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

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

doi:10.1016/j.freeradbiomed.2020.10.023

Cited by 8 publications

(6 citation statements)

References 50 publications

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“…This is in sharp contrast to a dysfunction of xCT, a cystineglutamate antiporter encoded by SLC7A11; the inhibition of xCT results in the prompt decline in cellular Cys levels and rapidly leads to the development of robust ferroptosis [9]. While the anti-ferroptotic action of GSH is solely attributed to the donation of an electron to GPX4, free intracellular Cys appears to exert an additional function in terms of protection against ferroptosis, although the overall process is not clearly understood at this time [117]. Several proteins and other compounds, such as vitamin E and nitric oxide, have been found to exert antiferroptotic activity independently of GPX4, as discussed below.…”

Section: Gsh-gpx Systemmentioning

confidence: 99%

“…Aldehyde reductase (Akr1a) is involved in Asc synthesis through the catalytic conversion of D-glucuronic acid to L-gulonate in the Asc synthesis pathway, such that Akr1a-deficient mice produce approximately 10% Asc of wild-type mice [217]. The double knockout of Akr1a and SOD1, therefore, has pathological consequences due to increased superoxide, i.e., death within two weeks, irrespective of their sex or ages [117]. The lung is the most affected organ in the Akr1a-and SOD1-double knockout mice, which is consistent with the presence of the highest concentrations of oxygen in body.…”

Section: Vitamin C Is a Hydrophilic Antioxidant But Suppresses Lipid ...mentioning

confidence: 99%

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Superoxide Radicals in the Execution of Cell Death

2022

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Superoxide is a primary oxygen radical that is produced when an oxygen molecule receives one electron. Superoxide dismutase (SOD) plays a primary role in the cellular defense against an oxidative insult by ROS. However, the resulting hydrogen peroxide is still reactive and, in the presence of free ferrous iron, may produce hydroxyl radicals and exacerbate diseases. Polyunsaturated fatty acids are the preferred target of hydroxyl radicals. Ferroptosis, a type of necrotic cell death induced by lipid peroxides in the presence of free iron, has attracted considerable interest because of its role in the pathogenesis of many diseases. Radical electrons, namely those released from mitochondrial electron transfer complexes, and those produced by enzymatic reactions, such as lipoxygenases, appear to cause lipid peroxidation. While GPX4 is the most potent anti-ferroptotic enzyme that is known to reduce lipid peroxides to alcohols, other antioxidative enzymes are also indirectly involved in protection against ferroptosis. Moreover, several low molecular weight compounds that include α-tocopherol, ascorbate, and nitric oxide also efficiently neutralize radical electrons, thereby suppressing ferroptosis. The removal of radical electrons in the early stages is of primary importance in protecting against ferroptosis and other diseases that are related to oxidative stress.

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Section: Gsh-gpx Systemmentioning

confidence: 99%

Section: Vitamin C Is a Hydrophilic Antioxidant But Suppresses Lipid ...mentioning

confidence: 99%

Superoxide Radicals in the Execution of Cell Death

2022

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“…The authors suggest that a malfunction in plasma lipid metabolism and the accumulation of hepatic lipids due to elevated oxidative stress are the potential cause for this death. However, mice with a double deficiency of AKR1A, another gene responsible for Asc synthesis, and SOD1 die due to the development of acute pneumonia after Asc administration is stopped [ 175 ] as described below. Thus, this issue needs to be re-examined from a pathological standpoint.…”

Section: In Vivo Antioxidative Action Of Asc Revealed By Animal Studiesmentioning

confidence: 99%

Ascorbate Is a Primary Antioxidant in Mammals

Fujii

Osaki

2022

Molecules

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Ascorbate (vitamin C in primates) functions as a cofactor for a number of enzymatic reactions represented by prolyl hydroxylases and as an antioxidant due to its ability to donate electrons, which is mostly accomplished through non-enzymatic reaction in mammals. Ascorbate directly reacts with radical species and is converted to ascorbyl radical followed by dehydroascorbate. Ambiguities in physiological relevance of ascorbate observed during in vivo situations could be attributed in part to presence of other redox systems and the pro-oxidant properties of ascorbate. Most mammals are able to synthesize ascorbate from glucose, which is also considered to be an obstacle to verify its action. In addition to animals with natural deficiency in the ascorbate synthesis, such as guinea pigs and ODS rats, three strains of mice with genetic removal of the responsive genes (GULO, RGN, or AKR1A) for the ascorbate synthesis have been established and are being used to investigate the physiological roles of ascorbate. Studies using these mice, along with ascorbate transporter (SVCT)-deficient mice, largely support its ability in protection against oxidative insults. While combined actions of ascorbate in regulating epigenetics and antioxidation appear to effectively prevent cancer development, pharmacological doses of ascorbate and dehydroascorbate may exert tumoricidal activity through redox-dependent mechanisms.

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“…However, because of the abundance of Asc in tissues, this allows the reaction between superoxide and Asc to proceed sufficiently rapidly to suppress superoxide to permissible levels in vivo . ( 25 ) Because superoxide is the oxygen radical that is first produced under a variety of reactions with oxygen consumption, its elimination would be of importance for suppressing subsequent radical chain reactions and hence provide relief from oxidative stress.…”

Section: Anti-oxidative and Redox Reaction Of Ascmentioning

confidence: 99%

“…( 88 ) We recently found that a double deficiency of Akr1a and SOD1 causes inevitable death in the mice within several weeks after the Asc supplementation is ceased. ( 25 ) Among the organs examined, oxidative lung injury appears to be the primary cause for the death of the double KO mouse. These observations strongly support the requisite role of Asc in eliminating superoxide from the body, notably in the lung that is continuously exposed to hyperoxygenic conditions compared to other organs.…”

Section: Animal Models With Defected Asc Synthesismentioning

confidence: 99%

Ascorbate is a multifunctional micronutrient whose synthesis is lacking in primates

Fujii

2021

J. Clin. Biochem. Nutr.

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Ascorbate (vitamin C) is an essential micronutrient in primates, and exhibits multiple physiological functions. In addition to antioxidative action, ascorbate provides reducing power to α-ketoglutarate-dependent non-heme iron dioxygenases, such as prolyl hydroxylases. Demethylation of histones and DNA with the aid of ascorbate results in the reactivation of epigenetically silenced genes. Ascorbate and its oxidized form, dehydroascorbate, have attracted interest in terms of their roles in cancer therapy. The last step in the biosynthesis of ascorbate is catalyzed by L-gulono-γ-lactone oxidase whose gene Gulo is commonly mutated in all animals that do not synthesize ascorbate. One common explanation for this deficiency is based on the increased availability of ascorbate from foods. In fact, pathways for ascorbate synthesis and the detoxification of xenobiotics by glucuronate conjugation share the metabolic processes up to UDP-glucuronate, which prompts another hypothesis, namely, that ascorbate-incompetent animals might have developed stronger detoxification systems in return for their lack of ability to produce ascorbate, which would allow them to cope with their situation. Here, we overview recent advances in ascorbate research and propose that an enhanced glucuronate conjugation reaction may have applied positive selection pressure on ascorbate-incompetent animals, thus allowing them to dominate the animal kingdom.

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

Cited by 8 publications

References 50 publications

Superoxide Radicals in the Execution of Cell Death

Superoxide Radicals in the Execution of Cell Death

Ascorbate Is a Primary Antioxidant in Mammals

Ascorbate is a multifunctional micronutrient whose synthesis is lacking in primates

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