# Role of sulfide catabolism in ischemic brain injury

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $349,650

## Abstract

The brain is exquisitely sensitive to the lack of oxygen. Acute oxygen deprivation inhibits mitochondrial energy
production impairing the cellular integrity. Although ischemic brain injury is a leading cause of morbidity and
mortality, mechanism responsible for the ischemia-induced energy failure of the brain is incompletely
understood.
Hydrogen sulfide is an environmental hazard well known for its neurotoxicity. In mammalian cells, H2S is
produced by the transsulfuration pathway and is oxidized in mitochondria by sulfide oxidation enzymes
including sulfide quinone oxidoreductase (SQR). When oxygen is abundant, sulfide oxidation donates
electrons to the mitochondrial electron transport chain (ETC), thereby promoting adenosine triphosphate (ATP)
synthesis. In contrast, oxygen deprivation stimulates sulfide synthesis and hinders sulfide oxidation, leading to
sulfide accumulation. Accumulated sulfide inhibits ETC complex IV during ischemia and aggravate reperfusion
injury. Therefore, sulfide catabolism may play a pivotal role in the energy homeostasis during oxygen shortage
and cellular injury upon reoxygenation. However, role of sulfide catabolism on the bioenergetics of the brain
during acute oxygen deprivation has thus far attracted little attention. SQR is normally expressed at very low
levels in the central nervous system, explaining the particularly slow rate of sulfide consumption in the brain.
In preliminary studies, we observed that female mice had higher levels of SQR in the brain and were more
resistant to hypoxia than male mice, whereas, knockdown of brain SQR increased the sensitivity of female
mice to hypoxia. SQR overexpression in the brain of mice prevented neurologic dysfunction and death after
global cerebral ischemia and reperfusion (I/R). Pharmacological sulfide scavengers prevented ETC dysfunction
and improved energy production in human cells incubated in hypoxia or in the brains of mice subjected to
cerebral ischemia. Based on these observations, we hypothesize that preventing sulfide accumulation in the
brain either by enhanced sulfide oxidation or pharmacologic sulfide scavenger prevents ETC dysfunction
during oxygen shortage and attenuates ischemia/reperfusion injury of the brain. To address this hypothesis, we
propose: To determine the effects of enhanced sulfide oxidation on the severity of ischemic brain injury (Aim1),
to characterize the role of endogenous sulfide catabolism in the mitochondrial function and response to
ischemic brain injury (Aim 2), and to define the mechanism of the neuroprotective effects of sulfide oxidation
and therapeutic potential of sulfide scavenging after cerebral I/R. (Aim 3). Proposed studies are anticipated to
illuminate the critical role of sulfide in mitochondrial respiration and uncover a therapeutic potential of sulfide
catabolism in ischemic brain injury.

## Key facts

- **NIH application ID:** 10378758
- **Project number:** 5R01NS112373-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** FUMITO ICHINOSE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $349,650
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10378758

## Citation

> US National Institutes of Health, RePORTER application 10378758, Role of sulfide catabolism in ischemic brain injury (5R01NS112373-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10378758. Licensed CC0.

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