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EMBO Molecular Medicine Nov 2018The mTOR inhibitor rapamycin ameliorates the clinical and biochemical phenotype of mouse, worm, and cellular models of mitochondrial disease, via an unclear mechanism....
The mTOR inhibitor rapamycin ameliorates the clinical and biochemical phenotype of mouse, worm, and cellular models of mitochondrial disease, via an unclear mechanism. Here, we show that prolonged rapamycin treatment improved motor endurance, corrected morphological abnormalities of muscle, and increased cytochrome c oxidase (COX) activity of a muscle-specific knockout mouse ( ). Rapamycin treatment restored autophagic flux, which was impaired in naïve muscle, and reduced the number of damaged mitochondria, which accumulated in untreated mice. Conversely, rilmenidine, an mTORC1-independent autophagy inducer, was ineffective on the myopathic features of animals. This stark difference supports the idea that inhibition of mTORC1 by rapamycin has a key role in the improvement of the mitochondrial function in muscle. In contrast to rilmenidine, rapamycin treatment also activated lysosomal biogenesis in muscle. This effect was associated with increased nuclear localization of TFEB, a master regulator of lysosomal biogenesis, which is inhibited by mTORC1-dependent phosphorylation. We propose that the coordinated activation of autophagic flux and lysosomal biogenesis contribute to the effective clearance of dysfunctional mitochondria by rapamycin.
Topics: Animals; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Electron Transport Complex IV; Lysosomes; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Mitochondrial Myopathies; Motor Activity; Muscles; Organelle Biogenesis; Phenotype; Rilmenidine; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 30309855
DOI: 10.15252/emmm.201708799 -
FEBS Letters Jul 1999A revolution in chemical pathology occurred about 40 years ago with the discovery of a patient with mitochondrial dysfunction. The field of mitochondrial medicine has... (Review)
Review
A revolution in chemical pathology occurred about 40 years ago with the discovery of a patient with mitochondrial dysfunction. The field of mitochondrial medicine has experienced explosive growth during the last decade. More than 50 mtDNA mutations and several nuclear gene mutations have been identified in affected patients. The recent development of animal models will continue the revolution in mitochondrial medicine by facilitating in depth studies of the molecular pathogenesis and development of novel drug and gene therapy strategies for mitochondrial dysfunction. As we enter the next millennium, we can expect mitochondrial medicine to remain a dynamic and rapidly developing field.
Topics: Aging; Animals; DNA, Mitochondrial; Disease Models, Animal; Humans; Mitochondria; Mitochondrial Myopathies; Mutation
PubMed: 10437772
DOI: 10.1016/s0014-5793(99)00854-6 -
Journal of Medical Genetics Mar 2021Mitochondria provide ATP through the process of oxidative phosphorylation, physically located in the inner mitochondrial membrane (IMM). The mitochondrial contact site...
BACKGROUND
Mitochondria provide ATP through the process of oxidative phosphorylation, physically located in the inner mitochondrial membrane (IMM). The mitochondrial contact site and organising system (MICOS) complex is known as the 'mitoskeleton' due to its role in maintaining IMM architecture. encodes MIC26, a component of MICOS, whose exact function in its maintenance or assembly has still not been completely elucidated.
METHODS
We have studied a family in which the most affected subject presented progressive developmental delay, lactic acidosis, muscle weakness, hypotonia, weight loss, gastrointestinal and body temperature dysautonomia, repetitive infections, cognitive impairment and autistic behaviour. Other family members showed variable phenotype presentation. Whole exome sequencing was used to screen for pathological variants. Patient-derived skin fibroblasts were used to confirm the pathogenicity of the variant found in . Knockout models in and were employed to validate MIC26 involvement in MICOS assembly and mitochondrial function.
RESULTS
A likely pathogenic c.350T>C transition was found in predicting an I117T substitution in MIC26. The mutation caused impaired processing of the protein during import and faulty insertion into the IMM. This was associated with altered MICOS assembly and cristae junction disruption. The corresponding mutation in MIC26 or complete loss was associated with mitochondrial structural and functional deficiencies in yeast and models.
CONCLUSION
This is the first case of pathogenic mutation in , causing altered MICOS assembly and neuromuscular impairment. MIC26 is involved in the assembly or stability of MICOS in humans, yeast and flies.
