| Literature DB >> 34035265 |
Eizo Marutani1,2, Masanobu Morita3, Shuichi Hirai1,2, Shinichi Kai1,2, Robert M H Grange1,2, Yusuke Miyazaki1,2, Fumiaki Nagashima1,2, Lisa Traeger1,2, Aurora Magliocca1,2, Tomoaki Ida3, Tetsuro Matsunaga3, Daniel R Flicker4,5,6, Benjamin Corman1,7, Naohiro Mori1,2, Yumiko Yamazaki1, Annabelle Batten1, Rebecca Li1, Tomohiro Tanaka8, Takamitsu Ikeda1,2, Akito Nakagawa1,2, Dmitriy N Atochin2,9, Hideshi Ihara10, Benjamin A Olenchock2,11, Xinggui Shen12, Motohiro Nishida8,13, Kenjiro Hanaoka14, Christopher G Kevil12, Ming Xian15, Donald B Bloch1,2,7, Takaaki Akaike3, Allyson G Hindle1,2,16, Hozumi Motohashi17, Fumito Ichinose18,19.
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.Entities:
Year: 2021 PMID： 34035265 DOI： 10.1038/s41467-021-23363-x
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919