Parkinson's disease-associated pathogenic VPS35 mutation causes complex I deficits.
Parkinson's disease-associated pathogenic VPS35 mutation causes complex I deficits.
复制标题
帕金森病相关的致病性 VPS35 突变会导致复合物 I 缺陷。
DOI：
10.1016/j.bbadis.2017.07.032
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Zhu X
中科院分区：
文献类型：
--
作者：
Zhou L;Wang W;Hoppel C;Liu J;Zhu X
线粒体电子传递链复合体I的缺陷是帕金森病（PD）的特征之一，被认为在疾病的发病机制中起着关键作用。空泡分选蛋白35（VPS35）突变导致常染色体显性PD，我们最近证明，致病性VPS35突变通过增强线粒体碎片化导致线粒体损伤。在这项研究中，我们的目的是确定致病性VPS35突变是否影响复合物I的活性及其潜在的机制。事实上，VPS35 D620 N突变导致患者成纤维细胞中复合物I和II的酶活性降低和呼吸缺陷。虽然复合物I和II亚基的表达没有变化，但组装的复合物I和II以及超复合物的水平在D620 N成纤维细胞中显著降低。重要的是，线粒体分裂的抑制拯救了组装复合物的内容物以及复合物I和II中的功能缺陷。总体而言，这些结果表明，VPS35 D620 N突变诱导的过度线粒体分裂导致组装的复合物I和超复合物中的缺陷，并导致生物能量学缺陷。
Defect in the complex I of the mitochondrial electron-transport chain is a characteristic of Parkinson’s disease (PD) which is thought to play a critical role in the disease pathogenesis. Mutations in vacuolar sorting protein 35 (VPS35) cause autosomal dominant PD and we recently demonstrated that pathogenic VPS35 mutations cause mitochondrial damage through enhanced mitochondrial fragmentation. In this study, we aimed to determine whether pathogenic VPS35 mutation impacts the activity of complex I and its underlying mechanism. Indeed, VPS35 D620N mutation led to decreased enzymatic activity and respiratory defects in complex I and II in patient fibroblasts. While no changes in the expression of the complex I and II subunits were noted, the level of assembled complex I and II as well as the supercomplex was significantly reduced in D620N fibroblasts. Importantly, inhibition of mitochondrial fission rescued the contents of assembled complexes as well as the functional defects in complex I and II. Overall, these results suggest that VPS35 D620N mutation-induced excessive mitochondrial fission leads to the defects in the assembled complex I and supercomplex and causes bioenergetics deficits.
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影响因子：
9.2
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影响因子：
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影响因子：
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作者：
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