnormalities with SSRI antidepressants.

    PubMed

    2015-01-01

    Despite decades of widespread use, the adverse effect profile of "selective" serotonin reuptake inhibitor (SSRI) antidepressants has still not been fully elucidated. Studies in male animals have shown delayed sexual development and reduced fertility. Three prospective cohort studies conducted in over one hundred patients exposed to an SSRI for periods ranging from 5 weeks to 24 months found altered semen param-eters after as little as 3 months of exposure: reduced sperm concentration, reduced sperm motility, a higher percentage of abnormal spermatozoa, and increased levels of sperm DNA fragmentation. One clinical trial showed growth retardation in children considered depressed who were exposed to SSRls. SSRls may have endocrine disrupting properties. Dapoxetine is a short-acting serotonin reuptake inhibitor that is chemically related to fluoxetine and marketed in the European Union for men complaining of premature ejaculation. But the corresponding European summary of product characteristics does not mention any effects on fertility. In practice, based on the data available as of mid-2014, the effects of SSRI exposure on male fertility are unclear. However, it is a risk that should be taken into account and pointed out to male patients who would like to father a child or who are experiencing fertility problems. PMID:25729824

  11. The XXXXY Sex Chromosome Abnormality

    PubMed Central

    Barr, M. L.; Carr, D. H.; Pozsonyi, J.; Wilson, R. A.; Dunn, H. G.; Jacobson, T. S.; Miller, J. R.; Chown, B.

    1962-01-01

    The most common sex chromosome complex in sex chromatin-positive males with Klinefelter's syndrome is XXY. When the complex is XXYY or XXXY, the clinical findings do not seem to differ materially from those seen in XXY subjects, although more patients with these intersexual chromosome complements need to be studied to establish possible phenotypical expressions of the chromosomal variants. Two male children with an XXXXY sex chromosome abnormality are described. The data obtained from the study of these cases and five others described in the literature suggest that the XXXXY patient is likely to have congenital defects not usually seen in the common form of the Klinefelter syndrome. These include a triad of (1) skeletal anomalies (including radioulnar synostosis), (2) hypogenitalism (hypoplasia of penis and scrotum, incomplete descent of testes and defective prepubertal development of seminiferous tubules), and (3) greater risk of severe mental deficiency. That the conclusions are based on data from a small number of patients is emphasized, together with the need for a cytogenetic survey of a large control or unselected population. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8Fig. 9Fig. 10 PMID:13969480

  12. Chromosomal abnormalities in child psychiatric patients.

    PubMed

    Hong, K E; Kim, J H; Moon, S Y; Oh, S K

    1999-08-01

    To determine the frequency of chromosomal abnormalities in a child psychiatric population, and to evaluate possible associations between types of abnormalities and patient's clinical characteristics, cytogenetic examination was performed on 604 patients. Demographic data, reasons for karyotyping, clinical signs, and other patient characteristics were assessed and correlated with the results from karyotyping. Chromosomal abnormalities were found in 69 patients (11.3%); these were structural in 49 cases and numerical in 20. Inversion of chromosome nine was found in 15 subjects, trisomy of chromosome 21 in 11, and fragile X in five patients. When karyotyping was performed because of intellectual impairment or multiple developmental delay, significantly more abnormalities were found than average; when performed because autistic disorder was suspected, the number of abnormalities was significantly fewer. There were no differences in clinical variables between structural and numerical abnormalities, nor among nine types of chromosomal abnormalities, except that numerical abnormalities and polymorphism were found at a later age, and that walking was more delayed and IQ was lower in patients with Down syndrome. Clinicians should be aware of the possible presence of chromosomal abnormalities in child psychiatric populations; the close collaboration with geneticists and the use of more defined guidelines for cytogenetic investigation are important. PMID:10485616

  13. Radiologic atlas of pulmonary abnormalities in children

    SciTech Connect

    Singleton, E.B.; Wagner, M.L.; Dutton, R.V.

    1988-01-01

    This book is an atlas about thoracic abnormalities in infants and children. The authors include computed tomographic, digital subtraction angiographic, ultrasonographic, and a few magnetic resonance (MR) images. They recognize and discuss how changes in the medical treatment of premature infants and the management of infection and pediatric tumors have altered some of the appearances and considerations in these diseases. Oriented toward all aspects of pulmonary abnormalities, the book starts with radiographic techniques and then discusses the normal chest, the newborn, infections, tumors, and pulmonary vascular diseases. There is comprehensive treatment of mediastinal abnormalities and a discussion of airway abnormalities.

