Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Biochim Biophys Acta Mol Basis Dis. 2017 Nov;1863(11):2791-2795. doi: 10.1016/j.bbadis.2017.07.032. Epub 2017 Jul 29.
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 protein sorting 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.
线粒体电子传递链复合物 I 的缺陷是帕金森病 (PD) 的特征，被认为在疾病发病机制中起关键作用。液泡蛋白分选 35 (VPS35) 的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片段化引起线粒体损伤。在这项研究中，我们旨在确定致病性 VPS35 突变是否会影响复合物 I 的活性及其潜在机制。事实上，VPS35 D620N 突变导致患者成纤维细胞中复合物 I 和 II 的酶活性和呼吸缺陷降低。虽然复合物 I 和 II 的亚基表达没有变化，但 D620N 成纤维细胞中组装的复合物 I 和 II 以及超复合物的水平显著降低。重要的是，线粒体分裂的抑制挽救了组装复合物的含量以及复合物 I 和 II 的功能缺陷。总体而言，这些结果表明，VPS35 D620N 突变诱导的过度线粒体分裂导致组装复合物 I 和超复合物的缺陷，并导致生物能量不足。
