Sulfide catabolism ameliorates hypoxic brain injury

Eizo Marutani,Donald B Bloch,Robert M H Grange,Daniel Flicker ,Hozumi Motohashi,Tomohiro Tanaka,Shuichi Hirai,Annabelle Batten,Dmitriy N Atochin,Lisa Traeger,Benjamin Harris Peterson Corman ,Takaaki Akaike,Toshihide Ikeda ,Akito Nakagawa,Yusuke Miyazaki,Tomoaki Ida,Masanobu Morita,Tetsuro Matsunaga,Yumiko Yamazaki,Christopher G Kevil,Shinichi Kai,Fumiaki Nagashima,Ming Xian,Rebecca Li,Allyson G Hindle,Benjamin A Olenchock,Xinggui Shen,Kenjiro Hanaoka,Motohiro Nishida,Aurora Magliocca,Naohiro Mori,Hideshi Ihara,Fumito Ichinose

doi:10.1038/s41467-021-23363-x

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.

Highlights

The mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain’s sensitivity to hypoxia is incompletely understood
To investigate the role of sulfide:quinone oxidoreductase (SQOR) in sulfide catabolism and mitochondrial respiration, we examined the impact of exogenous sulfide, which mimics hypoxia, on mitochondrial respiration in suspensions of brain mitochondria isolated from male and female mice
Our discovery that acceleration of sulfide oxidation in the murine brain induces tolerance to hypoxia prompted us to hypothesize that enhancement of sulfide catabolism may prevent sulfide accumulation and mitigate the impairment of mitochondrial energy homeostasis during oxygen shortage, resulting in decreased ischemic brain injury

Summary

Introduction

The mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain’s sensitivity to hypoxia is incompletely understood. At the critical brain tissue PO2 level of 6–8 mmHg, when ATP production by oxidative phosphorylation drastically decreases, there appears to be more than sufficient oxygen in the brain tissue for COX to sustain normal electron flow in the ETC. This apparent gap between the critical brain tissue PO2 level and the Km of COX suggests that there is a role for additional factors that contribute to the inhibition of ETC under hypoxic conditions.

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Results

Conclusion