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Biomolecules Mar 2020Mitochondria are highly dynamic organelles that constantly fuse, divide, and move, and their function is regulated and maintained by their morphologic changes....
Mitochondria are highly dynamic organelles that constantly fuse, divide, and move, and their function is regulated and maintained by their morphologic changes. Mitochondrial disease (MD) comprises a group of disorders involving mitochondrial dysfunction. However, it is not clear whether changes in mitochondrial morphology are related to MD. In this study, we examined mitochondrial morphology in fibroblasts from patients with MD (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and Leigh syndrome). We observed that MD fibroblasts exhibited significant mitochondrial fragmentation by upregulation of Drp1, which is responsible for mitochondrial fission. Interestingly, the inhibition of mitochondrial fragmentation by Drp1 knockdown enhanced cellular toxicity and led to cell death in MD fibroblasts. These results suggest that mitochondrial fission plays a critical role in the attenuation of mitochondrial damage in MD fibroblasts.
Topics: Cell Death; Cells, Cultured; Dynamins; Fibroblasts; Humans; Leigh Disease; MELAS Syndrome; Mitochondria; Skin
PubMed: 32183225
DOI: 10.3390/biom10030450 -
Medecine Sciences : M/S Dec 2022
Topics: Humans; Mitochondrial Trifunctional Protein; Mitochondrial Myopathies; Cardiomyopathies; Lipid Metabolism, Inborn Errors
PubMed: 36649635
DOI: 10.1051/medsci/2022181 -
Anesthesia and Analgesia Jun 2020Frailty is a syndrome characterized by decreased reserves across multiple physiologic systems resulting in functional limitations and vulnerability to new stressors.... (Review)
Review
Frailty is a syndrome characterized by decreased reserves across multiple physiologic systems resulting in functional limitations and vulnerability to new stressors. Physical frailty develops over years in community-dwelling older adults but presents or worsens within days in the intensive care unit (ICU) because common mechanisms governing age-related physical frailty are often exacerbated by critical illness. The hallmark of physical frailty is a combined loss of muscle mass, force, and endurance. About one-third of ICU patients have frailty before hospitalization, which increases their risk for both short- and long-term disability and mortality. While there are several valid ways to measure clinical frailty in patients before or after an ICU admission, the mechanistic underpinnings of frailty in critically ill patients and ICU survivors have not been thoroughly investigated. Furthermore, therapeutic interventions to treat frailty during and after time in the ICU are lacking. In this narrative review, we examine studies that identify potential biological mechanisms underlying the development and propagation of physical frailty in both aging and critical illness (eg, inflammation, mitochondrial myopathy, and neuroendocrinopathy). We discuss specific aspects of these frailty mechanisms in older adults, critically ill patients, and ICU survivors that may represent therapeutic targets. Consistent with complexity underlying frailty, this syndrome is unlikely to result from an excess of a single harmful mediator or deficit of a single protective mediator. Rather, frailty occurs in the presence of an incompletely understood state of multisystem dysregulation. We further describe knowledge gaps that warrant clinical and translational research in frailty and critical care with an overall goal of developing effective frailty treatments in critically ill patients and ICU survivors.
Topics: Aged; Critical Illness; Frail Elderly; Frailty; Hospitalization; Humans; Inflammation; Intensive Care Units; Mitochondrial Myopathies; Neurosecretory Systems; Patient Admission; Phenotype; Quality of Life; Treatment Outcome
PubMed: 32384344
DOI: 10.1213/ANE.0000000000004792 -
Mitochondrion Jun 2007Deficiency of Coenzyme Q10 (CoQ10) in muscle has been associated with a spectrum of diseases including infantile-onset multi-systemic diseases, encephalomyopathies with... (Review)
Review
Deficiency of Coenzyme Q10 (CoQ10) in muscle has been associated with a spectrum of diseases including infantile-onset multi-systemic diseases, encephalomyopathies with recurrent myobinuria, cerebellar ataxia, and pure myopathy. CoQ10 deficiency predominantly affects children, but patients have presented with adult-onset cerebellar ataxia or myopathy. Mutations in the CoQ10 biosynthetic genes, COQ2 and PDSS2, have been identified in children with the infantile form of CoQ10 deficiency; however, the molecular genetic bases of adult-onset CoQ10 deficiency remains undefined.
Topics: Adult; Cerebellar Ataxia; Electron Transport; Female; Humans; Male; Middle Aged; Mitochondrial Encephalomyopathies; Models, Biological; Models, Chemical; Muscle, Skeletal; Muscles; Muscular Diseases; Ubiquinone
PubMed: 17485248
DOI: 10.1016/j.mito.2007.03.004 -
Cell Metabolism Nov 2018Alternative oxidases (AOXs) bypass respiratory complexes III and IV by transferring electrons from coenzyme Q directly to O. They have therefore been proposed as a...
