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Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue
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 dysfu...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992032/ https://www.ncbi.nlm.nih.gov/pubmed/27393313 http://dx.doi.org/10.1007/s00401-016-1592-7 |
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author | 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. |
author_facet | 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. |
author_sort | Winter, Lilli |
collection | PubMed |
description | 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 MATERIAL: The online version of this article (doi:10.1007/s00401-016-1592-7) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4992032 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-49920322016-09-06 Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue 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. Acta Neuropathol Original Paper 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 MATERIAL: The online version of this article (doi:10.1007/s00401-016-1592-7) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2016-07-08 2016 /pmc/articles/PMC4992032/ /pubmed/27393313 http://dx.doi.org/10.1007/s00401-016-1592-7 Text en © The Author(s) 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Original Paper 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. Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue |
title | Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue |
title_full | Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue |
title_fullStr | Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue |
title_full_unstemmed | Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue |
title_short | Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue |
title_sort | mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4992032/ https://www.ncbi.nlm.nih.gov/pubmed/27393313 http://dx.doi.org/10.1007/s00401-016-1592-7 |
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