Human OXR1 maintains mitochondrial DNA integrity and counteracts hydrogen peroxide-induced oxidative stress by regulating antioxidant pathways involving p21

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...

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Published in:Free radical biology & medicine 2014-12, Vol.77, p.41-48
Main Authors: Yang, Mingyi, Luna, Luisa, Sørbø, Jan Gunnar, Alseth, Ingrun, Johansen, Rune F., Backe, Paul H., Danbolt, Niels C., Eide, Lars, Bjørås, Magnar
Format: Article
Language:English
Subjects:
Antioxidants - metabolism
Apoptosis
Cyclin-Dependent Kinase Inhibitor p21 - metabolism
DNA damage
DNA, Mitochondrial - genetics
Free radicals
Gene Dosage
Gene Expression
GPX2
HEK293 Cells
HeLa Cells
HO-1
Humans
Hydrogen Peroxide - metabolism
Mitochondria
Oxidative Stress
OXR1
p21
Proteins - physiology
ROS
Signal Transduction
Up-Regulation
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Summary: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. [Display omitted] •Depletion of human (h) OXR1 sensitizes human cells to hydrogen peroxide.•Depletion of hOXR1 increases ROS and mtDNA damage upon oxidative stress.•OXR1 counteracts a vicious cycle of increased mtDNA damage and ROS formation.•hOXR1 upregulates p21 expression.•hOXR1 upregulates antioxidant enzymes GPX2 and HO-1 partly via p21 signaling.
ISSN:0891-5849
1873-4596
DOI:10.1016/j.freeradbiomed.2014.09.003