Topics: Acidosis, Lactic; Animals; Apolipoproteins; Autistic Disorder; Cognitive Dysfunction; Drosophila melanogaster; Fibroblasts; Genetic Diseases, X-Linked; Humans; Membrane Proteins; Mitochondrial Membranes; Mitochondrial Myopathies; Mitochondrial Proteins; Protein Binding; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 32439808
DOI: 10.1136/jmedgenet-2020-106861 -
Arthritis and Rheumatism Jan 2008Zidovudine is an antiretroviral nucleoside analog reverse transcriptase inhibitor that induces mitochondrial myopathy by interfering with the replication of...
OBJECTIVE
Zidovudine is an antiretroviral nucleoside analog reverse transcriptase inhibitor that induces mitochondrial myopathy by interfering with the replication of mitochondrial DNA (mtDNA). Because zidovudine inhibits thymidine kinases, the mechanism of mtDNA depletion may be related to an impairment of the de novo synthesis of pyrimidine nucleotides, which are required building blocks of mtDNA. This study was undertaken to determine whether mitochondrial myopathy is a class effect of antiretroviral nucleoside analogs, and whether the muscle disease can be prevented by treatment with uridine as a pyrimidine nucleotide precursor.
METHODS
BALB/c mice were treated with zidovudine or zalcitabine. Some of the mice were cotreated with mitocnol, a dietary supplement with high uridine bioavailability. Mice hind limb muscles were examined after 10 weeks.
RESULTS
Zidovudine induced muscle fiber thinning, myocellular fat deposition, and abnormalities of mitochondrial ultrastructure. In mice treated with zidovudine, organelles contained low mtDNA copy numbers and reduced cytochrome c oxidase activity. The expression of the mtDNA-encoded cytochrome c oxidase I subunit, but not of nucleus-encoded mitochondrial proteins, was impaired. Zidovudine also increased the levels of myocellular reactive oxygen species and blood lactate. Uridine supplementation attenuated or normalized all pathologic abnormalities and had no intrinsic effects. Zalcitabine did not elicit muscle toxicity.
CONCLUSION
Our findings indicate that zidovudine, but not zalcitabine, induces mitochondrial myopathy, which is substantially antagonized by uridine supplementation. These results provide proof of the importance of pyrimidine pools in the pathogenesis of zidovudine myopathy. Since uridine supplementation is tolerated well by humans, this treatment strategy should be investigated in clinical trials.
Topics: Animals; DNA, Mitochondrial; Drug Interactions; Electron Transport; Electron Transport Complex IV; Gene Dosage; Lactates; Lipid Peroxidation; Male; Malondialdehyde; Mice; Mice, Inbred BALB C; Mitochondrial Myopathies; Muscle, Skeletal; Reverse Transcriptase Inhibitors; Triglycerides; Uridine; Zalcitabine; Zidovudine
PubMed: 18163507
DOI: 10.1002/art.23235 -
Current Opinion in Pharmacology Dec 2009Mitochondria play a key role in energy metabolism in many tissues, including skeletal muscle and liver. Inherent disorders of mitochondria such as DNA deletions cause... (Review)
Review
Mitochondria play a key role in energy metabolism in many tissues, including skeletal muscle and liver. Inherent disorders of mitochondria such as DNA deletions cause major disruption of metabolism and can result in severe impairment or death. However, the occurrence of such disorders is extremely rare and cannot account for the majority of metabolic disease. Recently, mitochondrial dysfunction of a more subtle nature in skeletal muscle has been implicated in the pathology of chronic metabolic disease characterized by insulin resistance such as obesity, type 2 diabetes mellitus, and aging. This hypothesis has been substantiated by work from Shulman and colleagues, showing that reduced mitochondrial oxidative capacity underlies the accumulation of intramuscular fat causing insulin resistance with aging. However, recent work by Nair and coworkers has demonstrated that mitochondrial activity may actually be higher in persons exposed to high-calorie diet leading to obesity, suggesting that the accumulation of intramuscular fat and associated fatty acid metabolites may be directly responsible for the development of insulin resistance, independent of mitochondrial function. These inconsistent findings have promoted ongoing investigation into mitochondrial function to determine whether impaired function is a cause or consequence of metabolic disorders.
