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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antioxidant Response Elements
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Cell Line
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Heat-Shock Proteins / genetics
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Heat-Shock Proteins / metabolism
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Membrane Potential, Mitochondrial / drug effects
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Mice
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Microtubule-Associated Proteins / metabolism
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Mitochondria / metabolism*
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Mitophagy / drug effects*
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NF-E2-Related Factor 2 / metabolism
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Protein Kinases / deficiency
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Protein Kinases / genetics
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Protein Kinases / metabolism
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RNA Interference
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RNA, Messenger / metabolism
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RNA, Small Interfering / metabolism
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Sequestosome-1 Protein
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Signal Transduction / drug effects
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Triazoles / chemistry
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Triazoles / pharmacology*
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Ubiquitin-Protein Ligases / antagonists & inhibitors
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
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Ubiquitination / drug effects
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Up-Regulation / drug effects
Substances
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1-(3-iodophenyl)-4-(3-nitrophenyl)-1,2,3-triazole
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Adaptor Proteins, Signal Transducing
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Heat-Shock Proteins
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Microtubule-Associated Proteins
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NF-E2-Related Factor 2
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Nfe2l2 protein, mouse
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RNA, Messenger
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RNA, Small Interfering
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Sequestosome-1 Protein
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Sqstm1 protein, mouse
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Triazoles
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Ubiquitin-Protein Ligases
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parkin protein
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Protein Kinases
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PTEN-induced putative kinase