Pyruvate stimulates mitophagy via PINK1 stabilization

• Published in: Cellular signalling 2015-09, Vol.27 (9), p.1824-1830
• Main Authors: Park, Sungwoo, Choi, Seon-Guk, Yoo, Seung-Min, Nah, Jihoon, Jeong, Eunil, Kim, Hyunjoo, Jung, Yong-Keun
• Format: Article
• Language: English
• Subjects: Carbonyl Cyanide m-Chlorophenyl Hydrazone - pharmacology; Enzyme Stability - drug effects; Enzyme Stability - genetics; HEK293 Cells; Humans; LC3; Membrane Potential, Mitochondrial - drug effects; Membrane Potential, Mitochondrial - physiology; Membrane Transport Proteins - genetics; Membrane Transport Proteins - metabolism; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial Degradation - drug effects; Mitophagy; PARK2; PDK4; PINK1; Protein Kinases - genetics; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Pyruvate; Pyruvic Acid - metabolism; Pyruvic Acid - pharmacology; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2015.05.020

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. •Screening of mitochondrial proteins identified PDK4 as a mitophagy regulator.•PDK4 mediates CCCP-induced mitophagy via pyruvate.•Mitophagy-stimulating activity of pyruvate is not related to energy metabolism.•Pyruvate induces PINK1 accumulation to recruit PARK2 and LC3 onto mitochondria.•Pyruvate affects mitophagy and dopaminergic cell death triggered by MPP+.