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; Fumito Ichinose

doi:10.1038/s41467-021-23363-x

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 NakagawaDmitriy 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, Fumito Ichinose

Research output: Contribution to journal › Article › peer-review

41 Citations (Scopus)

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.

Original language	English
Article number	3108
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-23363-x
Publication status	Published - 2021 Dec 1
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-021-23363-x

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Marutani, E., Morita, M., Hirai, S., Kai, S., Grange, R. M. H., Miyazaki, Y., Nagashima, F., Traeger, L., Magliocca, A., Ida, T., Matsunaga, T., Flicker, D. R., Corman, B., Mori, N., Yamazaki, Y., Batten, A., Li, R., Tanaka, T., Ikeda, T., ... Ichinose, F. (2021). Sulfide catabolism ameliorates hypoxic brain injury. Nature communications, 12(1), Article 3108. https://doi.org/10.1038/s41467-021-23363-x

Marutani, E, Morita, M, Hirai, S, Kai, S, Grange, RMH, Miyazaki, Y, Nagashima, F, Traeger, L, Magliocca, A, Ida, T, Matsunaga, T, Flicker, DR, Corman, B, Mori, N, Yamazaki, Y, Batten, A, Li, R, Tanaka, T, Ikeda, T, Nakagawa, A, Atochin, DN, Ihara, H, Olenchock, BA, Shen, X, Nishida, M, Hanaoka, K, Kevil, CG, Xian, M, Bloch, DB, Akaike, T, Hindle, AG, Motohashi, H & Ichinose, F 2021, 'Sulfide catabolism ameliorates hypoxic brain injury', Nature communications, vol. 12, no. 1, 3108. https://doi.org/10.1038/s41467-021-23363-x

@article{3ad43ce1d1224db9aaf88defaaf41b83,

title = "Sulfide catabolism ameliorates hypoxic brain injury",

abstract = "The mammalian brain is highly vulnerable to oxygen deprivation, yet the mechanism underlying the brain{\textquoteright}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.",

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

note = "Funding Information: This work was supported in part by Grants-in-Aid for Scientific Research (S and C) from the Ministry of Education, Sciences, Sports, and Technology (MEXT), Japan, to M.M. (grant no. 19K07341), T.I. (20K07306), T.M. (19K07554), and T.A. (18H05277). M.N. and T.A. were supported by CREST, Japan Science and Technology Agency (JST) (grant no. JPMJCR2024). H.M. was supported by Japan Agency for Medical Research and Development (AMED) (grant no. JP21gm5010002). D.N.A. was supported by the National Institute of Neurological Disorders and Stroke (NINDS) (grant no. R01NS096237). C.G.K. was supported by the National Heart, Lung, and Blood Institute (NHLBI) (grant nos. R01HL113303 and R01HL149264) and the National Institute of General Medical Science (NIGMS) (grant no. P20GM121307). F.I. was supported by the NHLBI (grant no. R01HL101930) and the NINDS (grant no. R01NS112373). F.I. and M.X. were supported by the NINDS (grant no. R21NS116671). A.H. and F.I. were supported by the National Science Foundation (grant no. #1929592). We thank Dr. Sandra L. Martin for contribution of 13-lined ground squirrel tissues and Drs. S. Martin and Katharine R. Grabek for the identification of brain-specific Sqor transcript isoform sequences for the 13-lined ground squirrel. Authors thank Drs. Vamsi Mootha and Warren M. Zapol for valuable discussion and support. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-23363-x",

language = "English",

volume = "12",

journal = "Nature communications",

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TY - JOUR

T1 - Sulfide catabolism ameliorates hypoxic brain injury

AU - Marutani, Eizo

AU - Morita, Masanobu

AU - Hirai, Shuichi

AU - Kai, Shinichi

AU - Grange, Robert M.H.

AU - Miyazaki, Yusuke

AU - Nagashima, Fumiaki

AU - Traeger, Lisa

AU - Magliocca, Aurora

AU - Ida, Tomoaki

AU - Matsunaga, Tetsuro

AU - Flicker, Daniel R.

AU - Corman, Benjamin

AU - Mori, Naohiro

AU - Yamazaki, Yumiko

AU - Batten, Annabelle

AU - Li, Rebecca

AU - Tanaka, Tomohiro

AU - Ikeda, Takamitsu

AU - Nakagawa, Akito

AU - Atochin, Dmitriy N.

AU - Ihara, Hideshi

AU - Olenchock, Benjamin A.

AU - Shen, Xinggui

AU - Nishida, Motohiro

AU - Hanaoka, Kenjiro

AU - Kevil, Christopher G.

AU - Xian, Ming

AU - Bloch, Donald B.

AU - Akaike, Takaaki

AU - Hindle, Allyson G.

AU - Motohashi, Hozumi

AU - Ichinose, Fumito

N1 - Funding Information: This work was supported in part by Grants-in-Aid for Scientific Research (S and C) from the Ministry of Education, Sciences, Sports, and Technology (MEXT), Japan, to M.M. (grant no. 19K07341), T.I. (20K07306), T.M. (19K07554), and T.A. (18H05277). M.N. and T.A. were supported by CREST, Japan Science and Technology Agency (JST) (grant no. JPMJCR2024). H.M. was supported by Japan Agency for Medical Research and Development (AMED) (grant no. JP21gm5010002). D.N.A. was supported by the National Institute of Neurological Disorders and Stroke (NINDS) (grant no. R01NS096237). C.G.K. was supported by the National Heart, Lung, and Blood Institute (NHLBI) (grant nos. R01HL113303 and R01HL149264) and the National Institute of General Medical Science (NIGMS) (grant no. P20GM121307). F.I. was supported by the NHLBI (grant no. R01HL101930) and the NINDS (grant no. R01NS112373). F.I. and M.X. were supported by the NINDS (grant no. R21NS116671). A.H. and F.I. were supported by the National Science Foundation (grant no. #1929592). We thank Dr. Sandra L. Martin for contribution of 13-lined ground squirrel tissues and Drs. S. Martin and Katharine R. Grabek for the identification of brain-specific Sqor transcript isoform sequences for the 13-lined ground squirrel. Authors thank Drs. Vamsi Mootha and Warren M. Zapol for valuable discussion and support. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-021-23363-x

DO - 10.1038/s41467-021-23363-x

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SN - 2041-1723

VL - 12

JO - Nature communications

JF - Nature communications

IS - 1

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ER -

Sulfide catabolism ameliorates hypoxic brain injury

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