Jacquemin, G. Margiotta, D. Kasahara, A. Bassoy, E. Y. Walch, Michael Thiery, J. Lieberman, J. Martinvalet, Denis 2015-04-01 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. application/pdf https://folia.unifr.ch/global/documents/304251 https://folia.unifr.ch/documents/304251/files/wal_gbi.pdf https://folia.unifr.ch/documents/304251/files/wal_gbi_sm.pdf eng info:eu-repo/semantics/altIdentifier/doi/10.1038/cdd.2014.180 info:eu-repo/semantics/openAccess License undefined Cell Death & Differentiation. - 2015, vol. 22, no. 5, p. 862–874 info:eu-repo/classification/udc/57 Granzyme B-induced mitochondrial ROS are required for apoptosis http://purl.org/coar/resource_type/c_6501