title: Pyruvate stimulates mitophagy via PINK1 stabilization.
abstract: Damaged mitochondria are targeted for degradation by an autophagy pathway known as mitophagy. Despite efforts to unravel the mechanisms underlying mitophagy, aspects of mitophagy regulation remain largely unknown. In this study, by using a cell-based fluorescence assay reflecting CCCP-induced mitophagy, we have screened cDNA expression library encoding mitochondrial proteins and identified PDK4 as a mitophagy regulator. Ectopic expression of PDK4 stimulated the clearance of mitochondrial proteins during CCCP-induced mitophagy and enhanced pyruvate levels in both the cytosol and mitochondria. Interestingly, mitochondrial degradation during the mitophagy was not efficient in the absence of pyruvate. Pyruvate was required for PINK1 stabilization during mitochondrial depolarization and subsequent PARK2 translocation and LC3 recruitment onto damaged mitochondria. This pyruvate-mediated mitophagy was not affected by OXPHOS or cellular ATP levels, thus independent of energy metabolism. Rather, pyruvate was required for the interaction between PINK1 and TOMM20 under CCCP condition. These results suggest that pyruvate is required for CCCP-induced PINK1/PARK2-mediated mitophagy.
authors.affiliation: Global Research Laboratory, School of Biological Science, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-747, South Korea.
authors.forename: Sungwoo
authors.initials: S
authors.lastname: Park
authors.affiliation: Global Research Laboratory, School of Biological Science, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-747, South Korea.
authors.forename: Seon-Guk
authors.initials: SG
authors.lastname: Choi
authors.affiliation: Global Research Laboratory, School of Biological Science, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-747, South Korea.
authors.forename: Seung-Min
authors.initials: SM
authors.lastname: Yoo
authors.affiliation: Global Research Laboratory, School of Biological Science, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-747, South Korea.
authors.forename: Jihoon
authors.initials: J
authors.lastname: Nah
authors.affiliation: Global Research Laboratory, School of Biological Science, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-747, South Korea.
authors.forename: Eunil
authors.initials: E
authors.lastname: Jeong
authors.affiliation: Global Research Laboratory, School of Biological Science, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-747, South Korea.
authors.forename: Hyunjoo
authors.initials: H
authors.lastname: Kim
authors.affiliation: Global Research Laboratory, School of Biological Science, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-747, South Korea. Electronic address: ykjung@snu.ac.kr.
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
mesh_terms: D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D004795:Enzyme Stability / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D063306:Mitophagy / Q000187:drug effects*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019289:Pyruvic Acid / Q000378:metabolism / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D026901:Membrane Transport Proteins; D008869:Microtubule-Associated Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019289:Pyruvic Acid; D011956:Receptors, Cell Surface; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C477012:MAP1LC3A protein, human; C000631432:PDK4 protein, human; C084008:TOMM20 protein, human; C111567:parkin protein
keywords: LC3; Mitophagy; PARK2; PDK4; PINK1; Pyruvate