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

• Published in: Acta neuropathologica Vol. 132; no. 3; pp. 453 - 473
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-09-2016; Springer; Springer Nature B.V
• Subjects: Analysis; Animals; Biochemistry; Cardiomyopathy; Cytoskeleton; Cytoskeleton - metabolism; Cytoskeleton - pathology; Desmin - genetics; Desmin - metabolism; Disease; Genetic aspects; Hospitals; Humans; Informatics; Intermediate filament proteins; Intermediate Filaments - genetics; Intermediate Filaments - pathology; Medicine; Medicine & Public Health; Mice, Transgenic; Mitochondria; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial DNA; Morphology; Muscle, Skeletal - pathology; Muscular Diseases - genetics; Muscular Diseases - pathology; Musculoskeletal system; Mutation; Mutation - genetics; Neurosciences; Original Paper; Pathology; Proteins; Skeletal muscle; Germany; Desmin knock-out; Mitochondria; Desminopathy; R350P desmin; R349P desmin knock-in; mtDNA; Proteome; Myofibrillar myopathy; Intermediate filament; Protein aggregate myopathy
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-016-1592-7

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.