Role of Glucose Metabolism and ATP in Maintaining PINK1 Levels during Parkin-mediated Mitochondrial Damage Responses

• Published in: The Journal of biological chemistry Vol. 290; no. 2; pp. 904 - 917
• Main Authors: Lee, Schuyler, Zhang, Conggang, Liu, Xuedong
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.01.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Adenosine Triphosphate - metabolism; ATP; Carbonyl Cyanide m-Chlorophenyl Hydrazone - pharmacology; Cell Biology; Energy Metabolism; Glucose - metabolism; Humans; Mitochondria - drug effects; Mitochondria - metabolism; Mitophagy; Mitophagy - genetics; Parkin; Parkinson Disease (Autosomal Recessive, Early Onset) 7 (PARK7); Parkinson Disease - genetics; Parkinson Disease - pathology; Protein Kinases - biosynthesis; Protein Kinases - genetics; PTEN-induced Putative Kinase 1 (PINK1); Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Parkinson Disease (Autosomal Recessive, Early Onset) 7 (PARK7); Mitophagy; ATP; PTEN-induced Putative Kinase 1 (PINK1); Glucose Metabolism; Parkin
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.606798

Mutations in several genes, including PINK1 and Parkin, are known to cause autosomal recessive cases of Parkinson disease in humans. These genes operate in the same pathway and play a crucial role in mitochondrial dynamics and maintenance. PINK1 is required to recruit Parkin to mitochondria and initiate mitophagy upon mitochondrial depolarization. In this study, we show that PINK1-dependent Parkin mitochondrial recruitment in response to global mitochondrial damage by carbonyl cyanide m-chlorophenylhydrazine (CCCP) requires active glucose metabolism. Parkin accumulation on mitochondria and subsequent Parkin-dependent mitophagy is abrogated in glucose-free medium or in the presence of 2-deoxy-d-glucose upon CCCP treatment. The defects in Parkin recruitment correlate with intracellular ATP levels and can be attributed to suppression of PINK1 up-regulation in response to mitochondria depolarization. Low levels of ATP appear to prevent PINK1 translation instead of affecting PINK1 mRNA expression or reducing its stability. Consistent with a requirement of ATP for elevated PINK1 levels and Parkin mitochondrial recruitment, local or individual mitochondrial damage via photoirradiation does not affect Parkin recruitment to damaged mitochondria as long as a pool of functional mitochondria is present in the photoirradiated cells even in glucose-free or 2-deoxy-d-glucose-treated conditions. Thus, our data identify ATP as a key regulator for Parkin mitochondrial translocation and sustaining elevated PINK1 levels during mitophagy. PINK1 functions as an AND gate and a metabolic sensor coupling biogenetics of cells and stress signals to mitochondria dynamics.Parkin mitochondrial recruitment upon CCCP treatment requires active glucose metabolism. ATP is a key regulator of PINK1-mediated mitophagy by controlling PINK1 translation levels. PINK1 levels decrease in response to low ATP, resulting in inactivation of Parkin-mediate mitophagy. Short half-life of PINK1 renders it sensitive to metabolic changes and ATP level. The finding offers insight into bioenergetics of the PINK1-Parkin pathway.