title: The mitochondrial protein NLRX1 controls the balance between extrinsic and intrinsic apoptosis.
abstract: NLRX1 is a mitochondrial Nod-like receptor (NLR) protein whose function remains enigmatic. Here, we observed that NLRX1 expression was glucose-regulated and blunted by SV40 transformation. In transformed but not primary murine embryonic fibroblasts, NLRX1 expression mediated resistance to an extrinsic apoptotic signal, whereas conferring susceptibility to intrinsic apoptotic signals, such as glycolysis inhibition, increased cytosolic calcium and endoplasmic reticulum stress. In a murine model of colorectal cancer induced by azoxymethane, NLRX1-/- mice developed fewer tumors than wild type mice. In contrast, in a colitis-associated cancer model combining azoxymethane and dextran sulfate sodium, NLRX1-/- mice developed a more severe pathology likely due to the increased sensitivity to dextran sulfate sodium colitis. Together, these results identify NLRX1 as a critical mitochondrial protein implicated in the regulation of apoptosis in cancer cells. The unique capacity of NLRX1 to regulate the cellular sensitivity toward intrinsic versus extrinsic apoptotic signals suggests a critical role for this protein in numerous physiological processes and pathological conditions.
authors.affiliation: From the Departments of Laboratory Medicine and Pathobiology and.
authors.forename: Fraser
authors.initials: F
authors.lastname: Soares
authors.affiliation: From the Departments of Laboratory Medicine and Pathobiology and Immunology.
authors.forename: Ivan
authors.initials: I
authors.lastname: Tattoli
authors.affiliation: From the Departments of Laboratory Medicine and Pathobiology and Immunology.
authors.forename: Muhammed A
authors.initials: MA
authors.lastname: Rahman
authors.affiliation: Immunology.
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Robertson
authors.affiliation: Immunology.
authors.forename: Antoaneta
authors.initials: A
authors.lastname: Belcheva
authors.affiliation: From the Departments of Laboratory Medicine and Pathobiology and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Liu
authors.affiliation: From the Departments of Laboratory Medicine and Pathobiology and Saint Michael's Hospital, and.
authors.forename: Catherine
authors.initials: C
authors.lastname: Streutker
authors.affiliation: Department of Pathology, Toronto General Hospital, University of Toronto, Toronto M6G 2T6, Canada and.
authors.forename: Shawn
authors.initials: S
authors.lastname: Winer
authors.affiliation: Department of Pathology, Toronto General Hospital, University of Toronto, Toronto M6G 2T6, Canada and.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Winer
authors.affiliation: Immunology.
authors.forename: Alberto
authors.initials: A
authors.lastname: Martin
authors.affiliation: Immunology.
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
authors.affiliation: INSERM U1014, Hôpital Paul Brousse, Bâtiment Lavoisier, 14 avenue Paul Vaillant Couturier, 94807 Villejuif Cedex, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Arnoult
authors.affiliation: From the Departments of Laboratory Medicine and Pathobiology and stephen.girardin@utoronto.ca.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Girardin
mesh_terms: D000818:Animals; D017209:Apoptosis; D002461:Cell Line, Transformed; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; C555655:NLRX1 protein, mouse; D009363:Neoplasm Proteins; D016264:Dextran Sulfate
keywords: Apoptosis; Carcinogenesis; Cell Death; Colon Cancer; Innate Immunity; Mitochondria; NLRs; Nod-like Receptor (NLR); Transformation