Sulfide catabolism ameliorates hypoxic brain injury

• Published in: Nature communications Vol. 12; no. 1; pp. 3108 - 19
• Main Authors: Marutani, Eizo, Morita, Masanobu, Hirai, Shuichi, Kai, Shinichi, Grange, Robert M H, Miyazaki, Yusuke, Nagashima, Fumiaki, Traeger, Lisa, Magliocca, Aurora, Ida, Tomoaki, Matsunaga, Tetsuro, Flicker, Daniel R, Corman, Benjamin, Mori, Naohiro, Yamazaki, Yumiko, Batten, Annabelle, Li, Rebecca, Tanaka, Tomohiro, Ikeda, Takamitsu, Nakagawa, Akito, Atochin, Dmitriy N, Ihara, Hideshi, Olenchock, Benjamin A, Shen, Xinggui, Nishida, Motohiro, Hanaoka, Kenjiro, Kevil, Christopher G, Xian, Ming, Bloch, Donald B, Akaike, Takaaki, Hindle, Allyson G, Motohashi, Hozumi, Ichinose, Fumito
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 25.05.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Accumulation; Animals; Brain; Brain - metabolism; Brain - pathology; Brain Injuries - genetics; Brain Injuries - metabolism; Brain injury; Catabolism; Cells, Cultured; Deprivation; Energy balance; Female; Ground squirrels; Head injuries; Homeostasis; Hydrogen sulfide; Hydrogen Sulfide - metabolism; Hypoxia; Injury prevention; Ischemia; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Mitochondria; Mitochondria - metabolism; NAD - metabolism; Oxygen; Quinone oxidoreductase; Quinone Reductases - genetics; Quinone Reductases - metabolism; Quinones; Rats; Rats, Sprague-Dawley; Respiration; RNA Interference; Scavenging; Sensitivity; Target recognition; Therapeutic targets; Traumatic brain injury
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23363-x

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.