PMI: A ΔΨm independent pharmacological regulator of mitophagy

Daniel A. East, Francesca Fagiani, James Crosby, Nikolaos D. Georgakopoulos, Hélène Bertrand, Marjolein Schaap, Adrian Fowkes, Geoff Wells, Michelangelo Campanella

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1585-1596
Number of pages12
JournalChemistry and Biology
Volume21
Issue number11
DOIs
Publication statusPublished - Nov 20 2014

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Molecular Biology
  • Clinical Biochemistry
  • Molecular Medicine
  • Pharmacology

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