PMI: A Delta Psi(m) Independent Pharmacological Regulator of Mitophagy

East, D A; Fagiani, F; Crosby, J; Georgakopoulos, N D; Bertrand, H; Schaap, M; Fowkes, A; Wells, G; Campanella, M

Abstract

Mitophagy is central to mitochondrial and cellular homeostasis and operates via the PINK1/Parkin pathway targeting mitochondria devoid of membrane potential (??m) 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 ??m 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 ??m by ionophores routinely used to induce mitophagy and represents a prototype pharmacological tool to investigate the molecular mechanisms of mitophagy.

Citation

East, D. A., Fagiani, F., Crosby, J., Georgakopoulos, N. D., Bertrand, H., Schaap, M., …Campanella, M. (2014). PMI: A Delta Psi(m) Independent Pharmacological Regulator of Mitophagy. https://doi.org/10.1016/j.chembiol.2014.09.019

• Journal Article Type: Article
• Acceptance Date: Sep 10, 2014
• Publication Date: Nov 20, 2014
• Deposit Date: Jan 16, 2015
• Publicly Available Date: Nov 21, 2020
• Journal: Chemistry & Biology
• Peer Reviewed: Peer Reviewed
• Volume: 21
• Issue: 11
• Pages: 1585-1596
• DOI: https://doi.org/10.1016/j.chembiol.2014.09.019
• Public URL: https://rvc-repository.worktribe.com/output/1404667