title: 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.
authors.affiliation: Institute of Neuropathology, University Hospital Erlangen, Schwabachanlage 6, 91054, Erlangen, Germany.
authors.forename: Lilli
authors.initials: L
authors.lastname: Winter
authors.affiliation: Functional Proteomics, SFB815 Core Unit, Medical School, Goethe University, 60590, Frankfurt, Germany.|German Center for Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt am Main, Germany.
authors.forename: Ilka
authors.initials: I
authors.lastname: Wittig
authors.affiliation: Life and Brain Center, University Hospital of Bonn, 53127, Bonn, Germany.|Department of Epileptology, University Hospital of Bonn, 53105, Bonn, Germany.
authors.forename: Viktoriya
authors.initials: V
authors.lastname: Peeva
authors.affiliation: Medizinisches Proteom-Center, Medical Faculty, Ruhr University Bochum, 44801, Bochum, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Eggers
authors.affiliation: Functional Proteomics, SFB815 Core Unit, Medical School, Goethe University, 60590, Frankfurt, Germany.
authors.forename: Juliana
authors.initials: J
authors.lastname: Heidler
authors.affiliation: Institute of Neuropathology, University Hospital Erlangen, Schwabachanlage 6, 91054, Erlangen, Germany.
authors.forename: Frederic
authors.initials: F
authors.lastname: Chevessier
authors.affiliation: Department of Neurology, University Hospital Bergmannsheil, Ruhr-University Bochum, 44789, Bochum, Germany.
authors.forename: Rudolf A
authors.initials: RA
authors.lastname: Kley
authors.affiliation: Medizinisches Proteom-Center, Medical Faculty, Ruhr University Bochum, 44801, Bochum, Germany.
authors.forename: Katalin
authors.initials: K
authors.lastname: Barkovits
authors.affiliation: Functional Proteomics, SFB815 Core Unit, Medical School, Goethe University, 60590, Frankfurt, Germany.
authors.forename: Valentina
authors.initials: V
authors.lastname: Strecker
authors.affiliation: Center for Biochemistry, Institute of Biochemistry I, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931, Cologne, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Berwanger
authors.affiliation: Institute of Neuropathology, University Hospital Erlangen, Schwabachanlage 6, 91054, Erlangen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Herrmann
authors.affiliation: Medizinisches Proteom-Center, Medical Faculty, Ruhr University Bochum, 44801, Bochum, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Marcus
authors.affiliation: Department of Neurology, University Hospital of Bonn, 53105, Bonn, Germany.|Center for Rare Diseases Bonn (ZSEB), University Hospital of Bonn, 53105, Bonn, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Kornblum
authors.affiliation: Life and Brain Center, University Hospital of Bonn, 53127, Bonn, Germany.|Department of Epileptology, University Hospital of Bonn, 53105, Bonn, Germany.
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
authors.affiliation: Institute of Neuropathology, University Hospital Erlangen, Schwabachanlage 6, 91054, Erlangen, Germany. rolf.schroeder@uk-erlangen.de.
authors.forename: Rolf
authors.initials: R
authors.lastname: Schröder
authors.affiliation: Center for Biochemistry, Institute of Biochemistry I, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931, Cologne, Germany. christoph.clemen@uni-koeln.de.
authors.forename: Christoph S
authors.initials: CS
authors.lastname: Clemen
mesh_terms: D000818:Animals; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D003893:Desmin / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007382:Intermediate Filaments / Q000235:genetics / Q000473:pathology*; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000473:pathology*; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics
chemical_list: D003893:Desmin
keywords: Desmin knock-out; Desminopathy; Intermediate filament; Mitochondria; Myofibrillar myopathy; Protein aggregate myopathy; Proteome; R349P desmin knock-in; R350P desmin; mtDNA