  14. Mitochondrial Targets for Pharmacological Intervention in Human Disease

    PubMed Central

    2015-01-01

    Over the past several years, mitochondrial dysfunction has been linked to an increasing number of human illnesses, making mitochondrial proteins (MPs) an ever more appealing target for therapeutic intervention. With 20% of the mitochondrial proteome (312 of an estimated 1500 MPs) having known interactions with small molecules, MPs appear to be highly targetable. Yet, despite these targeted proteins functioning in a range of biological processes (including induction of apoptosis, calcium homeostasis, and metabolism), very few of the compounds targeting MPs find clinical use. Recent work has greatly expanded the number of proteins known to localize to the mitochondria and has generated a considerable increase in MP 3D structures available in public databases, allowing experimental screening and in silico prediction of mitochondrial drug targets on an unprecedented scale. Here, we summarize the current literature on clinically active drugs that target MPs, with a focus on how existing drug targets are distributed across biochemical pathways and organelle substructures. Also, we examine current strategies for mitochondrial drug discovery, focusing on genetic, proteomic, and chemogenomic assays, and relevant model systems. As cell models and screening techniques improve, MPs appear poised to emerge as relevant targets for a wide range of complex human diseases, an eventuality that can be expedited through systematic analysis of MP function. PMID:25367773

  15. Mitochondrial dysfunction: a crucial event in okadaic acid (ICV) induced memory impairment and apoptotic cell death in rat brain.

    PubMed

    Kamat, Pradeep K; Tota, Santoshkumar; Shukla, Rakesh; Ali, Shakir; Najmi, Abul Kalam; Nath, Chandishwar

    2011-12-01

    Mitochondrial abnormalities have been identified in a large proportion of neurodegenerative diseases. Recently we have reported that intracerebroventricular (ICV) administration of okadaic acid (OKA) causes memory impairment in rat. However involvement of mitochondrial function in OKA induced memory impairment and neuronal damage has not been determined. OKA (200 ng) was administered by ICV route. After 13th day of OKA administration memory function was evaluated by Morris Water Maze test. Following completion of behavioral studies on 16th day, mitochondrial membrane potential, Ca(2+) and reactive oxygen species were evaluated in mitochondrial preparation of cortex, hippocampus, striatum and cerebellum of rat brain. While ATP, mitochondrial activity, lipid peroxidation and nitrite were investigated in synaptosomal preparation of rat brain areas. The activities and mRNA expression of apoptotic factors, caspase-3 and caspase-9, were studied in rat brain regions. The neuronal damage was also confirmed by histopathological study. OKA treated rats showed memory impairment including increased Ca(2+) and reactive oxygen species and decreased mitochondrial membrane potential, ATP and mitochondrial activity in mitochondrial preparation. There was a significant increase in lipid peroxidation and nitrite in synaptosomal preparations. Preventive treatment daily for 13 days with antidementic drugs, donepezil (5 mg/kg, p.o) and memantine (10 mg/kg, p.o), significantly attenuated OKA induced mitochondrial dysfunction, apoptotic cell death, memory impairment and histological changes. Mitochondrial dysfunction appeared as a key factor in OKA induced memory impairment and apoptotic cell death. This study indicates that clinically used antidementic drugs are effective against OKA induced adverse changes at behavioral, cellular, and histological levels and mitochondrial dysfunction. PMID:21893081

  16. Mitochondrial division in Caenorhabditis elegans.

    PubMed

    Gandre, Shilpa; van der Bliek, Alexander M

    2007-01-01

    The study of mitochondrial division proteins has largely focused on yeast and mammalian cells. We describe methods to use Caenorhabditis elegans as an alternative model for studying mitochondrial division, taking advantage of the many wonderful resources provided by the C. elegans community. Our methods are largely based on manipulation of gene expression using classic and molecular genetic techniques combined with fluorescence microscopy. Some biochemical methods are also included. As antibodies become available, these biochemical methods are likely to become more sophisticated. PMID:18314747

