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SOD1 PNAS 2023.pdf (1.56 MB)

SOD1 is an essential H2S detoxifying enzyme

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journal contribution
posted on 2023-12-08, 16:10 authored by Christopher H Switzer, Shingo Kasamatsu, Hideshi Ihara, Philip Eaton

Although hydrogen sulfide (H 2 S) is an endogenous signaling molecule with antioxidant properties, it is also cytotoxic by potently inhibiting cytochrome c oxidase and mitochondrial respiration. Paradoxically, the primary route of H 2 S detoxification is thought to occur inside the mitochondrial matrix via a series of relatively slow enzymatic reactions that are unlikely to compete with its rapid inhibition of cytochrome c oxidase. Therefore, alternative or complementary cellular mechanisms of H 2 S detoxification are predicted to exist. Here, superoxide dismutase [Cu-Zn] (SOD1) is shown to be an efficient H 2 S oxidase that has an essential role in limiting cytotoxicity from endogenous and exogenous sulfide. Decreased SOD1 expression resulted in increased sensitivity to H 2 S toxicity in yeast and human cells, while increased SOD1 expression enhanced tolerance to H 2 S. SOD1 rapidly converted H 2 S to sulfate under conditions of limiting sulfide; however, when sulfide was in molar excess, SOD1 catalyzed the formation of per- and polysulfides, which induce cellular thiol oxidation. Furthermore, in SOD1-deficient cells, elevated levels of reactive oxygen species catalyzed sulfide oxidation to per- and polysulfides. These data reveal that a fundamental function of SOD1 is to regulate H 2 S and related reactive sulfur species.

Funding

British Heart Foundation project grant PG/19/33/34385

The Barts Charity Cardiovascular Programme Award G00913 and by program grants from the British Heart Foundation and the Medical Research Council

This work was supported, in part, by a Grant-in-Aid for Scientific Research (C), Challenging Exploratory Research, and Transformative Research Areas “Life Science Innovation Driven by Supersulfide Biology”(AIII) from the Ministry of Education, Sciences, Sports, Technology (MEXT), Japan, to S.K. (22K06148) and to H.I. (21H05263)

History

Author affiliation

Department of Molecular and Cell Biology, University of Leicester

Version

  • VoR (Version of Record)

Published in

Proceedings of the National Academy of Sciences

Volume

120

Issue

3

Publisher

Proceedings of the National Academy of Sciences

issn

0027-8424

eissn

1091-6490

Copyright date

2023

Available date

2023-12-08

Language

en

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