Sulfide catabolism ameliorates hypoxic brain injury

Eizo Marutani, Masanobu Morita, Shuichi Hirai, Shinichi Kai, Robert M. H. Grange, Yusuke Miyazaki, Fumiaki Nagashima, Lisa Traeger, Aurora Magliocca, Tomoaki Ida, Tetsuro Matsunaga, Daniel R. Flicker, Benjamin Corman, Naohiro Mori, Yumiko Yamazaki, Annabelle Batten, Rebecca Li, Tomohiro Tanaka, Takamitsu Ikeda, Akito Nakagawa, Dmitriy N. Atochin, Hideshi Ihara, Benjamin A. Olenchock, Xinggui Shen, Motohiro Nishida, Kenjiro Hanaoka, Christopher G. Kevil, Ming Xian, Donald B. Bloch, Takaaki Akaike, Allyson G. Hindle, Hozumi Motohashi () and Fumito Ichinose ()
Additional contact information
Eizo Marutani: Massachusetts General Hospital
Masanobu Morita: Tohoku University Graduate School of Medicine
Shuichi Hirai: Massachusetts General Hospital
Shinichi Kai: Massachusetts General Hospital
Robert M. H. Grange: Massachusetts General Hospital
Yusuke Miyazaki: Massachusetts General Hospital
Fumiaki Nagashima: Massachusetts General Hospital
Lisa Traeger: Massachusetts General Hospital
Aurora Magliocca: Massachusetts General Hospital
Tomoaki Ida: Tohoku University Graduate School of Medicine
Tetsuro Matsunaga: Tohoku University Graduate School of Medicine
Daniel R. Flicker: Harvard Medical School
Benjamin Corman: Massachusetts General Hospital
Naohiro Mori: Massachusetts General Hospital
Yumiko Yamazaki: Massachusetts General Hospital
Annabelle Batten: Massachusetts General Hospital
Rebecca Li: Massachusetts General Hospital
Tomohiro Tanaka: National Institutes of Natural Sciences
Takamitsu Ikeda: Massachusetts General Hospital
Akito Nakagawa: Massachusetts General Hospital
Dmitriy N. Atochin: Harvard Medical School
Hideshi Ihara: Osaka Prefecture University
Benjamin A. Olenchock: Harvard Medical School
Xinggui Shen: Louisiana State University Health Sciences Center-Shreveport
Motohiro Nishida: National Institutes of Natural Sciences
Kenjiro Hanaoka: The University of Tokyo
Christopher G. Kevil: Louisiana State University Health Sciences Center-Shreveport
Ming Xian: Brown University
Donald B. Bloch: Massachusetts General Hospital
Takaaki Akaike: Tohoku University Graduate School of Medicine
Allyson G. Hindle: Massachusetts General Hospital
Hozumi Motohashi: Tohoku University
Fumito Ichinose: Massachusetts General Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23363-x

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