  17. Mitochondrial dysfunction and organophosphorus compounds

    SciTech Connect

    Karami-Mohajeri, Somayyeh; Abdollahi, Mohammad

    2013-07-01

    Organophosphorous (OPs) pesticides are the most widely used pesticides in the agriculture and home. However, many acute or chronic poisoning reports about OPs have been published in the recent years. Mitochondria as a site of cellular oxygen consumption and energy production can be a target for OPs poisoning as a non-cholinergic mechanism of toxicity of OPs. In the present review, we have reviewed and criticized all the evidences about the mitochondrial dysfunctions as a mechanism of toxicity of OPs. For this purpose, all biochemical, molecular, and morphological data were retrieved from various studies. Some toxicities of OPs are arisen from dysfunction of mitochondrial oxidative phosphorylation through alteration of complexes I, II, III, IV and V activities and disruption of mitochondrial membrane. Reductions of adenosine triphosphate (ATP) synthesis or induction of its hydrolysis can impair the cellular energy. The OPs disrupt cellular and mitochondrial antioxidant defense, reactive oxygen species generation, and calcium uptake and promote oxidative and genotoxic damage triggering cell death via cytochrome C released from mitochondria and consequent activation of caspases. The mitochondrial dysfunction induced by OPs can be restored by use of antioxidants such as vitamin E and C, alpha-tocopherol, electron donors, and through increasing the cytosolic ATP level. However, to elucidate many aspect of mitochondrial toxicity of Ops, further studies should be performed. - Highlights: • As a non-cholinergic mechanism of toxicity, mitochondria is a target for OPs. • OPs affect action of complexes I, II, III, IV and V in the mitochondria. • OPs reduce mitochondrial ATP. • OPs promote oxidative and genotoxic damage via release of cytochrome C from mitochondria. • OP-induced mitochondrial dysfunction can be restored by increasing the cytosolic ATP.

  18. Mitochondrial Transcription Factor A (TFAM) Binds to RNA Containing 4-Way Junctions and Mitochondrial tRNA

    PubMed Central

    Brown, Timothy A.; Tkachuk, Ariana N.; Clayton, David A.

    2015-01-01

    Mitochondrial DNA (mtDNA) is maintained within nucleoprotein complexes known as nucleoids. These structures are highly condensed by the DNA packaging protein, mitochondrial Transcription Factor A (TFAM). Nucleoids also include RNA, RNA:DNA hybrids, and are associated with proteins involved with RNA processing and mitochondrial ribosome biogenesis. Here we characterize the ability of TFAM to bind various RNA containing substrates in order to determine their role in TFAM distribution and function within the nucleoid. We find that TFAM binds to RNA-containing 4-way junctions but does not bind appreciably to RNA hairpins, internal loops, or linear RNA:DNA hybrids. Therefore the RNA within nucleoids largely excludes TFAM, and its distribution is not grossly altered with removal of RNA. Within the cell, TFAM binds to mitochondrial tRNAs, consistent with our RNA 4-way junction data. Kinetic binding assays and RNase-insensitive TFAM distribution indicate that DNA remains the preferred substrate within the nucleoid. However, TFAM binds to tRNA with nanomolar affinity and these complexes are not rare. TFAM-immunoprecipitated tRNAs have processed ends, suggesting that binding is not specific to RNA precursors. The amount of each immunoprecipitated tRNA is not well correlated with tRNA celluar abundance, indicating unequal TFAM binding preferences. TFAM-mt-tRNA interaction suggests potentially new functions for this protein. PMID:26545237

  19. Mitochondrial morphology, topology, and membrane interactions in skeletal muscle: a quantitative three-dimensional electron microscopy study.

