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

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

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

“…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.…”

“…Previous reports have noted that both mitochondrial morphology and positioning are altered in the muscles of DRCs 10, 16. It is unknown whether these alterations result in maladaptive changes in mitochondrial dynamics and directly contribute to mitochondrial dysfunction, resulting in cardiomyopathies in DRC.…”

Targeting Mitochondrial Dysfunction with L-Alpha Glycerylphosphorylcholine

“…It has been shown that point mutations in genes of the subunits of an OxPhos complex affect the stability of another complex. Thus, complex III and complex IV are necessary for the assembly or stability of complex I [34, 35]. Moreover, it appears that supercomplexes are further organized into larger string structures.…”

Impaired muscle relaxation and mitochondrial fission associated with genetic ablation of cytoplasmic actin isoforms

“…Mitochondrial electron density and cristae morphology appear to be maintained in knockout muscle. Another cytoskeletal protein, the intermediate filament desmin is known to be important for proper mitochondrial morphology [28,29]. However the observed mitochondrial phenotype in Actg1-msKO and Actb-msKO is likely not impacted by changes in desmin, which was expressed at similar levels (Figure 3 A–B) and localization (Figure 3 C–E) relative to control muscle.…”