Pink1 regulates the oxidative phosphorylation machinery via mitochondrial fission
- 18 July 2011
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 108 (31), 12920-12924
- https://doi.org/10.1073/pnas.1107332108
Abstract
Mutations in PTEN-induced kinase 1 (PINK1), a mitochondrial Ser/Thr kinase, cause an autosomal recessive form of Parkinson's disease (PD), PARK6. To investigate the mechanism of PINK1 pathogenesis, we used the Drosophila Pink1 knockout (KO) model. In mitochondria isolated from Pink1-KO flies, mitochondrial respiration driven by the electron transport chain (ETC) is significantly reduced. This reduction is the result of a decrease in ETC complex I and IV enzymatic activity. As a consequence, Pink1-KO flies also display a reduced mitochondrial ATP synthesis. Because mitochondrial dynamics is important for mitochondrial function and Pink1-KO flies have defects in mitochondrial fission, we explored whether fission machinery deficits underlie the bioenergetic defect in Pink1-KO flies. We found that the bioenergetic defects in the Pink1-KO can be ameliorated by expression of Drp1, a key molecule in mitochondrial fission. Further investigation of the ETC complex integrity in wild type, Pink1-KO, PInk1-KO/Drp1 transgenic, or Drp1 transgenic flies indicates that the reduced ETC complex activity is likely derived from a defect in the ETC complex assembly, which can be partially rescued by increasing mitochondrial fission. Taken together, these results suggest a unique pathogenic mechanism of PINK1 PD: The loss of PINK1 impairs mitochondrial fission, which causes defective assembly of the ETC complexes, leading to abnormal bioenergetics.This publication has 48 references indexed in Scilit:
- PINK1-dependent recruitment of Parkin to mitochondria in mitophagyProceedings of the National Academy of Sciences of the United States of America, 2009
- Mitochondrial DNA background modifies the bioenergetics of NARP/MILS ATP6 mutant cellsHuman Molecular Genetics, 2009
- Parkinson's disease mutations in PINK1 result in decreased Complex I activity and deficient synaptic functionEMBO Molecular Medicine, 2009
- Loss of PINK1 Function Promotes Mitophagy through Effects on Oxidative Stress and Mitochondrial FissionOnline Journal of Public Health Informatics, 2009
- The Parkinson's disease genes pink1 and parkin promote mitochondrial fission and/or inhibit fusion in DrosophilaProceedings of the National Academy of Sciences of the United States of America, 2008
- Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stressProceedings of the National Academy of Sciences of the United States of America, 2008
- Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machineryProceedings of the National Academy of Sciences of the United States of America, 2008
- The PINK1/Parkin pathway regulates mitochondrial morphologyProceedings of the National Academy of Sciences of the United States of America, 2008
- Hypersensitivity to oxygen and shortened lifespan in a Drosophila mitochondrial complex II mutantProceedings of the National Academy of Sciences of the United States of America, 2006
- Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by ParkinProceedings of the National Academy of Sciences of the United States of America, 2006