The Mitochondrial Rhomboid Protease PARL Is Regulated by PDK2 to Integrate Mitochondrial Quality Control and Metabolism.
Mitochondrial quality control (MQC) systems are essential for mitochondrial health and normal cellular function. Dysfunction of MQC is emerging as a central mechanism for the pathogenesis of various diseases, including Parkinson's disease. The mammalian mitochondrial rhomboid protease, PARL, has been proposed as a regulator of PINK1/PARKIN-mediated mitophagy, which is an essential component of MQC. PARL undergoes an N-terminal autocatalytic cleavage (β cleavage), which is required for efficient mitophagy. We demonstrate that β cleavage responds to mitochondrial stress, triggered by the depletion of mitochondrial ATP. Furthermore, we show that PDK2, a key regulator in metabolic plasticity, phosphorylates PARL and regulates β cleavage. Through regulating β cleavage and the production of a less active enzyme, PACT, PDK2 negatively regulates PINK1/PARKIN-mediated mitophagy. Taken together, we propose that PDK2/PARL senses defects in mitochondrial bioenergetics, integrating mitochondrial metabolism to mitophagy and MQC in human health and disease.
Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
Guang
G
Shi
Department of Biochemistry, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada. Electronic address: angus.mcquibban@utoronto.ca.
G Angus
GA
McQuibban
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D004734:Energy Metabolism / Q000502:physiology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D045726:Metalloproteases / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D063306:Mitophagy / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D044767:Ubiquitin-Protein Ligases
D024101:Mitochondrial Proteins; C000631430:PDK2 protein, human; C000631435:Pdk2 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D017346:Protein Serine-Threonine Kinases; D045726:Metalloproteases; C485223:PARL protein, human
intramembrane proteolysis; metabolism; mitochondrial biogenesis; mitophagy; rhomboid protease