Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue.
Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue.
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DOI：
10.1007/s00401-016-1592-7
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发表时间：
2016-09
影响因子：
12.7
通讯作者：
Clemen CS
中科院分区：
文献类型：
--
作者：
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;Schröder R;Clemen CS
继发性线粒体功能障碍是由中枢神经系统和横纹肌中不同蛋白质突变引起的多种人类蛋白质聚集性疾病的特征。突变蛋白的表达和线粒体功能障碍之间的功能关系在很大程度上是未知的。特别是，这种功能障碍如何推动疾病进程的机制仍然难以捉摸。为了解决蛋白质聚集性肌病的这个问题，我们对中间丝蛋白结蛋白突变的人类骨骼肌患者的骨骼肌以及携带R349P结蛋白突变的杂合和纯合敲入小鼠的肌肉中的线粒体病理进行了全面、多水平的分析。我们证明，突变结蛋白的表达导致瘤外结蛋白细胞骨架的破坏和广泛的线粒体亚细胞分布、数量和形状的异常。在分子水平上，我们发现呼吸链复合体和超复合体的丰度和组装发生了变化。此外，我们发现mtDNA和核DNA编码的线粒体蛋白显著减少，同时mtDNA大规模缺失，mtDNA拷贝数减少。因此，我们的数据表明，突变型结蛋白的表达导致线粒体的多层次损伤，这些损伤已经在结缔组织病的早期阶段发生。本文的在线版本(doi：10.1007/s00401-0161592-7)包含补充材料，授权用户可以使用。
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. The online version of this article (doi:10.1007/s00401-016-1592-7) contains supplementary material, which is available to authorized users.