Alternative oxidases (AOXs) bypass respiratory complexes III and IV by transferring electrons from coenzyme Q directly to O. They have therefore been proposed as a potential therapeutic tool for mitochondrial diseases. We crossed the severely myopathic skeletal muscle-specific COX15 knockout (KO) mouse with an AOX-transgenic mouse. Surprisingly, the double KO-AOX mutants had decreased lifespan and a substantial worsening of the myopathy compared with KO alone. Decreased ROS production in KO-AOX versus KO mice led to impaired AMPK/PGC-1α signaling and PAX7/MYOD-dependent muscle regeneration, blunting compensatory responses. Importantly, the antioxidant N-acetylcysteine had a similar effect, decreasing the lifespan of KO mice. Our findings have major implications for understanding pathogenic mechanisms in mitochondrial diseases and for the design of therapies, highlighting the benefits of ROS signaling and the potential hazards of antioxidant treatment.
Topics: Animals; Autophagy; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Myopathies; Mitochondrial Proteins; Muscle, Skeletal; Organelle Biogenesis; Oxidation-Reduction; Oxidoreductases; Plant Proteins; Reactive Oxygen Species; Signal Transduction
PubMed: 30122554
DOI: 10.1016/j.cmet.2018.07.012 -
BMC Cardiovascular Disorders Sep 2023Mitochondrial myopathies (MMs) are a group of multi-system diseases caused by abnormalities in mitochondrial DNA (mtDNA) or mutations of nuclear DNA (nDNA). The...
BACKGROUND
Mitochondrial myopathies (MMs) are a group of multi-system diseases caused by abnormalities in mitochondrial DNA (mtDNA) or mutations of nuclear DNA (nDNA). The diagnosis of mitochondrial myopathy (MM) is reliant on the combination of history and physical examination, muscle biopsy, histochemical studies, and next-generation sequencing. Patients with MMs have diverse clinical manifestations. In the contemporary literature, there is a paucity of reports on cardiac structure and function in this rare disease. We report a Chinese man with MM accompanied with both acute right heart failure and left ventricular hypertrophy.
CASE PRESENTATION
A 49-year-old man presented with clinical features suggestive of MM, i.e., ophthalmoparesis, weakness of the pharyngeal and extremity muscles, and respiratory muscles which gradually progressed to respiratory insufficiency. He had a family history of mitochondrial myopathy. He had increased levels of serum creatine kinase and lactate. Muscle biopsy of left lateral thigh revealed 8% ragged red fibers (RRF) and 42% COX-negative fibers. Gene sequencing revealed a novel heterozygote TK2 variant (NM_001172644: c.584T>C, p.Leu195Pro) and another heterozygous variant (NM_004614.4:c.156+958G>A; rs1965661603) in the intron of TK2 gene. Based on these findings, we diagnosed the patient as a case of MM. Echocardiography revealed right heart enlargement, pulmonary hypertension, left ventricular hypertrophy, and thickening of the main pulmonary artery and its branches. The patient received non-invasive ventilation and coenzyme Q10 (CoQ10). The cardiac structure and function were restored at 1-month follow-up.
CONCLUSIONS
This is the first report of reversible cardiac function impairment and left ventricular hypertrophy in a case of adult-onset MM, nocturnal hypoxia is a potential mechanism for left ventricular hypertrophy in patients with MM.
Topics: Adult; Male; Humans; Middle Aged; Hypertrophy, Left Ventricular; East Asian People; Heart; Mitochondrial Myopathies; Cardiomegaly
PubMed: 37715114
DOI: 10.1186/s12872-023-03444-z -
BioFactors (Oxford, England) 2011CoQ(10) deficiencies are clinically and genetically heterogeneous. This syndrome has been associated with five major clinical phenotypes: (1) encephalomyopathy, (2)... (Review)
Review
CoQ(10) deficiencies are clinically and genetically heterogeneous. This syndrome has been associated with five major clinical phenotypes: (1) encephalomyopathy, (2) severe infantile multisystemic disease, (3) cerebellar ataxia, (4) isolated myopathy, and (5) nephrotic syndrome. In a few patients, pathogenic mutations have been identified in genes involved in the biosynthesis of CoQ(10) (primary CoQ(10) deficiencies) or in genes not directly related to CoQ(10) biosynthesis (secondary CoQ(10) deficiencies). Respiratory chain defects, ROS production, and apoptosis variably contribute to the pathogenesis of primary CoQ(10) deficiencies.