    PubMed

    Picard, Martin; White, Kathryn; Turnbull, Douglass M

    2013-01-15

    Dynamic remodeling of mitochondrial morphology through membrane dynamics are linked to changes in mitochondrial and cellular function. Although mitochondrial membrane fusion/fission events are frequent in cell culture models, whether mitochondrial membranes dynamically interact in postmitotic muscle fibers in vivo remains unclear. Furthermore, a quantitative assessment of mitochondrial morphology in intact muscle is lacking. Here, using electron microscopy (EM), we provide evidence of interacting membranes from adjacent mitochondria in intact mouse skeletal muscle. Electron-dense mitochondrial contact sites consistent with events of outer mitochondrial membrane tethering are also described. These data suggest that mitochondrial membranes interact in vivo among mitochondria, possibly to induce morphology transitions, for kiss-and-run behavior, or other processes involving contact between mitochondrial membranes. Furthermore, a combination of freeze-fracture scanning EM and transmission EM in orthogonal planes was used to characterize and quantify mitochondrial morphology. Two subpopulations of mitochondria were studied: subsarcolemmal (SS) and intermyofibrillar (IMF), which exhibited significant differences in morphological descriptors, including form factor (means ± SD for SS: 1.41 ± 0.45 vs. IMF: 2.89 ± 1.76, P < 0.01) and aspect ratio (1.97 ± 0.83 vs. 3.63 ± 2.13, P < 0.01) and circularity (0.75 ± 0.16 vs. 0.45 ± 0.22, P < 0.01) but not size (0.28 ± 0.31 vs. 0.27 ± 0.20 μm(2)). Frequency distributions for mitochondrial size and morphological parameters were highly skewed, suggesting the presence of mechanisms to influence mitochondrial size and shape. In addition, physical continuities between SS and IMF mitochondria indicated mixing of both subpopulations. These data provide evidence that mitochondrial membranes interact in vivo in mouse skeletal muscle and that factors may be involved in regulating skeletal muscle mitochondrial morphology. PMID

  20. Mutant Huntingtin and Elusive Defects in Oxidative Metabolism and Mitochondrial Calcium Handling.

    PubMed

    Brustovetsky, Nickolay

    2016-07-01

    Elongation of a polyglutamine (polyQ) stretch in huntingtin protein (Htt) is linked to Huntington's disease (HD) pathogenesis. The mutation in Htt correlates with neuronal dysfunction in the striatum and cerebral cortex and eventually leads to neuronal cell death. The exact mechanisms of the injurious effect of mutant Htt (mHtt) on neurons are not completely understood but might include aberrant gene transcription, defective autophagy, abnormal mitochondrial biogenesis, anomalous mitochondrial dynamics, and trafficking. In addition, deficiency in oxidative metabolism and defects in mitochondrial Ca(2+) handling are considered essential contributing factors to neuronal dysfunction in HD and, consequently, in HD pathogenesis. Since the discovery of the mutation in Htt, the questions whether mHtt affects oxidative metabolism and mitochondrial Ca(2+) handling and, if it does, what mechanisms could be involved were in focus of numerous investigations. However, despite significant research efforts, the detrimental effect of mHtt and the mechanisms by which mHtt might impair oxidative metabolism and mitochondrial Ca(2+) handling remain elusive. In this paper, I will briefly review studies aimed at clarifying the consequences of mHtt interaction with mitochondria and discuss experimental results supporting or arguing against the mHtt effects on oxidative metabolism and mitochondrial Ca(2+) handling. PMID:25941077

  1. Mitochondrial fission is an acute and adaptive response in injured motor neurons.

    PubMed

    Kiryu-Seo, Sumiko; Tamada, Hiromi; Kato, Yukina; Yasuda, Katsura; Ishihara, Naotada; Nomura, Masatoshi; Mihara, Katsuyoshi; Kiyama, Hiroshi

    2016-01-01

    Successful recovery from neuronal damage requires a huge energy supply, which is provided by mitochondria. However, the physiological relevance of mitochondrial dynamics in damaged neurons in vivo is poorly understood. To address this issue, we established unique bacterial artificial chromosome transgenic (BAC Tg) mice, which develop and function normally, but in which neuronal injury induces labelling of mitochondria with green fluorescent protein (GFP) and expression of cre recombinase. GFP-labelled mitochondria in BAC Tg mice appear shorter in regenerating motor axons soon after nerve injury compared with mitochondria in non-injured axons, suggesting the importance of increased mitochondrial fission during the early phase of nerve regeneration. Crossing the BAC Tg mice with mice carrying a floxed dynamin-related protein 1 gene (Drp1), which is necessary for mitochondrial fission, ablates mitochondrial fission specifically in injured neurons. Injury-induced Drp1-deficient motor neurons show elongated or abnormally gigantic mitochondria, which have impaired membrane potential and axonal transport velocity during the early phase after injury, and eventually promote neuronal death. Our in vivo data suggest that acute and prominent mitochondrial fission during the early stage after nerve injury is an adaptive response and is involved in the maintenance of mitochondrial and neuronal integrity to prevent neurodegeneration. PMID:27319806

  2. In vivo imaging of mitochondrial function in methamphetamine-treated rats.

    PubMed

    Shiba, Takeshi; Yamato, Mayumi; Kudo, Wataru; Watanabe, Toshiaki; Utsumi, Hideo; Yamada, Ken-ichi

