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ARS Home » Southeast Area » Gainesville, Florida » Center for Medical, Agricultural and Veterinary Entomology » Mosquito and Fly Research » Research » Publications at this Location » Publication #211170
Title: PINK1 protects against oxidative stress by phosphorylating mitochondrial chaperone TRAP1

Author
item Wei Pridgeon, Yuping
item OLZMANN, JAMES - EMORY UNIVERSITY
item CHIN, LIH-SHEN - EMORY UNIVERSITY
item LI, LIAN - EMORY UNIVERSITY

Submitted to: PLoS Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/24/2007
Publication Date: 6/19/2007
Citation: Pridgeon, J.W., Olzmann, J.A., Chin, L.S., Li, L. 2007. PINK1 Protects against Oxidative Stress by Phosphorylating Mitochondrial Chaperone TRAP1. PLoS Biol. 5(7):e172.

Interpretive Summary: Mutations in the PTEN-induced putative kinase 1 (PINK1) gene cause an autosomal recessive form of Parkinson's disease (PD). To date, the substrates of PINK1 have not been reported and the mechanism by which PINK1 mutations lead to neurodegeneration is unknown. Here we report the identification of tumor necrosis factor 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 to 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 function 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 reduced by PD-linked PINK1 G309D, L347P, and W437X mutations. Our findings suggest a novel function of PINK1 in preventing oxidative stress-induced apoptosis and implicate the molecular mechanisms involved in the dysregulation in mitochondrial pathway in PD pathogenesis.

Technical Abstract: Mutations in the PTEN-induced putative kinase 1 (PINK1) gene cause an autosomal recessive form of Parkinson's 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 tumor necrosis factor 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.