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Granzyme B-induced mitochondrial ROS are required for apoptosis

  • Jacquemin, G. CMU, Cell Physiology and Metabolism, Faculté de Médecine, Université de Genève, Switzerland
  • Margiotta, D. CMU, Cell Physiology and Metabolism, Faculté de Médecine, Université de Genève, Switzerland
  • Kasahara, A. CMU, Cell Physiology and Metabolism, Faculté de Médecine, Université de Genève, Switzerland
  • Bassoy, E. Y. CMU, Cell Physiology and Metabolism, Faculté de Médecine, Université de Genève, Switzerland
  • Walch, Michael Unité d’Anatomie, Departement de Médecine, Université de Fribourg, Switzerland
  • Thiery, J. INSERM U753, Gustave Roussy Cancer Campus, Villejuif, France
  • Lieberman, J. Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
  • Martinvalet, Denis CMU, Cell Physiology and Metabolism, Faculté de Médecine, Université de Genève, Switzerland
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    01.04.2015
Published in:
  • Cell Death & Differentiation. - 2015, vol. 22, no. 5, p. 862–874
English 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.
Faculty
Faculté des sciences et de médecine
Department
Département de Médecine
Language
  • English
Classification
Biological sciences
License
License undefined
Identifiers
Persistent URL
https://folia.unifr.ch/unifr/documents/304251
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