    2011-08-01

    Abuse of the powerfully addictive psychostimulant, methamphetamine, occurs worldwide. Recent studies have suggested that methamphetamine-induced dopaminergic neurotoxicity is related to oxidative stress. In response to nerve activation, the mitochondrial respiratory chain is rapidly activated. The enhancement of mitochondrial respiratory chain activation may induce oxidative stress in the brain. However, there is little experimental evidence regarding the mitochondrial function after methamphetamine administration in vivo. Here, we evaluated whether a single administration of methamphetamine induces ATP consumption and overactivation of mitochondria. We measured mitochondrial function in two different ways: by monitoring oxygen partial pressure using an oxygen-selective electrode, and by imaging of redox reactions using a nitroxyl radical (i.e., nitroxide) coupled with Overhauser-enhanced magnetic resonance imaging (OMRI). A single administration of methamphetamine to Wistar rats induced dopaminergic nerve activation, ATP consumption and an increase in mitochondrial respiratory chain function in both the striatum and cortex. Furthermore, antioxidant TEMPOL prevented the increase in mitochondrial oxidative damage and methamphetamine-induced sensitization. These findings suggest that energy-supplying reactions after dopaminergic nerve activation are associated with oxidative stress in both the striatum and cortex, leading to abnormal behavior. PMID:21624473

  3. The Role of Mitochondrial Functional Proteins in ROS Production in Ischemic Heart Diseases

    PubMed Central

    Pei, Haifeng; Yang, Yi; Zhao, Heng; Li, Xiuchuan; Yang, Dachun; Li, De; Yang, Yongjian

    2016-01-01

    Ischemic heart diseases (IHD) have become the leading cause of death around the world, killing more than 7 million people annually. In IHD, the blockage of coronary vessels will cause irreversible cell injury and even death. As the “powerhouse” and “apoptosis center” in cardiomyocytes, mitochondria play critical roles in IHD. Ischemia insult can reduce myocardial ATP content, resulting in energy stress and overproduction of reactive oxygen species (ROS). Thus, mitochondrial abnormality has been identified as a hallmark of multiple cardiovascular disorders. To date, many studies have suggested that these mitochondrial proteins, such as electron transport chain (ETC) complexes, uncoupling proteins (UCPs), mitochondrial dynamic proteins, translocases of outer membrane (Tom) complex, and mitochondrial permeability transition pore (MPTP), can directly or indirectly influence mitochondria-originated ROS production, consequently determining the degree of mitochondrial dysfunction and myocardial impairment. Here, the focus of this review is to summarize the present understanding of the relationship between some mitochondrial functional proteins and ROS production in IHD. PMID:27119006

  4. Mitochondrial fission is an acute and adaptive response in injured motor neurons

    PubMed Central

    Kiryu-Seo, Sumiko; Tamada, Hiromi; Kato, Yukina; Yasuda, Katsura; Ishihara, Naotada; Nomura, Masatoshi; Mihara, Katsuyoshi; Kiyama, Hiroshi

    2016-01-01

    Successful recovery from neuronal damage requires a huge energy supply, which is provided by mitochondria. However, the physiological relevance of mitochondrial dynamics in damaged neurons in vivo is poorly understood. To address this issue, we established unique bacterial artificial chromosome transgenic (BAC Tg) mice, which develop and function normally, but in which neuronal injury induces labelling of mitochondria with green fluorescent protein (GFP) and expression of cre recombinase. GFP-labelled mitochondria in BAC Tg mice appear shorter in regenerating motor axons soon after nerve injury compared with mitochondria in non-injured axons, suggesting the importance of increased mitochondrial fission during the early phase of nerve regeneration. Crossing the BAC Tg mice with mice carrying a floxed dynamin-related protein 1 gene (Drp1), which is necessary for mitochondrial fission, ablates mitochondrial fission specifically in injured neurons. Injury-induced Drp1-deficient motor neurons show elongated or abnormally gigantic mitochondria, which have impaired membrane potential and axonal transport velocity during the early phase after injury, and eventually promote neuronal death. Our in vivo data suggest that acute and prominent mitochondrial fission during the early stage after nerve injury is an adaptive response and is involved in the maintenance of mitochondrial and neuronal integrity to prevent neurodegeneration. PMID:27319806

