title: PK11195 inhibits mitophagy targeting the F1Fo-ATPsynthase in Bcl-2 knock-down cells.
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.
authors.affiliation: Royal Veterinary College, University of London, NW1 0TU, London, United Kingdom.
authors.forename: M S D
authors.initials: MS
authors.lastname: Seneviratne
authors.forename: D
authors.initials: D
authors.lastname: Faccenda
authors.forename: V
authors.initials: V
authors.lastname: De Biase
authors.forename: M
authors.initials: M
authors.lastname: Campanella
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D007700:Kinetics; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009840:Oligomycins / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D061209:Proton Ionophores / Q000494:pharmacology; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D007546:Isoquinolines; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D009840:Oligomycins; D019253:Proto-Oncogene Proteins c-bcl-2; D061209:Proton Ionophores; D014475:Uncoupling Agents; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D000255:Adenosine Triphosphate; D006180:Proton-Translocating ATPases; C037850:PK 11195