title: Role of glucose metabolism and ATP in maintaining PINK1 levels during Parkin-mediated mitochondrial damage responses.
abstract: 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.
authors.affiliation: From the Department of Chemistry and Biochemistry, University of Colorado-Boulder, Boulder, Colorado 80303.
authors.forename: Schuyler
authors.initials: S
authors.lastname: Lee
authors.affiliation: From the Department of Chemistry and Biochemistry, University of Colorado-Boulder, Boulder, Colorado 80303.
authors.forename: Conggang
authors.initials: C
authors.lastname: Zhang
authors.affiliation: From the Department of Chemistry and Biochemistry, University of Colorado-Boulder, Boulder, Colorado 80303 Xuedong.Liu@colorado.edu.
authors.forename: Xuedong
authors.initials: X
authors.lastname: Liu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D063306:Mitophagy / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000255:Adenosine Triphosphate; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D005947:Glucose; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein
keywords: ATP; Glucose Metabolism; Mitophagy; PTEN-induced Putative Kinase 1 (PINK1); Parkin; Parkinson Disease (Autosomal Recessive, Early Onset) 7 (PARK7)