  5. Mitochondrial efficiency and insulin resistance.

    PubMed

    Crescenzo, Raffaella; Bianco, Francesca; Mazzoli, Arianna; Giacco, Antonia; Liverini, Giovanna; Iossa, Susanna

    2014-01-01

    Insulin resistance, "a relative impairment in the ability of insulin to exert its effects on glucose, protein and lipid metabolism in target tissues," has many detrimental effects on metabolism and is strongly correlated to deposition of lipids in non-adipose tissues. Mitochondria are the main cellular sites devoted to ATP production and fatty acid oxidation. Therefore, a role for mitochondrial dysfunction in the onset of skeletal muscle insulin resistance has been proposed and many studies have dealt with possible alteration in mitochondrial function in obesity and diabetes, both in humans and animal models. Data reporting evidence of mitochondrial dysfunction in type two diabetes mellitus are numerous, even though the issue that this reduced mitochondrial function is causal in the development of the disease is not yet solved, also because a variety of parameters have been used in the studies carried out on this subject. By assessing the alterations in mitochondrial efficiency as well as the impact of this parameter on metabolic homeostasis of skeletal muscle cells, we have obtained results that allow us to suggest that an increase in mitochondrial efficiency precedes and therefore can contribute to the development of high-fat-induced insulin resistance in skeletal muscle. PMID:25601841

  6. Mitochondrial Metabolism in Aging Heart.

    PubMed

    Lesnefsky, Edward J; Chen, Qun; Hoppel, Charles L

    2016-05-13

    Altered mitochondrial metabolism is the underlying basis for the increased sensitivity in the aged heart to stress. The aged heart exhibits impaired metabolic flexibility, with a decreased capacity to oxidize fatty acids and enhanced dependence on glucose metabolism. Aging impairs mitochondrial oxidative phosphorylation, with a greater role played by the mitochondria located between the myofibrils, the interfibrillar mitochondria. With aging, there is a decrease in activity of complexes III and IV, which account for the decrease in respiration. Furthermore, aging decreases mitochondrial content among the myofibrils. The end result is that in the interfibrillar area, there is ≈50% decrease in mitochondrial function, affecting all substrates. The defective mitochondria persist in the aged heart, leading to enhanced oxidant production and oxidative injury and the activation of oxidant signaling for cell death. Aging defects in mitochondria represent new therapeutic targets, whether by manipulation of the mitochondrial proteome, modulation of electron transport, activation of biogenesis or mitophagy, or the regulation of mitochondrial fission and fusion. These mechanisms provide new ways to attenuate cardiac disease in elders by preemptive treatment of age-related defects, in contrast to the treatment of disease-induced dysfunction. PMID:27174952

  7. Mitochondrial sirtuins in the heart.

    PubMed

    Bugger, Heiko; Witt, Constantin N; Bode, Christoph

    2016-09-01

    Sirtuins (SIRTs) are NAD(+)-dependent enzymes that catalyze deacylation of protein lysine residues. In mammals, seven sirtuins have been identified, SIRT1-7. SIRT3-5 are mainly or exclusively localized within mitochondria and mainly participate in the regulation of energy metabolic pathways. Since mitochondrial ATP regeneration is inevitably linked to the maintenance of cardiac pump function, it is not surprising that recent studies revealed a role for mitochondrial sirtuins in the regulation of myocardial energetics and function. In addition, mitochondrial sirtuins modulate the extent of myocardial ischemia reperfusion injury and the development of cardiac hypertrophy and failure. Thus, targeting mitochondrial sirtuins has been proposed as a novel approach to improve myocardial mitochondrial energetics, which is frequently impaired in cardiac disease and considered an important underlying cause contributing to several cardiac pathologies, including myocardial ischemia reperfusion injury and heart failure. In the current review, we present and discuss the available literature on mitochondrial sirtuins and their potential roles in cardiac physiology and disease. PMID:27295248

