Pink1 regulates the oxidative phosphorylation machinery via mitochondrial fission

W Liu, R Acín-Peréz, KD Geghman… - Proceedings of the …, 2011 - National Acad Sciences
W Liu, R Acín-Peréz, KD Geghman, G Manfredi, B Lu, C Li
Proceedings of the National Academy of Sciences, 2011National Acad Sciences
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 …
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.
National Acad Sciences