Parkinson's disease-associated pathogenic VPS35 mutation causes complex I deficits

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1863

Article

Zhou, Leping^1,2,3  Wang, Wenzhang³  Hoppel, Charles^4,5  Liu, Jun^1,2  Zhu, Xiongwei³ 

[1] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Neurol, Shanghai, Peoples R China

[2] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Inst Neurol, Shanghai, Peoples R China

[3] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA

[4] Case Western Reserve Univ, Dept Pharmacol, Cleveland, OH 44106 USA

[5] Case Western Reserve Univ, Dept Med, Ctr Mitochondrial Dis, Cleveland, OH 44106 USA

关键词: Parkinson's disease;    Mitochondrial fission;    VPS35;    Complex I deficits;    Blue native gel electrophoresis;   

DOI  :  10.1016/j.bbadis.2017.07.032

来源: Elsevier

【 摘 要 】

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.

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