Pink1 regulates mitochondrial dynamics through interaction with the fission/fusion machinery.
Mitochondria form dynamic tubular networks that undergo frequent morphological changes through fission and fusion, the imbalance of which can affect cell survival in general and impact synaptic transmission and plasticity in neurons in particular. Some core components of the mitochondrial fission/fusion machinery, including the dynamin-like GTPases Drp1, Mitofusin, Opa1, and the Drp1-interacting protein Fis1, have been identified. How the fission and fusion processes are regulated under normal conditions and the extent to which defects in mitochondrial fission/fusion are involved in various disease conditions are poorly understood. Mitochondrial malfunction tends to cause diseases with brain and skeletal muscle manifestations and has been implicated in neurodegenerative diseases such as Parkinson's disease (PD). Whether abnormal mitochondrial fission or fusion plays a role in PD pathogenesis has not been shown. Here, we show that Pink1, a mitochondria-targeted Ser/Thr kinase linked to familial PD, genetically interacts with the mitochondrial fission/fusion machinery and modulates mitochondrial dynamics. Genetic manipulations that promote mitochondrial fission suppress Drosophila Pink1 mutant phenotypes in indirect flight muscle and dopamine neurons, whereas decreased fission has opposite effects. In Drosophila and mammalian cells, overexpression of Pink1 promotes mitochondrial fission, whereas inhibition of Pink1 leads to excessive fusion. Our genetic interaction results suggest that Fis1 may act in-between Pink1 and Drp1 in controlling mitochondrial fission. These results reveal a cell biological role for Pink1 and establish mitochondrial fission/fusion as a paradigm for PD research. Compounds that modulate mitochondrial fission/fusion could have therapeutic value in PD intervention.
Yang
Yufeng
Y
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Ouyang
Yingshi
Y
Yang
Lichuan
L
Beal
M Flint
MF
McQuibban
Angus
A
Vogel
Hannes
H
Lu
Bingwei
B
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology / Q000201:enzymology* / Q000235:genetics / Q000648:ultrastructure; D019204:GTP-Binding Proteins / Q000378:metabolism; D017344:Genes, Insect; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000201:enzymology; D010641:Phenotype; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
D003598:Cytoskeletal Proteins; D004298:Dopamine; D029721:Drosophila Proteins; D019204:GTP-Binding Proteins; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C504426:DRP1 protein, Drosophila