Almazov National Medical Research Centre, Saint Petersburg, Russia; Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden.
Almazov National Medical Research Centre, Saint Petersburg, Russia.
Biochim Biophys Acta Mol Basis Dis. 2020 Jun 1;1866(6):165745. doi: 10.1016/j.bbadis.2020.165745. Epub 2020 Feb 25.
Desmin, being a major intermediate filament of muscle cells, contributes to stabilization and positioning of mitochondria. Desmin mutations have been reported in conjunction with skeletal myopathies accompanied by mitochondrial dysfunction. Depending on the ability to promote intracellular aggregates formation, mutations can be considered aggregate-prone or non-aggregate-prone. The aim of the present study was to describe how expression of different desmin mutant isoforms effects mitochondria and contributes to the development of myocyte dysfunction. To achieve this goal, two non-aggregate-prone (Des S12F and Des A213V) and four aggregate-prone (Des L345P, Des A357P, Des L370P, Des D399Y) desmin mutations were expressed in skeletal muscle cells. We showed that all evaluated mutations affected the morphology of mitochondrial network, suppressed parameters of mitochondrial respiration, diminished mitochondrial membrane potential, increased ADP/ATP ratio, and enhanced mitochondrial DNA (mtDNA) release. mtDNA was partially secreted through exosomes as demonstrated by GW4869 treatment. Dysfunction of mitochondria was observed regardless the type of mutation: aggregate-prone or non-aggregate-prone. However, expression of aggregate-prone mutations resulted in more prominent phenotype. Thus, in this comparative study of six pathogenic desmin mutations that cause skeletal myopathy development, we confirmed a role of mitochondrial dysfunction and mtDNA release in the pathogenesis of desmin myopathies, regardless of the aggregation capacity of the mutated desmin.
结蛋白是肌肉细胞的主要中间丝，有助于稳定和定位线粒体。已经报道了与伴有线粒体功能障碍的骨骼肌病相关的结蛋白突变。根据促进细胞内聚集体形成的能力，突变可以被认为是易于聚集的或不易聚集的。本研究的目的是描述不同结蛋白突变体亚型如何影响线粒体并有助于肌细胞功能障碍的发展。为了实现这一目标，在骨骼肌细胞中表达了两种不易聚集的（Des S12F 和 Des A213V）和四种易于聚集的（Des L345P、Des A357P、Des L370P、Des D399Y）结蛋白突变。我们表明，所有评估的突变都影响了线粒体网络的形态，抑制了线粒体呼吸的参数，降低了线粒体膜电位，增加了 ADP/ATP 比，并增强了线粒体 DNA（mtDNA）的释放。GW4869 处理表明，mtDNA 部分通过外泌体分泌。无论突变类型是易于聚集的还是不易聚集的，都观察到了线粒体功能障碍。然而，易于聚集的突变的表达导致了更明显的表型。因此，在这项对导致骨骼肌病发展的六种致病性结蛋白突变的比较研究中，我们证实了线粒体功能障碍和 mtDNA 释放在结蛋白肌病发病机制中的作用，而与突变结蛋白的聚集能力无关。
