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Curr Mol Med. 2012 May;12(4):476-82.

PK11195 inhibits mitophagy targeting the F1Fo-ATPsynthase in Bcl-2 knock-down cells.

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1
Royal Veterinary College, University of London, NW1 0TU, London, United Kingdom.

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 F1Fo-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 F1Fo-ATPsynthase in mitochondrial quality control.

PMID:
22348615
[Indexed for MEDLINE]
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