Topics: Apraxias; Ataxia Telangiectasia; Cells, Cultured; Cerebellar Ataxia; DNA-Binding Proteins; Electron-Transferring Flavoproteins; Fibroblasts; Humans; Hypoalbuminemia; Iron-Sulfur Proteins; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Mutation; Nuclear Proteins; Oxidoreductases Acting on CH-NH Group Donors; Ubiquinone
PubMed: 21990098
DOI: 10.1002/biof.155 -
Acta Myologica : Myopathies and... Dec 2019Muscle and lower motor neuron diseases share a common denominator of perturbed muscle function, most often related to wasting and weakness of muscles. This leads to a... (Review)
Review
Muscle and lower motor neuron diseases share a common denominator of perturbed muscle function, most often related to wasting and weakness of muscles. This leads to a number of challenges, such as restricted mobility and respiratory difficulties. Currently there is no cure for these diseases. The purpose of this review is to present research that examines the effects of exercise in muscle and lower motor neuron diseases. Evidence indicates that moderate intensity aerobic- and strength exercise is advantageous for patients with muscle diseases, without causing harmful exercise-induced muscle damage. On the contrary, motor neuron diseases show a rather blunted response from exercise training. High-intensity training is a modality that seems safe and a promising exercise method, which may circumvent neural fatigue and provide effect to patients with motor neuron disease. Although we have come far in changing the view on exercise therapy in neuromuscular diseases to a positive one, much knowledge is still needed on what dose of time, intensity and duration should be implemented for different disease and how we should provide exercise therapy to very weak, non-ambulatory and wheelchair bound patients.
Topics: Electric Stimulation Therapy; Exercise; Exercise Therapy; Glycogen Storage Disease Type II; Glycogen Storage Disease Type V; Humans; Mitochondrial Myopathies; Motor Neuron Disease; Muscular Diseases; Muscular Dystrophies; Resistance Training
PubMed: 31970320
DOI: No ID Found -
Journal of Inherited Metabolic Disease Nov 2018Although there are no effective disease-modifying therapies for mitochondrial diseases, an increasing number of trials are being conducted in this rare disease group....
Although there are no effective disease-modifying therapies for mitochondrial diseases, an increasing number of trials are being conducted in this rare disease group. The use of sensitive and valid endpoints is essential to test the effectiveness of potential treatments. There is no consensus on which outcome measures to use in children with mitochondrial disease. The aims of this two-day Delphi-based workshop were to (i) define the protocol for an international, multi-centre natural history study in children with mitochondrial myopathy and (ii) to select appropriate outcome measures for a validation study in children with mitochondrial encephalopathy. We suggest two sets of outcome measures for a natural history study in children with mitochondrial myopathy and for a proposed validation study in children with mitochondrial encephalopathy.
Topics: Child; Consensus; Delphi Technique; Humans; Internationality; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Multicenter Studies as Topic; Muscle Development; Treatment Outcome; Validation Studies as Topic
PubMed: 30027425
DOI: 10.1007/s10545-018-0229-5 -
Cell Metabolism Dec 2019Mitochondrial dysfunction elicits stress responses that safeguard cellular homeostasis against metabolic insults. Mitochondrial integrated stress response (ISR) is a...
Mitochondrial dysfunction elicits stress responses that safeguard cellular homeostasis against metabolic insults. Mitochondrial integrated stress response (ISR) is a major response to mitochondrial (mt)DNA expression stress (mtDNA maintenance, translation defects), but the knowledge of dynamics or interdependence of components is lacking. We report that in mitochondrial myopathy, ISR progresses in temporal stages and development from early to chronic and is regulated by autocrine and endocrine effects of FGF21, a metabolic hormone with pleiotropic effects. Initial disease signs induce transcriptional ISR (ATF5, mitochondrial one-carbon cycle, FGF21, and GDF15). The local progression to 2 metabolic ISR stage (ATF3, ATF4, glucose uptake, serine biosynthesis, and transsulfuration) is FGF21 dependent. Mitochondrial unfolded protein response marks the 3 ISR stage of failing tissue. Systemically, FGF21 drives weight loss and glucose preference, and modifies metabolism and respiratory chain deficiency in a specific hippocampal brain region. Our evidence indicates that FGF21 is a local and systemic messenger of mtDNA stress in mice and humans with mitochondrial disease.
Topics: Activating Transcription Factors; Animals; Cell Line; DNA, Mitochondrial; Escherichia coli; Female; Fibroblast Growth Factors; Growth Differentiation Factor 15; Humans; Male; Mice; Mitochondria; Mitochondrial Myopathies; Sequence Deletion; Stress, Physiological
PubMed: 31523008
DOI: 10.1016/j.cmet.2019.08.019