title: Human OXR1 maintains mitochondrial DNA integrity and counteracts hydrogen peroxide-induced oxidative stress by regulating antioxidant pathways involving p21.
abstract: The oxidation resistance gene 1 (OXR1) prevents oxidative stress-induced cell death by an unknown pathway. Here, depletion of human OXR1 (hOXR1) sensitized several human cell lines to hydrogen peroxide-induced oxidative stress, reduced mtDNA integrity, and increased apoptosis. In contrast, depletion of hOXR1 in cells lacking mtDNA showed no significant change in ROS or viability, suggesting that OXR1 prevents intracellular hydrogen peroxide-induced increase in oxidative stress levels to avoid a vicious cycle of increased oxidative mtDNA damage and ROS formation. Furthermore, expression of p21 and the antioxidant genes GPX2 and HO-1 was reduced in hOXR1-depleted cells. In sum, these data reveal that human OXR1 upregulates the expression of antioxidant genes via the p21 signaling pathway to suppress hydrogen peroxide-induced oxidative stress and maintain mtDNA integrity.
authors.affiliation: Department of Microbiology, University of Oslo, N-0424 Oslo, Norway; Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, N-0424 Oslo, Norway.
authors.forename: Mingyi
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Microbiology, University of Oslo, N-0424 Oslo, Norway.
authors.forename: Luisa
authors.initials: L
authors.lastname: Luna
authors.affiliation: Department of Microbiology, University of Oslo, N-0424 Oslo, Norway; Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, N-0424 Oslo, Norway.
authors.forename: Jan Gunnar
authors.initials: JG
authors.lastname: Sørbø
authors.affiliation: Department of Microbiology, University of Oslo, N-0424 Oslo, Norway.
authors.forename: Ingrun
authors.initials: I
authors.lastname: Alseth
authors.affiliation: Department of Microbiology, University of Oslo, N-0424 Oslo, Norway.
authors.forename: Rune F
authors.initials: RF
authors.lastname: Johansen
authors.affiliation: Department of Microbiology, University of Oslo, N-0424 Oslo, Norway; Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, N-0424 Oslo, Norway.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Backe
authors.affiliation: Department of Anatomy, University of Oslo, N-0424 Oslo, Norway.
authors.forename: Niels C
authors.initials: NC
authors.lastname: Danbolt
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, N-0424 Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Eide
authors.affiliation: Department of Microbiology, University of Oslo, N-0424 Oslo, Norway; Department of Medical Biochemistry, Oslo University Hospital, University of Oslo, N-0424 Oslo, Norway. Electronic address: magnar.bjoras@rr-research.no.
authors.forename: Magnar
authors.initials: M
authors.lastname: Bjørås
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000235:genetics*; D018628:Gene Dosage; D015870:Gene Expression; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D024101:Mitochondrial Proteins; D018384:Oxidative Stress; D011506:Proteins / Q000502:physiology*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; C419777:OXR1 protein, human; D011506:Proteins; D006861:Hydrogen Peroxide
keywords: DNA damage; Free radicals; GPX2; HO-1; Mitochondria; OXR1; Oxidative stress; ROS; p21