title: Widespread mitochondrial depletion via mitophagy does not compromise necroptosis.
abstract: 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.
authors.affiliation: CR-UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1BD, UK. Electronic address: stephen.tait@glasgow.ac.uk.
authors.forename: Stephen W G
authors.initials: SW
authors.lastname: Tait
authors.affiliation: Department of Immunology, University of Washington, 750 Republican Street, Seattle, WA 98109, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Oberst
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Quarato
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Milasta
authors.affiliation: CR-UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Martina
authors.initials: M
authors.lastname: Haller
authors.affiliation: 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.
authors.forename: Ruoning
authors.initials: R
authors.lastname: Wang
authors.affiliation: CR-UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Karvela
authors.affiliation: CR-UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Ichim
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA; Unité d'Immunobiologie des Cellules Dendritiques, Department of Immunology, Institut Pasteur, 25 Rue du Docteur Roux, 75724 Paris, France; INSERM U818, Department of Immunology, Institut Pasteur, 25 Rue du Docteur Roux, 75724 Paris, France.
authors.forename: Nader
authors.initials: N
authors.lastname: Yatim
authors.affiliation: Unité d'Immunobiologie des Cellules Dendritiques, Department of Immunology, Institut Pasteur, 25 Rue du Docteur Roux, 75724 Paris, France; INSERM U818, Department of Immunology, Institut Pasteur, 25 Rue du Docteur Roux, 75724 Paris, France.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Albert
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Grahame
authors.initials: G
authors.lastname: Kidd
authors.affiliation: Cell and Tissue Imaging Center, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Randall
authors.initials: R
authors.lastname: Wakefield
authors.affiliation: Cell and Tissue Imaging Center, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Frase
authors.affiliation: Division of Nephrology and Hypertension, Christian Albrechts University, Kiel 24105, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Krautwald
authors.affiliation: Division of Nephrology and Hypertension, Christian Albrechts University, Kiel 24105, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Linkermann
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA. Electronic address: douglas.green@stjude.org.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002083:Butylated Hydroxyanisole / Q000494:pharmacology; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D063306:Mitophagy / Q000187:drug effects; D009336:Necrosis / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D002083:Butylated Hydroxyanisole; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; C505526:Casp8 protein, mouse; D053181:Caspase 8