title: Lysosomal membrane permeabilization induces cell death in a mitochondrion-dependent fashion.
abstract: A number of diseases are due to lysosomal destabilization, which results in damaging cell loss. To investigate the mechanisms of lysosomal cell death, we characterized the cytotoxic action of two widely used quinolone antibiotics: ciprofloxacin (CPX) or norfloxacin (NFX). CPX or NFX plus UV light (NFX*) induce lysosomal membrane permeabilization (LMP), as detected by the release of cathepsins from lysosomes. Inhibition of the lysosomal accumulation of CPX or NFX suppresses their capacity to induce LMP and to kill cells. CPX- or NFX-triggered LMP results in caspase-independent cell death, with hallmarks of apoptosis such as chromatin condensation and phosphatidylserine exposure on the plasma membrane. LMP triggers mitochondrial membrane permeabilization (MMP), as detected by the release of cytochrome c. Both CPX and NFX* cause Bax and Bak to adopt their apoptotic conformation and to insert into mitochondrial membranes. Bax-/- Bak-/- double knockout cells fail to undergo MMP and cell death in response to CPX- or NFX-induced LMP. The single knockout of Bax or Bak (but not Bid) or the transfection-enforced expression of mitochondrion-targeted (but not endoplasmic reticulum-targeted) Bcl-2 conferred protection against CPX (but not NFX*)-induced MMP and death. Altogether, our data indicate that mitochondria are indispensable for cell death initiated by lysosomal destabilization.
authors.affiliation: Centre National de la Recherche Scientifique, UMR 8125, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, F-94805 Villejuif, France.
authors.forename: Patricia
authors.initials: P
authors.lastname: Boya
authors.forename: Karine
authors.initials: K
authors.lastname: Andreau
authors.forename: Delphine
authors.initials: D
authors.lastname: Poncet
authors.forename: Naoufal
authors.initials: N
authors.lastname: Zamzami
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Perfettini
authors.forename: Didier
authors.initials: D
authors.lastname: Metivier
authors.forename: David M
authors.initials: DM
authors.lastname: Ojcius
authors.forename: Marja
authors.initials: M
authors.lastname: Jäättelä
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis; D002463:Cell Membrane Permeability / Q000187:drug effects; D002939:Ciprofloxacin / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008565:Membrane Proteins / Q000502:physiology; D008666:Metalloendopeptidases / Q000502:physiology; D008928:Mitochondria / Q000502:physiology*; D009643:Norfloxacin / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D017382:Reactive Oxygen Species; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
chemical_list: D000590:Amino Acid Chloromethyl Ketones; C494772:BAK1 protein, human; C494826:BAX protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D002939:Ciprofloxacin; D008666:Metalloendopeptidases; D009643:Norfloxacin