Xanthine Oxidoreductase-Mediated Superoxide Production Is Not Involved in the Age-Related Pathologies in Sod1 -Deficient Mice

• Published in: International journal of molecular sciences Vol. 22; no. 7; p. 3542
• Main Authors: Shibuya, Shuichi, Watanabe, Kenji, Ozawa, Yusuke, Shimizu, Takahiko
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 29.03.2021; MDPI
• Subjects: Acetophenones - pharmacology; Adenine; Aging; Aging (artificial); Aging - drug effects; Aging - physiology; Allopurinol; Allopurinol - pharmacology; Alzheimer's disease; Anemia; Anemia - genetics; Animals; Antioxidants; Atrophy; Bioaccumulation; Bone loss; Degeneration; Fatty liver; Fatty Liver - genetics; Gene expression; Hypoxanthine; Liver; Metabolism; Mice; Mice, Mutant Strains; Mitochondria; Muscles; Muscular Atrophy - genetics; Mutants; Mutation; NAD(P)H oxidase; NADPH Oxidases - antagonists & inhibitors; NADPH Oxidases - metabolism; NADPH-diaphorase; Nicotinamide; Oxidative stress; Phenotypes; Physiology; Rodents; Skin; SOD1; superoxide; Superoxide dismutase; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism; Superoxides - metabolism; Uric acid; Xanthine dehydrogenase; Xanthine Dehydrogenase - antagonists & inhibitors; Xanthine Dehydrogenase - genetics; Xanthine Dehydrogenase - metabolism; Xanthine oxidase; Xanthine oxidoreductase; xanthine oxidoreductase; aging; superoxide; oxidative stress; SOD1
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22073542

Reactive oxygen species (ROS) metabolism is regulated by the oxygen-mediated enzyme reaction and antioxidant mechanism within cells under physiological conditions. Xanthine oxidoreductase (XOR) exhibits two inter-convertible forms (xanthine oxidase (XO) and xanthine dehydrogenase (XDH)), depending on the substrates. XO uses oxygen as a substrate and generates superoxide (O ) in the catalytic pathway of hypoxanthine. We previously showed that superoxide dismutase 1 (SOD1) loss induced various aging-like pathologies via oxidative damage due to the accumulation of O in mice. However, the pathological contribution of XO-derived O production to aging-like tissue damage induced by SOD1 loss remains unclear. To investigate the pathological significance of O derived from XOR in mice, we generated -null and XO-type- or XDH-type-knock-in (KI) double-mutant mice. Neither XO-type- nor XDH-type KI mutants altered aging-like phenotypes, such as anemia, fatty liver, muscle atrophy, and bone loss, in mice. Furthermore, allopurinol, an XO inhibitor, or apocynin, a nicotinamide adenine dinucleotide phosphate oxidase (NOX) inhibitor, failed to improve aging-like tissue degeneration and ROS accumulation in mice. These results showed that XOR-mediated O production is relatively uninvolved in the age-related pathologies in mice.