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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, Geneva, Switzerland.
  • Margiotta D CMU, Cell Physiology and Metabolism, Faculté de Médecine, Université de Genève, Geneva, Switzerland.
  • Kasahara A CMU, Cell Physiology and Metabolism, Faculté de Médecine, Université de Genève, Geneva, Switzerland.
  • Bassoy EY CMU, Cell Physiology and Metabolism, Faculté de Médecine, Université de Genève, Geneva, Switzerland.
  • Walch M Unité d'Anatomie, Departement de Médecine, Université de Fribourg, 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 D CMU, Cell Physiology and Metabolism, Faculté de Médecine, Université de Genève, Geneva, Switzerland.
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  • 2014-11-01
Published in:
  • Cell death and differentiation. - 2015
Animals
Apoptosis
Electron Transport Complex I
Electron Transport Complex III
Granzymes
Humans
K562 Cells
Mitochondria
Mitochondrial Membranes
Rats
Reactive Oxygen Species
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.
Language
  • English
Open access status
bronze
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Persistent URL
https://folia.unifr.ch/global/documents/21243
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