PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1.
Mutations in the PTEN induced putative kinase 1 (PINK1) gene cause an autosomal recessive form of Parkinson disease (PD). So far, no substrates of PINK1 have been reported, and the mechanism by which PINK1 mutations lead to neurodegeneration is unknown. Here we report the identification of TNF receptor-associated protein 1 (TRAP1), a mitochondrial molecular chaperone also known as heat shock protein 75 (Hsp75), as a cellular substrate for PINK1 kinase. PINK1 binds and colocalizes with TRAP1 in the mitochondria and phosphorylates TRAP1 both in vitro and in vivo. We show that PINK1 protects against oxidative-stress-induced cell death by suppressing cytochrome c release from mitochondria, and this protective action of PINK1 depends on its kinase activity to phosphorylate TRAP1. Moreover, we find that the ability of PINK1 to promote TRAP1 phosphorylation and cell survival is impaired by PD-linked PINK1 G309D, L347P, and W437X mutations. Our findings suggest a novel pathway by which PINK1 phosphorylates downstream effector TRAP1 to prevent oxidative-stress-induced apoptosis and implicate the dysregulation of this mitochondrial pathway in PD pathogenesis.
Pridgeon
Julia W
JW
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Olzmann
James A
JA
Chin
Lih-Shen
LS
Li
Lian
L
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D045304:Cytochromes c / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D016716:PC12 Cells; D020734:Parkinsonian Disorders / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017354:Point Mutation; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D014162:Transfection; D000099202:PTEN-Induced Putative Kinase
D045304:Cytochromes c; D018841:HSP90 Heat-Shock Proteins; D011494:Protein Kinases; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D000099202:PTEN-Induced Putative Kinase; C092306:TRAP1 protein, human