Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue
Winter L, Wittig I, Peeva V, Eggers B, Heidler J, Chevessier F, Kley RA, Barkovits K, Strecker V, Berwanger C, Herrmann H, Marcus K, Kornblum C, Kunz WS, Schroeder R, Clemen CS (2016)
Publication Type: Journal article
Publication year: 2016
Journal
Book Volume: 132
Pages Range: 453-73
Journal Issue: 3
DOI: 10.1007/s00401-016-1592-7
Abstract
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.
Involved external institutions
Goethe-Universität Frankfurt am Main
Germany (DE)
Universitätsklinikum Bonn
Germany (DE)
Ruhr-Universität Bochum (RUB)
Germany (DE)
Universität zu Köln
Germany (DE)
Germany (DE)
Universitätsklinikum Bonn
Germany (DE)
Ruhr-Universität Bochum (RUB)
Germany (DE)
Universität zu Köln
Germany (DE)
How to cite
APA:
Winter, L., Wittig, I., Peeva, V., Eggers, B., Heidler, J., Chevessier, F.,... Clemen, C.S. (2016). Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue. Acta Neuropathologica, 132(3), 453-73. https://doi.org/10.1007/s00401-016-1592-7
MLA:
Winter, Lilli, et al. "Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue." Acta Neuropathologica 132.3 (2016): 453-73.
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