title: Granzyme B-induced mitochondrial ROS are required for apoptosis.
abstract: Caspases and the cytotoxic lymphocyte protease granzyme B (GB) induce reactive oxygen species (ROS) formation, loss of transmembrane potential and mitochondrial outer membrane permeabilization (MOMP). Whether ROS are required for GB-mediated apoptosis and how GB induces ROS is unclear. Here, we found that GB induces cell death in an ROS-dependent manner, independently of caspases and MOMP. GB triggers ROS increase in target cell by directly attacking the mitochondria to cleave NDUFV1, NDUFS1 and NDUFS2 subunits of the NADH: ubiquinone oxidoreductase complex I inside mitochondria. This leads to mitocentric ROS production, loss of complex I and III activity, disorganization of the respiratory chain, impaired mitochondrial respiration and loss of the mitochondrial cristae junctions. Furthermore, we have also found that GB-induced mitocentric ROS are necessary for optimal apoptogenic factor release, rapid DNA fragmentation and lysosomal rupture. Interestingly, scavenging the ROS delays and reduces many of the features of GB-induced death. Consequently, GB-induced ROS significantly promote apoptosis.
authors.affiliation: CMU, Cell Physiology and Metabolism, Faculté de Médecine, Université de Genève, Geneva, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Jacquemin
authors.affiliation: CMU, Cell Physiology and Metabolism, Faculté de Médecine, Université de Genève, Geneva, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Margiotta
authors.affiliation: CMU, Cell Physiology and Metabolism, Faculté de Médecine, Université de Genève, Geneva, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Kasahara
authors.affiliation: CMU, Cell Physiology and Metabolism, Faculté de Médecine, Université de Genève, Geneva, Switzerland.
authors.forename: E Y
authors.initials: EY
authors.lastname: Bassoy
authors.affiliation: Unité d'Anatomie, Departement de Médecine, Université de Fribourg, Fribourg, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Walch
authors.affiliation: INSERM U753, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: J
authors.initials: J
authors.lastname: Thiery
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lieberman
authors.affiliation: CMU, Cell Physiology and Metabolism, Faculté de Médecine, Université de Genève, Geneva, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Martinvalet
mesh_terms: D000818:Animals; D017209:Apoptosis; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D014450:Electron Transport Complex III / Q000235:genetics / Q000378:metabolism; D053804:Granzymes / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; C509213:GZMB protein, human; D053804:Granzymes; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III