PINK1 Loss-of-Function Mutations Affect Mitochondrial Complex I Activity via NdufA10 Ubiquinone Uncoupling

被引：268

作者：

Morais, Vanessa A. ^{[1
,2
,3
,4
]}

Haddad, Dominik ^{[1
,2
,3
,4
]}

Craessaerts, Katleen ^{[1
,2
,3
,4
]}

De Bock, Pieter-Jan ^{[5
,6
]}

Swerts, Jef ^{[1
,2
,3
,4
]}

Vilain, Sven ^{[1
,2
,3
,4
]}

Aerts, Liesbeth ^{[1
,2
,3
,4
]}

Overbergh, Lut ^{[7
]}

Gruenewald, Anne ^{[8
]}

Seibler, Philip ^{[8
]}

Klein, Christine ^{[8
,9
]}

Gevaert, Kris ^{[5
,6
]}

Verstreken, Patrik ^{[1
,2
,3
,4
]}

De Strooper, Bart ^{[1
,2
,3
,4
,10
]}

机构：

[1] VIB Ctr Biol Dis, B-3000 Louvain, Belgium

[2] Katholieke Univ Leuven Hosp, Ctr Human Genet, B-3000 Louvain, Belgium

[3] Katholieke Univ Leuven, Dept Human Genet, B-3000 Louvain, Belgium

[4] Leuven Res Inst Neurosci & Dis LIND, B-3000 Louvain, Belgium

[5] Dept Med Prot Res, B-9000 Ghent, Belgium

[6] Univ Ghent, Dept Biochem, B-9000 Ghent, Belgium

[7] Katholieke Univ Leuven, Lab Clin & Expt Endocrinol, B-3000 Louvain, Belgium

[8] Med Univ Lubeck, Dept Neurol, Sect Clin & Mol Neurogenet, D-23538 Lubeck, Germany

[9] Newcastle Univ, Inst Ageing & Hlth, Wellcome Trust Ctr Mitochondrial Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[10] UCL, Inst Neurol, London, England

来源：

SCIENCE | 2014年 / 344卷 / 6180期

基金：

英国生物技术与生命科学研究理事会;

关键词：

PARKIN; DROSOPHILA; MITOPHAGY; PATHOLOGY; MACHINERY; MUTANTS; FISSION;

D O I：

10.1126/science.1249161

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Under resting conditions, Pink1 knockout cells and cells derived from patients with PINK1 mutations display a loss of mitochondrial complex I reductive activity, causing a decrease in the mitochondrial membrane potential. Analyzing the phosphoproteome of complex I in liver and brain from Pink1(-/-) mice, we found specific loss of phosphorylation of serine-250 in complex I subunit NdufA10. Phosphorylation of serine-250 was needed for ubiquinone reduction by complex I. Phosphomimetic NdufA10 reversed Pink1 deficits in mouse knockout cells and rescued mitochondrial depolarization and synaptic transmission defects in pink(B9)-null mutant Drosophila. Complex I deficits and adenosine triphosphate synthesis were also rescued in cells derived from PINK1 patients. Thus, this evolutionary conserved pathway may contribute to the pathogenic cascade that eventually leads to Parkinson's disease in patients with PINK1 mutations.

引用

页码：203 / 207

页数：5

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