Defective biosynthesis of ascorbic acid in Sod1-deficient mice results in lethal damage to lung tissue

Takujiro Homma, Yuji Takeda, Tomoyuki Nakano, Shinya Akatsuka, Daisuke Kinoshita, Toshihiro Kurahashi, Shinichi Saitoh, Ken ichi Yamada, Satoshi Miyata, Hironobu Asao, Kaoru Goto, Tetsu Watanabe, Masafumi Watanabe, Shinya Toyokuni, Junichi Fujii

Research output: Contribution to journalArticlepeer-review

Abstract

Superoxide dismutase 1 (Sod1) plays pivotal roles in antioxidation via accelerating the conversion of superoxide anion radicals into hydrogen peroxide, thus inhibiting the subsequent radical chain reactions. While Sod1 deficient cells inevitably undergo death in culture conditions, Sod1-knockout (KO) mice show relatively mild phenotypes and live approximately two years. We hypothesized that the presence of abundant levels of ascorbic acid (AsA), which is naturally produced in mice, contributes to the elimination of reactive oxygen species (ROS) in Sod1-KO mice. To verify this hypothesis, we employed mice with a genetic ablation of aldehyde reductase (Akr1a), an enzyme that is involved in the biosynthesis of AsA, and established double knockout (DKO) mice that lack both Sod1 and Akr1a. Supplementation of AsA (1.5 mg/ml in drinking water) was required for the DKO mice to breed, and, upon terminating the AsA supplementation, they died within approximately two weeks regardless of age or gender. We explored the etiology of the death from pathophysiological standpoints in principal organs of the mice. Marked changes were observed in the lungs in the form of macroscopic damage after the AsA withdrawal. Histological and immunological analyses of the lungs indicated oxidative damage of tissue and activated immune responses. Thus, preferential oxidative injury that occurred in pulmonary tissues appeared to be primary cause of the death in the mice. These collective results suggest that the pivotal function of AsA in coping with ROS in vivo, is largely in pulmonary tissues that are exposed to a hyperoxygenic microenvironment.

Original languageEnglish
JournalFree Radical Biology and Medicine
DOIs
Publication statusAccepted/In press - 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

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