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

• Published in: Science (American Association for the Advancement of Science) Vol. 344; no. 6180; pp. 203 - 207
• Main Authors: Morais, Vanessa A., Haddad, Dominik, Craessaerts, Katleen, De Bock, Pieter-Jan, Swerts, Jef, Vilain, Sven, Aerts, Liesbeth, Overbergh, Lut, Grünewald, Anne, Seibler, Philip, Klein, Christine, Gevaert, Kris, Verstreken, Patrik, De Strooper, Bart
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 11.04.2014; The American Association for the Advancement of Science
• Subjects: Amino Acid Sequence; Animals; Brain - enzymology; Cell lines; Drosophila; Drosophila Proteins - metabolism; Electron transfer; Electron Transport Complex I - metabolism; Fibroblasts; Fluorescence; Gene expression; Genetic mutation; Humans; Liver - enzymology; Membrane Potential, Mitochondrial - genetics; Mice; Mice, Knockout; Mitochondria; Mitochondrial membranes; Molecular Sequence Data; Mutation; NADH Dehydrogenase - metabolism; Parkinson Disease - enzymology; Parkinson Disease - genetics; Pathogenesis; Patients; Phosphorylation; Phosphorylation - genetics; Protein Kinases - genetics; Proteome; Quantification; Serine - chemistry; Serine - metabolism; Stem cells
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1249161

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.