Zhou 2017 Biochim Biophys Acta

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Zhou L, Wang W, Hoppel C, Liu J, Zhu X (2017) Parkinson's disease-associated pathogenic VPS35 mutation causes complex I deficits. Biochim Biophys Acta 1863:2791-5.

» PMID: 28765075

Zhou L, Wang W, Hoppel C, Liu J, Zhu X (2017) Biochim Biophys Acta

Abstract: 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.

Copyright © 2017 Elsevier B.V. All rights reserved.

Keywords: Blue native gel electrophoresis, Complex I deficits, Mitochondrial fission, Parkinson's disease, VPS35 Bioblast editor: Kandolf G O2k-Network Lab: US OH Cleveland Hoppel CL


Labels: MiParea: Respiration, mt-Structure;fission;fusion  Pathology: Parkinson's 

Organism: Human  Tissue;cell: Fibroblast  Preparation: Isolated mitochondria  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase 

Coupling state: OXPHOS, ET  Pathway: N, S, NS, ROX  HRR: Oxygraph-2k 

Labels, 2017-11