  8. Mitochondrial Epigenetics and Environmental Exposure.

    PubMed

    Lambertini, Luca; Byun, Hyang-Min

    2016-09-01

    The rising toll of chronic and debilitating diseases brought about by the exposure to an ever expanding number of environmental pollutants and socio-economic factors is calling for action. The understanding of the molecular mechanisms behind the effects of environmental exposures can lead to the development of biomarkers that can support the public health fields of both early diagnosis and intervention to limit the burden of environmental diseases. The study of mitochondrial epigenetics carries high hopes to provide important biomarkers of exposure and disease. Mitochondria are in fact on the frontline of the cellular response to the environment. Modifications of the epigenetic factors regulating the mitochondrial activity are emerging as informative tools that can effectively report on the effects of the environment on the phenotype. Here, we will discuss the emerging field of mitochondrial epigenetics. This review describes the main epigenetic phenomena that modify the activity of the mitochondrial DNA including DNA methylation, long and short non-coding RNAs. We will discuss the unique pattern of mitochondrial DNA methylation, describe the challenges of correctly measuring it, and report on the existing studies that have analysed the correlation between environmental exposures and mitochondrial DNA methylation. Finally, we provide a brief account of the therapeutic approaches targeting mitochondria currently under consideration. PMID:27344144

  9. CFTR activity and mitochondrial function☆

    PubMed Central

    Valdivieso, Angel Gabriel; Santa-Coloma, Tomás A.

    2013-01-01

    Cystic Fibrosis (CF) is a frequent and lethal autosomal recessive disease, caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Before the discovery of the CFTR gene, several hypotheses attempted to explain the etiology of this disease, including the possible role of a chloride channel, diverse alterations in mitochondrial functions, the overexpression of the lysosomal enzyme α-glucosidase and a deficiency in the cytosolic enzyme glucose 6-phosphate dehydrogenase. Because of the diverse mitochondrial changes found, some authors proposed that the affected gene should codify for a mitochondrial protein. Later, the CFTR cloning and the demonstration of its chloride channel activity turned the mitochondrial, lysosomal and cytosolic hypotheses obsolete. However, in recent years, using new approaches, several investigators reported similar or new alterations of mitochondrial functions in Cystic Fibrosis, thus rediscovering a possible role of mitochondria in this disease. Here, we review these CFTR-driven mitochondrial defects, including differential gene expression, alterations in oxidative phosphorylation, calcium homeostasis, oxidative stress, apoptosis and innate immune response, which might explain some characteristics of the complex CF phenotype and reveals potential new targets for therapy. PMID:24024153

  10. Human mitochondrial DNA nucleoids are linked to protein folding machinery and metabolic enzymes at the mitochondrial inner membrane.

    PubMed

    Wang, Yousong; Bogenhagen, Daniel F

    2006-09-01

    Mitochondrial DNA (mtDNA) is packaged into bacterial nucleoid-like structures, each containing several mtDNA molecules. The distribution of nucleoids during mitochondrial fission and fusion events and during cytokinesis is important to the segregation of mitochondrial genomes in heteroplasmic cells bearing a mixture of wild-type and mutant mtDNA molecules. We report fractionation of HeLa cell mtDNA nucleoids into two subsets of complexes that differ in their sedimentation velocity and their association with cytoskeletal proteins. Pulse labeling studies indicated that newly replicated mtDNA molecules are evenly represented in the rapidly and slowly sedimenting fractions. Slowly sedimenting nucleoids were immunoaffinity purified using antibodies to either of two abundant mtDNA-binding proteins, TFAM or mtSSB. These two different immunoaffinity procedures yielded very similar sets of proteins, with 21 proteins in common, including most of the proteins previously shown to play roles in mtDNA replication and transcription. In addition to previously identified mitochondrial proteins, multiple peptides were observed for one novel DNA metabolic protein, the DEAH-box helicase DHX30. Antibodies raised against a recombinant fragment of this protein confirmed the mitochondrial localization of a specific isoform of DHX30. PMID:16825194

  11. Abnormal high density lipoproteins in cerebrotendinous xanthomatosis

    SciTech Connect

    Shore, V.; Salen, G.; Cheng, F.W.; Forte, T.; Shefer, S.; Tint, G.S.

    1981-11-01

    The plasma lipoprotein profiles and high density lipoproteins (HDL) were characterized in patients with the genetic disease cerebrotendinous xanthomatosis (CTX). The mean HDL-cholesterol concentration in the CTX plasmas was 14.5 +/- 3.2 mg/dl, about one-third the normal value. The low HDL-cholesterol reflects a low concentration and an abnormal lipid composition of the plasma HDL. Relative to normal HDL, the cholesteryl esters are low, free cholesterol and phospholipids essentially normal, and triglycerides increased. The ratio of apoprotein (apo) to total cholesterol in the HDL of CTX was two to three times greater than normal. In the CTX HDL, the ratio of apoAI to apoAII was high, the proportion of apoC low, and a normally minor form of apoAI increased relative to other forms. The HDL in electron micrographs appeared normal morphologically and in particle size. The adnormalities in lipoprotein distribution profiles and composition of the plasma HDL result from metabolic defects that are not understood but may be linked to the genetic defect in bile acid synthesis in CTX. As a consequence, it is probable that the normal functions of the HDL, possibly including modulation of LDL-cholesterol uptake and the removal of excess cholesterol from peripheral tissues, are perturbed significantly in this disease.

