Widespread mitochondrial depletion via mitophagy does not compromise necroptosis.

Stephen w.G. Tait (1) , Andrew Oberst (2) , Giovanni Quarato (3) , Sandra Milasta (3) , Martina Haller (1) , Ruoning Wang (4) , Maria Karvela (1) , Gabriel Ichim (1) , Nader Yatim (3, 5) , Matthew L Albert (5) , Grahame Kidd (6) , Randall Wakefield (7) , Sharon Frase (7) , Stefan Krautwald (8) , Andreas Linkermann (8) , Douglas R Green (3)

1 CR-UK Beatson Institute, Institute of Cancer Sciences
2 University of Washington [Seattle]
3 Department of immunology
4 Center for Childhood Cancer and Blood Disease
5 Immunobiologie des Cellules Dendritiques
6 Lerner Research Institute [Cleveland, OH, USA]
7 Cell and Tissue Imaging Center,
8 Division of Nephrology and Hypertension

Programmed necrosis (or necroptosis) is a form of cell death triggered by the activation of receptor interacting protein kinase-3 (RIPK3). Several reports have implicated mitochondria and mitochondrial reactive oxygen species (ROS) generation as effectors of RIPK3-dependent cell death. Here, we directly test this idea by employing a method for the specific removal of mitochondria via mitophagy. Mitochondria-deficient cells were resistant to the mitochondrial pathway of apoptosis, but efficiently died via tumor necrosis factor (TNF)-induced, RIPK3-dependent programmed necrosis or as a result of direct oligomerization of RIPK3. Although the ROS scavenger butylated hydroxyanisole (BHA) delayed TNF-induced necroptosis, it had no effect on necroptosis induced by RIPK3 oligomerization. Furthermore, although TNF-induced ROS production was dependent on mitochondria, the inhibition of TNF-induced necroptosis by BHA was observed in mitochondria-depleted cells. Our data indicate that mitochondrial ROS production accompanies, but does not cause, RIPK3-dependent necroptotic cell death.

Domains: Life Sciences [q-bio]; Immunology; Life Sciences [q-bio]; Cellular Biology

Stephen w.G. Tait, Andrew Oberst, Giovanni Quarato, Sandra Milasta, Martina Haller, et al.. Widespread mitochondrial depletion via mitophagy does not compromise necroptosis.. Cell Reports, 2013, 5 (4), pp.438-41. ⟨10.1016/j.celrep.2013.10.034⟩. ⟨pasteur-01384556⟩