PK11195 inhibits mitophagy targeting the F1F0-ATPsynthase in Bcl-2 knock-down cells

M. S D Seneviratne, D. Faccenda, V. de Biase, M. Campanella

Research output: Contribution to journalArticlepeer-review

Abstract

The pharmacological agent 1-(2-Chlorophenyl-N-methylpropyl)-3-isoquinolinecarboxamide (PK11195) is the prototypical ligand of the 18-kDa Translocator Protein (TSPO) but at μM concentrations deactivates the oncoprotein Bcl-2 increasing the efficiency of chemotherapeutic agents and promoting the Ca2+-dependent macro-autophagy (or autophagy). In this paper, we report that PK11195, in HeLa cells, modifies the mitochondria-targeted type of autophagy -hereafter referred to as mitophagy-and the associated resizing of the mitochondrial network but does so exclusively in absence of the oncoprotein Bcl-2 (Bcl-2 Kd cells). This is consequence of a "side" targeting of the mitochondrial F1F0-ATPsynthase enzyme, since identical outcome is mimicked by the antibiotic Oligomycin, of which PK11195 matches the effect on: i) mitochondrial membrane potential (ΔΨm), ii) ATP homeostasis and iii) Reactive Oxygen Species (ROS) generation. Taken together, these data highlight a novel TSPO-independent biological effect for PK11195 and provide evidences for a hitherto uncovered Bcl-2-dependent role of the F1F0-ATPsynthase in mitochondrial quality control.

Original languageEnglish
Pages (from-to)476-482
Number of pages7
JournalCurrent Molecular Medicine
Volume12
Issue number4
Publication statusPublished - May 2012

Keywords

  • Bcl-2
  • FF-ATPsynthase
  • Mitophagy
  • PK11195

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Molecular Medicine

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