title: PMI: a ΔΨm independent pharmacological regulator of mitophagy.
abstract: Mitophagy is central to mitochondrial and cellular homeostasis and operates via the PINK1/Parkin pathway targeting mitochondria devoid of membrane potential (ΔΨm) to autophagosomes. Although mitophagy is recognized as a fundamental cellular process, selective pharmacologic modulators of mitophagy are almost nonexistent. We developed a compound that increases the expression and signaling of the autophagic adaptor molecule P62/SQSTM1 and forces mitochondria into autophagy. The compound, P62-mediated mitophagy inducer (PMI), activates mitophagy without recruiting Parkin or collapsing ΔΨm and retains activity in cells devoid of a fully functional PINK1/Parkin pathway. PMI drives mitochondria to a process of quality control without compromising the bio-energetic competence of the whole network while exposing just those organelles to be recycled. Thus, PMI circumvents the toxicity and some of the nonspecific effects associated with the abrupt dissipation of ΔΨm by ionophores routinely used to induce mitophagy and represents a prototype pharmacological tool to investigate the molecular mechanisms of mitophagy.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: East
authors.forename: Francesca
authors.initials: F
authors.lastname: Fagiani
authors.forename: James
authors.initials: J
authors.lastname: Crosby
authors.forename: Nikolaos D
authors.initials: ND
authors.lastname: Georgakopoulos
authors.forename: Hélène
authors.initials: H
authors.lastname: Bertrand
authors.forename: Marjolein
authors.initials: M
authors.lastname: Schaap
authors.forename: Adrian
authors.initials: A
authors.lastname: Fowkes
authors.forename: Geoff
authors.initials: G
authors.lastname: Wells
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Campanella
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D061745:Antioxidant Response Elements; D002460:Cell Line; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D063306:Mitophagy / Q000187:drug effects*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D000099202:PTEN-Induced Putative Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D008869:Microtubule-Associated Proteins; D051267:NF-E2-Related Factor 2; D011494:Protein Kinases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; D014230:Triazoles; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C000599894:1-(3-iodophenyl)-4-(3-nitrophenyl)-1,2,3-triazole; C495636:Nfe2l2 protein, mouse; C101343:Sqstm1 protein, mouse; C111567:parkin protein