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Sulfide catabolism ameliorates hypoxic brain injury.

ABSTRACT: The mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain's sensitivity to hypoxia is incompletely understood. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide. Silencing SQOR increased the sensitivity of the brain to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological scavenging of sulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to hypoxia. These results illuminate the critical role of sulfide catabolism in energy homeostasis during hypoxia and identify a therapeutic target for ischemic brain injury.

SUBMITTER: Marutani E

PROVIDER: S-EPMC8149856 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Sulfide catabolism ameliorates hypoxic brain injury.

Marutani Eizo E Morita Masanobu M Hirai Shuichi S Kai Shinichi S Grange Robert M H RMH Miyazaki Yusuke Y Nagashima Fumiaki F Traeger Lisa L Magliocca Aurora A Ida Tomoaki T Matsunaga Tetsuro T Flicker Daniel R DR Corman Benjamin B Mori Naohiro N Yamazaki Yumiko Y Batten Annabelle A Li Rebecca R Tanaka Tomohiro T Ikeda Takamitsu T Nakagawa Akito A Atochin Dmitriy N DN Ihara Hideshi H Olenchock Benjamin A BA Shen Xinggui X Nishida Motohiro M Hanaoka Kenjiro K Kevil Christopher G CG Xian Ming M Bloch Donald B DB Akaike Takaaki T Hindle Allyson G AG Motohashi Hozumi H Ichinose Fumito F

Nature communications 20210525 1

The mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain's sensitivity to hypoxia is incompletely understood. Hypoxia induces accumulation of hydrogen sulfide, a gas that inhibits mitochondrial respiration. Here, we show that, in mice, rats, and naturally hypoxia-tolerant ground squirrels, the sensitivity of the brain to hypoxia is inversely related to the levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize sulfide. Silenci ...[more]

PMID: 34035265

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Sulfide catabolism ameliorates hypoxic brain injury.

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Sulfide catabolism ameliorates hypoxic brain injury.

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