Mitochondrial dysfunction and neuromuscular disease

Nardin, Rachel; Johns, Donald R.

doi:10.1002/1097-4598(200102)24:2<170::aid-mus30>3.0.co;2-0

Cited by 88 publications

(44 citation statements)

References 204 publications

(355 reference statements)

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“…Ultrastructural analysis of postmortem muscles show characteristic myofibrillar disruption and aggregation of desmin filaments in the myocardium 38, 39. In addition, mitochondrial dysfunction occurs early and acts causally in a wide variety of human protein aggregate disease pathogenesis affecting the central nervous system40, 41 and striated muscle tissue 16, 42. Muscle biopsy specimens from human desminopathies and myofibrillar myopathies showed evidence of mitochondrial pathology 43, 44.…”

Section: Discussionmentioning

confidence: 99%

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

Alam

Abdullah

Aishwarya

et al. 2018

JAHA

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BackgroundDesmin filament proteins interlink the contractile myofibrillar apparatus with mitochondria, nuclei and the sarcolemma. Mutations in the human desmin gene cause cardiac disease, remodeling, and heart failure but the pathophysiological mechanisms remain unknown.Methods and ResultsCardiomyocyte‐specific overexpression of mutated desmin (a 7 amino acid deletion R172‐E178, D7‐Des Tg) causes accumulations of electron‐dense aggregates and myofibrillar degeneration associated with cardiac dysfunction. Though extensive studies demonstrated that these altered ultrastructural changes cause impairment of cardiac contractility, the molecular mechanism of cardiomyocyte death remains elusive. In the present study, we report that the D7‐Des Tg mouse hearts undergo aberrant mitochondrial fission associated with increased expression of mitochondrial fission regulatory proteins. Mitochondria isolated from D7‐Des Tg hearts showed decreased mitochondrial respiration and increased apoptotic cell death. Overexpression of mutant desmin by adenoviral infection in cultured cardiomyocytes led to increased mitochondrial fission, inhibition of mitochondrial respiration, and activation of cellular toxicity. Inhibition of mitochondrial fission by mitochondrial division inhibitor mdivi‐1 significantly improved mitochondrial respiration and inhibited cellular toxicity associated with D7‐Des overexpression in cardiomyocytes.ConclusionsAberrant mitochondrial fission results in mitochondrial respiratory defects and apoptotic cell death in D7‐Des Tg hearts. Inhibition of aberrant mitochondrial fission using mitochondrial division inhibitor significantly preserved mitochondrial function and decreased apoptotic cell death. Taken together, our study shows that maladaptive aberrant mitochondrial fission causes desminopathy‐associated cellular dysfunction.

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Section: Discussionmentioning

confidence: 99%

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

Alam

Abdullah

Aishwarya

et al. 2018

JAHA

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“…Mitochondrial dysfunction has been described in a wide variety of human degenerative diseases affecting the central nervous system [4, 5, 17, 36, 43, 52, 61, 72] and striated muscle tissue [35, 57]. In the context of myofibrillar myopathies, mitochondrial pathology has been reported in patients with mutations in filamin-C [34, 37, 46], myotilin [34, 59], ZASP [34], FHL1 [48], plectin [69, 77], and desmin [3, 67, 68].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1592-7) contains supplementary material, which is available to authorized users.

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“…It is well established that mitochondria also play key roles in the integration and execution of intrinsic apoptotic signals culminating in programmed cell death. Mitochondrial dysfunction is closely associated with numerous diseases including cancer, neuromuscular degenerative diseases, osteoporosis, ischemia/reperfusion injury, diabetes, and even in aging [136–138]. Mitochondrial membrane and genetic system is highly sensitive to the action of many drugs including doxorubicin, tamoxifen and various environmental carcinogens [139, 140].…”

Section: Expert Opinionmentioning

confidence: 99%

Bimodal targeting of microsomal cytochrome P450s to mitochondria: implications in drug metabolism and toxicity

Sangar

Bansal

Avadhani

2010

Expert Opinion on Drug Metabolism & Toxicology

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Importance of the field-Microsomal cytochrome P450s are critical for drug metabolism and toxicity. Recent studies show that these CYPs are also present in the mitochondrial compartment of human and rodent tissues. Mitochondrial CYP1A1 and 2E1 show both overlapping and distinct metabolic activities compared to microsomal forms. Mitochondrial CYP2E1 also induces oxidative stress. The mechanisms of mitochondria targeting of CYPs and their role in drug metabolism and toxicity are important factors to consider while determining the drug dose and in drug development.Areas covered in this review-This review highlights the mechanisms of bimodal targeting of CYP1A1, 2B1, 2E1 and 2D6 to mitochondria and microsomes. The review also discusses differences in structure and function of mitochondrial CYPs.What the readers will gain-A comprehensive review of the literature on drug metabolism in the mitochondrial compartment, and their potential for inducing mitochondrial dysfunction.Take home message-Studies on the biochemistry, pharmacology and pharmacogenetic analysis of CYPs are mostly focused on the molecular forms associated with the microsomal membrane. However, the mitochondrial CYPs in some individuals can represent a substantial part of the tissue pool and contribute in a significant way to drug metabolism, clearance and toxicity.

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Mitochondrial dysfunction and neuromuscular disease

Cited by 88 publications

References 204 publications

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

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

Bimodal targeting of microsomal cytochrome P450s to mitochondria: implications in drug metabolism and toxicity

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