PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling

Vanessa A. Morais*, Dominik Haddad, Katleen Craessaerts, Pieter Jan De Bock, Jef Swerts, Sven Vilain, Liesbeth Aerts, Lut Overbergh, Anne Grun̈ewald, Philip Seibler, Christine Klein, Kris Gevaert, Patrik Verstreken, Bart De Strooper

*Corresponding author for this work
117 Citations (Scopus)

Abstract

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 pinkB9-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.

Original languageEnglish
JournalScience
Volume344
Issue number6180
Pages (from-to)203-207
Number of pages5
ISSN0036-8075
DOIs
Publication statusPublished - 01.01.2014

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