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Article (Scientific journals)
PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling.
Morais, Vanessa A.; Haddad, Dominik; Craessaerts, Katleen et al.
2014In Science, 344 (6180), p. 203-7
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Keywords :
Amino Acid Sequence; Animals; Brain/enzymology; Drosophila Proteins/metabolism; Electron Transport Complex I/metabolism; Humans; Liver/enzymology; Membrane Potential, Mitochondrial/genetics; Mice; Mice, Knockout; Molecular Sequence Data; Mutation; NADH Dehydrogenase/metabolism; Parkinson Disease/enzymology/genetics; Phosphorylation/genetics; Protein Kinases/genetics; Proteome; Serine/chemistry/metabolism
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Morais, Vanessa A.
Haddad, Dominik
Craessaerts, Katleen
De Bock, Pieter-Jan
Swerts, Jef
Vilain, Sven
Aerts, Liesbeth
Overbergh, Lut
GRÜNEWALD, Anne  
Seibler, Philip
Gevaert, Kris
Verstreken, Patrik
De Strooper, Bart
More authors (4 more) Less
External co-authors :
yes
Language :
English
Title :
PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling.
Publication date :
2014
Journal title :
Science
ISSN :
1095-9203
Publisher :
American Association for the Advancement of Science, Washington, United States - District of Columbia
Volume :
344
Issue :
6180
Pages :
203-7
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
since 09 February 2016

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