Mitochondrial dysfunction in myofibrillar myopathy
Mitochondrial dysfunction in myofibrillar myopathy
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DOI：
10.1016/j.nmd.2016.08.004
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发表时间：
2016-10-01
影响因子：
2.8
通讯作者：
Turnbull, Doug M.
中科院分区：
文献类型：
--
作者：
Vincent, Amy E.;Grady, John P.;Turnbull, Doug M.
肌原纤维肌病（MFM）的特征在于局灶性肌原纤维破坏和肌原纤维成分作为蛋白质聚集体的积累。它们是由DES、MYOT、BTAAB、FLNC、BAG 3、DNAJB 6和ZASP基因以及其他尚未鉴定的基因突变引起的。先前的研究已经报道了线粒体形态和细胞定位的变化，以及MFM患者肌肉中的克隆扩增、大规模线粒体DNA（mtDNA）缺失和局灶性呼吸链缺陷。在这里，我们检查了结蛋白（n = 6），ZASP（n = 1）和肌球蛋白（n = 2）突变和MFM蛋白聚集体患者的骨骼肌，以了解线粒体功能障碍如何导致疾病病理学的潜在机制。我们已经使用了一种有效的定量免疫荧光测定研究呼吸链蛋白水平，氧化酶组织化学和单细胞线粒体DNA分析，以检查线粒体的变化。结果表明，少量的克隆扩展的线粒体DNA缺失，我们的结论是由于衰老和疾病病理。除此之外，我们还报告了与年龄匹配的对照组相比呼吸链复合物I和IV缺乏的水平更高，尽管患者活检中呼吸缺陷肌纤维的总体水平较低。更引人注目的是，与对照相比，肌原纤维性肌病患者肌纤维的显著更高百分比具有低线粒体质量。我们的结论是，这是机械无关的结蛋白和肌球蛋白蛋白的蛋白质聚集体，然而，线粒体质量和肌纤维面积之间的相关性found. We建议，这可能是由于减少线粒体生物合成结合肌纤维肥大。(C)2016作者由爱思唯尔公司出版。这是一篇开放获取的文章，使用CC BY许可证（http：//creativecommons.org/licenses/by/4.0/）。
Myofibrillar myopathies (MFM) are characterised by focal myofibrillar destruction and accumulation of myofibrillar elements as protein aggregates. They are caused by mutations in the DES, MYOT, CRYAB, FLNC, BAG3, DNAJB6 and ZASP genes as well as other as yet unidentified genes. Previous studies have reported changes in mitochondrial morphology and cellular positioning, as well as clonally-expanded, large-scale mitochondrial DNA (mtDNA) deletions and focal respiratory chain deficiency in muscle of MFM patients. Here we examine skeletal muscle from patients with desmin (n = 6), ZASP (n = 1) and myotilin (n = 2) mutations and MFM protein aggregates, to understand how mitochondrial dysfunction may contribute to the underlying mechanisms causing disease pathology. We have used a validated quantitative immunofluorescent assay to study respiratory chain protein levels, together with oxidative enzyme histochemistry and single cell mitochondrial DNA analysis, to examine mitochondrial changes. Results demonstrate a small number of clonally-expanded mitochondrial DNA deletions, which we conclude are due to both ageing and disease pathology. Further to this we report higher levels of respiratory chain complex I and IV deficiency compared to age matched controls, although overall levels of respiratory deficient muscle fibres in patient biopsies are low. More strikingly, a significantly higher percentage of myofibrillar myopathy patient muscle fibres have a low mitochondrial mass compared to controls. We concluded this is mechanistically unrelated to desmin and myotilin protein aggregates; however, correlation between mitochondrial mass and muscle fibre area is found. We suggest this may be due to reduced mitochondrial biogenesis in combination with muscle fibre hypertrophy. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).