title: Impaired oxidative phosphorylation regulates necroptosis in human lung epithelial cells.
abstract: Cellular metabolism can impact cell life or death outcomes. While metabolic dysfunction has been linked to cell death, the mechanisms by which metabolic dysfunction regulates the cell death mode called necroptosis remain unclear. Our study demonstrates that mitochondrial oxidative phosphorylation (OXPHOS) activates programmed necrotic cell death (necroptosis) in human lung epithelial cells. Inhibition of mitochondrial respiration and ATP synthesis induced the phosphorylation of mixed lineage kinase domain-like protein (MLKL) and necroptotic cell death. Furthermore, we demonstrate that the activation of AMP-activated protein kinase (AMPK), resulting from impaired mitochondrial OXPHOS, regulates necroptotic cell death. These results suggest that impaired mitochondrial OXPHOS contributes to necroptosis in human lung epithelial cells.
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, NY 10065, USA; Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Michael Jakun
authors.initials: MJ
authors.lastname: Koo
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, NY 10065, USA; Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Kristen T
authors.initials: KT
authors.lastname: Rooney
authors.affiliation: Division of Nephrology & Hypertension, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Choi
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, NY 10065, USA; Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, NY 10065, USA; Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
authors.affiliation: Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, NY 10065, USA; Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: jom2076@med.cornell.edu.
authors.forename: Jong-Seok
authors.initials: JS
authors.lastname: Moon
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000178:Acrylamides / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D019069:Cell Respiration / Q000187:drug effects; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D009336:Necrosis / Q000378:metabolism; D009840:Oligomycins / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D000178:Acrylamides; C570695:N-(4-(N-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acrylamide; D009840:Oligomycins; D009842:Oligopeptides; D013449:Sulfonamides; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; C031004:oligomycin A; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Mitochondria; Necroptosis; Oxidative phosphorylation