Topics: Aging; Diabetes Mellitus, Type 2; Health; Humans; Insulin Resistance; Mitochondria, Muscle; Mitochondrial Myopathies; Oxidative Phosphorylation; Rare Diseases
PubMed: 19796990
DOI: 10.1016/j.coph.2009.09.002 -
Traffic (Copenhagen, Denmark) Apr 2001The roles of mitochondria in cell death and in aging have generated much excitement in recent years. At the same time, however, a quiet revolution in our thinking about... (Review)
Review
The roles of mitochondria in cell death and in aging have generated much excitement in recent years. At the same time, however, a quiet revolution in our thinking about mitochondrial ultrastructure has begun. This revolution started with the use of vital dyes and of green fluorescent protein fusion proteins, showing that mitochondria are very dynamic structures that constantly move, divide and fuse throughout the life of a cell. More recently, some of the first proteins contributing to these various processes have been discovered. Our view of the internal structures of mitochondria has also changed. Three-dimensional reconstructions obtained with high voltage electron microscopy show that cristae are often connected to the mitochondrial inner membrane by thin tubules. These new insights are brought to bear on the wealth of data collected by conventional electron microscopic analysis.
Topics: Animals; Biological Transport; DNA, Mitochondrial; Humans; Intracellular Membranes; Membrane Fusion; Mitochondria; Mitochondrial Myopathies; Submitochondrial Particles
PubMed: 11285133
DOI: 10.1034/j.1600-0854.2001.1r008.x -
Neurotherapeutics : the Journal of the... Jan 2024This paper provides an overview of the different types of mitochondrial myopathies (MM), associated phenotypes, genotypes as well as a practical clinical approach... (Review)
Review
This paper provides an overview of the different types of mitochondrial myopathies (MM), associated phenotypes, genotypes as well as a practical clinical approach towards disease diagnosis, surveillance, and management. nDNA-related MM are more common in pediatric-onset disease whilst mtDNA-related MMs are more frequent in adults. Genotype-phenotype correlation in MM is challenging due to clinical and genetic heterogeneity. The multisystemic nature of many MMs adds to the diagnostic challenge. Diagnostic approaches utilizing genetic sequencing with next generation sequencing approaches such as gene panel, exome and genome sequencing are available. This aids molecular diagnosis, heteroplasmy detection in MM patients and furthers knowledge of known mitochondrial genes. Precise disease diagnosis can end the diagnostic odyssey for patients, avoid unnecessary testing, provide prognosis, facilitate anticipatory management, and enable access to available therapies or clinical trials. Adjunctive tests such as functional and exercise testing could aid surveillance of MM patients. Management requires a multi-disciplinary approach, systemic screening for comorbidities, cofactor supplementation, avoidance of substances that inhibit the respiratory chain and exercise training. This update of the current understanding on MMs provides practical perspectives on current diagnostic and management approaches for this complex group of disorders.
Topics: Humans; Child; Mitochondrial Myopathies; Mitochondria; High-Throughput Nucleotide Sequencing; Mitochondrial Diseases
PubMed: 38241155
DOI: 10.1016/j.neurot.2023.11.001 -
The Journal of Biological Chemistry Mar 2023Plasma thymidine levels in rodents are higher than in other mammals including humans, possibly due to a different pattern and lower level of thymidine phosphorylase...
Plasma thymidine levels in rodents are higher than in other mammals including humans, possibly due to a different pattern and lower level of thymidine phosphorylase expression. Here, we generated a novel knock-in (KI) mouse line with high systemic expression of human thymidine phosphorylase to investigate this difference in nucleotide metabolism in rodents. The KI mice showed growth retardation around weaning and died by 4 weeks of age with a decrease in plasma thymidine level compared with the litter-control WT mice. These phenotypes were completely or partially rescued by administration of the thymidine phosphorylase inhibitor 5-chloro-6-(2-iminopyrrolidin-1-yl) methyl-2,4(1H,3H)-pyrimidinedione hydrochloride or thymidine, respectively. Interestingly, when thymidine phosphorylase inhibitor administration was discontinued in adult animals, KI mice showed deteriorated grip strength and locomotor activity, decreased bodyweight, and subsequent hind-limb paralysis. Upon histological analyses, we observed axonal degeneration in the spinal cord, muscular atrophy with morphologically abnormal mitochondria in quadriceps, retinal degeneration, and abnormality in the exocrine pancreas. Moreover, we detected mitochondrial DNA depletion in multiple tissues of KI mice. These results indicate that the KI mouse represents a new animal model for mitochondrial diseases and should be applicable for the study of differences in nucleotide metabolism between humans and mice.
Topics: Animals; Humans; Mice; DNA, Mitochondrial; Growth Disorders; Mammals; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Nucleotides; Thymidine; Thymidine Phosphorylase
PubMed: 36773803
DOI: 10.1016/j.jbc.2023.103002 -
The Cochrane Database of Systematic... Jan 2010Strength training or aerobic exercise programmes might optimise muscle and cardiorespiratory function and prevent additional disuse atrophy and deconditioning in people... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Strength training or aerobic exercise programmes might optimise muscle and cardiorespiratory function and prevent additional disuse atrophy and deconditioning in people with a muscle disease.
