Widespread Mitochondrial Depletion via Mitophagy Does Not Compromise Necroptosis
Stephen W.G. Tait,
Andrew Oberst,
Giovanni Quarato,
Sandra Milasta,
Martina Haller,
Ruoning Wang,
Maria Karvela,
Gabriel Ichim,
Nader Yatim,
Matthew L. Albert,
Grahame Kidd,
Randall Wakefield,
Sharon Frase,
Stefan Krautwald,
Andreas Linkermann,
Douglas R. Green
Affiliations
Stephen W.G. Tait
CR-UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1BD, UK
Andrew Oberst
Department of Immunology, University of Washington, 750 Republican Street, Seattle, WA 98109, USA
Giovanni Quarato
Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Sandra Milasta
Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Martina Haller
CR-UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1BD, UK
Ruoning Wang
Center for Childhood Cancer and Blood Disease, The Research Institute at Nationwide Children’s Hospital, Department of Pediatrics, The Ohio State University School of Medicine, 700 Children’s Drive, Columbus, OH 43205, USA
Maria Karvela
CR-UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1BD, UK
Gabriel Ichim
CR-UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1BD, UK
Nader Yatim
Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Matthew L. Albert
Unité d’Immunobiologie des Cellules Dendritiques, Department of Immunology, Institut Pasteur, 25 Rue du Docteur Roux, 75724 Paris, France
Grahame Kidd
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
Randall Wakefield
Cell and Tissue Imaging Center, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Sharon Frase
Cell and Tissue Imaging Center, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
Stefan Krautwald
Division of Nephrology and Hypertension, Christian Albrechts University, Kiel 24105, Germany
Andreas Linkermann
Division of Nephrology and Hypertension, Christian Albrechts University, Kiel 24105, Germany
Douglas R. Green
Department of Immunology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA
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.