  12. Physiological consequences of abnormal connectivity in a developmental epilepsy

    PubMed Central

    Shafi, Mouhsin M.; Vernet, Marine; Klooster, Debby; Chu, Catherine J.; Boric, Katica; Barnard, Mollie E.; Romatoski, Kelsey; Westover, M. Brandon; Christodoulou, Joanna A.; Gabrieli, John D.E.; Whitfield-Gabrieli, Susan; Pascual-Leone, Alvaro; Chang, Bernard S.

    2015-01-01

    Objective Many forms of epilepsy are associated with aberrant neuronal connections, but the relationship between such pathological connectivity and the underlying physiological predisposition to seizures is unclear. We sought to characterize the cortical excitability profile of a developmental form of epilepsy known to have structural and functional connectivity abnormalities. Methods We employed transcranial magnetic stimulation (TMS) with simultaneous EEG recording in eight patients with epilepsy from periventricular nodular heterotopia (PNH) and matched healthy controls. We used connectivity imaging findings to guide TMS targeting and compared the evoked responses to single-pulse stimulation from different cortical regions. Results Heterotopia patients with active epilepsy demonstrated a relatively augmented late cortical response that was greater than that of matched controls. This abnormality was specific to cortical regions with connectivity to subcortical heterotopic gray matter. Topographic mapping of the late response differences showed distributed cortical networks that were not limited to the stimulation site, and source analysis in one subject revealed that the generator of abnormal TMS-evoked activity overlapped with the spike and seizure onset zone. Interpretation Our findings indicate that patients with epilepsy from gray matter heterotopia have altered cortical physiology consistent with hyperexcitability, and that this abnormality is specifically linked to the presence of aberrant connectivity. These results support the idea that TMS-EEG could be a useful biomarker in epilepsy in gray matter heterotopia, expand our understanding of circuit mechanisms of epileptogenesis, and have potential implications for therapeutic neuromodulation in similar epileptic conditions associated with deep lesions. PMID:25858773

  13. A study of the abnormal lipoproteins in abetalipoproteinemia.

    PubMed Central

    Scanu, A M; Aggerbeck, L P; Kruski, A W; Lim, C T; Kayden, H J

    1974-01-01

    The serum lipoproteins of five patients with abetalipoproteinemia (ABL) were separated by ultracentrifugation and then analyzed either intact or after delipidation. In accord with previous findings, all of the patients lacked serum particles with the characteristics of normal low-density lipoproteins (LDL) and of the LDL apoprotein as assessed by immunochemical methods. Each patient exhibited on every examination an abnormal particle, "LDL", which had the flotational properties of LDL, the polypeptide makeup of high-density lipoproteins HDL, the spectral and morphological characteristics of neither LDL nor HDL, and a relatively low content of cholesteryl esters. The HDL were abnormal in having a marked decrease in their total plasma content, an altered proportion of the subclasses HDL2 and HDL3, and a peculiar polypeptide distribution, comprising both normal and additional components, usually not seen in normal controls. The patients also exhibited a decrease of plasma lecithin-cholesterol acyl transferase (LCAT) activity which probably accounted for the low content of cholesteryl esters in both "LDL" and HDL, and in turn for the unusual appearance of "LDL" on electron microscopy. It is concluded that ABL is a disorder affecting all serum lipoprotein classes. Whether the abetalipoproteinemia previously described and noted in the current studies is related to or independent of the abnormalities observed in the other lipoproteins was not established. How the deficiency of LCAT activity, observed in all patients studied, contributed to some of the observed structural lipoprotein abnormalities also remained undetermined. Images PMID:11344558

  14. An Abnormal Psychology Community Based Interview Assignment

    ERIC Educational Resources Information Center

    White, Geoffry D.

    1977-01-01

    A course option in abnormal psychology involves students in interviewing and observing the activities of individuals in the off-campus community who are concerned with some aspect of abnormal psychology. The technique