OBJECTIVES
To examine the safety and efficacy of strength training and aerobic exercise training in people with a muscle disease.
SEARCH STRATEGY
We searched the Cochrane Neuromuscular Disease Group Trials Specialized Register (July 2009), the Cochrane Rehabilitation and Related Therapies Field Register (October 2002, August 2008 and July 2009), The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2009) MEDLINE (January 1966 to July 2009), EMBASE (January 1974 to July 2009), EMBASE Classic (1947 to 1973) and CINAHL (January 1982 to July 2009).
SELECTION CRITERIA
Randomised or quasi-randomised controlled trials comparing strength training or aerobic exercise programmes, or both, to no training, and lasting at least 10 weeks.For strength training Primary outcome: static or dynamic muscle strength. Secondary: muscle endurance or muscle fatigue, functional assessments, quality of life, muscle membrane permeability, pain and experienced fatigue.For aerobic exercise training Primary outcome: aerobic capacity expressed as work capacity. Secondary: aerobic capacity (oxygen consumption, parameters of cardiac or respiratory function), functional assessments, quality of life, muscle membrane permeability, pain and experienced fatigue.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed trial quality and extracted the data.
MAIN RESULTS
We included three trials (121 participants). The first compared the effect of strength training versus no training in 36 people with myotonic dystrophy. The second trial compared strength training versus no training, both combined with albuterol or placebo, in 65 people with facioscapulohumeral muscular dystrophy. The third trial compared combined strength training and aerobic exercise versus no training in 18 people with mitochondrial myopathy. In the myotonic dystrophy trial there were no significant differences between training and non-training groups for primary and secondary outcome measures. In the facioscapulohumeral muscular dystrophy trial only a +1.17 kg difference (95% confidence interval 0.18 to 2.16) in dynamic strength of elbow flexors in favour of the training group reached statistical significance. In the mitochondrial myopathy trial there were no significant differences in dynamic strength measures between training and non-training groups. Exercise duration and distance cycled in a submaximal endurance test increased significantly in the training group compared to the control group.
AUTHORS' CONCLUSIONS
In myotonic dystrophy and facioscapulohumeral muscular dystrophy, moderate-intensity strength training appears not to do harm but there is insufficient evidence to conclude that it offers benefit. In mitochondrial myopathy, aerobic exercise combined with strength training appears to be safe and may be effective in increasing submaximal endurance capacity. Limitations in the design of studies in other muscle diseases prevent more general conclusions in these disorders.
Topics: Exercise; Humans; Mitochondrial Myopathies; Muscular Dystrophy, Facioscapulohumeral; Myotonic Dystrophy; Physical Fitness; Randomized Controlled Trials as Topic
PubMed: 20091552
DOI: 10.1002/14651858.CD003907.pub3 -
Biochimica Et Biophysica Acta 2013The bc1 complex or complex III is a central component of the aerobic respiratory chain in prokaryotic and eukaryotic organisms. It catalyzes the oxidation of quinols and... (Review)
Review
The bc1 complex or complex III is a central component of the aerobic respiratory chain in prokaryotic and eukaryotic organisms. It catalyzes the oxidation of quinols and the reduction of cytochrome c, establishing a proton motive force used to synthesize adenosine triphosphate (ATP) by the F1Fo ATP synthase. In eukaryotes, the complex III is located in the inner mitochondrial membrane. The genes coding for the complex III have a dual origin. While cytochrome b is encoded by the mitochondrial genome, all the other subunits are encoded by the nuclear genome. In this review, we compile an exhaustive list of the known human mutations and associated pathologies found in the mitochondrially-encoded cytochrome b gene as well as the fewer mutations in the nuclear genes coding for the complex III structural subunits and accessory proteins such as BCS1L involved in the assembly of the complex III. Due to the inherent difficulties of studying human biopsy material associated with complex III dysfunction, we also review the work that has been conducted to study the pathologies with the easy to handle eukaryotic microorganism, the yeast Saccharomyces cerevisiae. Phenotypes, biochemical data and possible effects due to the mutations are also discussed in the context of the known three-dimensional structure of the eukaryotic complex III. This article is part of a Special Issue entitled: Respiratory complex III and related bc complexes.
Topics: Electron Transport; Electron Transport Complex III; Humans; Mitochondrial Myopathies; Models, Molecular; Mutation; Protein Conformation; Protein Subunits; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 23220121
DOI: 10.1016/j.bbabio.2012.11.015