Sulfide catabolism ameliorates hypoxic brain injury

Area of Science:

• Neuroscience
• Biochemistry
• Physiology

Background:

• Mammalian brain is sensitive to oxygen deprivation (hypoxia).
• Hypoxia causes hydrogen sulfide accumulation, inhibiting mitochondrial respiration.
• The precise mechanisms of brain hypoxia sensitivity are not fully understood.

Purpose of the Study:

• Investigate the role of sulfide catabolism in hypoxia tolerance.
• Identify the enzyme sulfide:quinone oxidoreductase (SQOR) as a key player.
• Explore SQOR as a therapeutic target for ischemic brain injury.

Main Methods:

• Compared hypoxia sensitivity and sulfide catabolism in mice, rats, and ground squirrels.
• Utilized gene silencing and neuron-specific expression of SQOR.
• Examined the effect of SQOR localization within mitochondria.
• Assessed mitochondrial respiration and employed pharmacological sulfide scavenging.

Main Results:

• Hypoxia sensitivity inversely correlates with SQOR levels and sulfide catabolism capacity.
• Silencing SQOR heightened brain hypoxia sensitivity.
• Neuron-specific SQOR expression protected against hypoxia-induced damage.
• Mitochondrial SQOR exclusion worsened hypoxia sensitivity in brain, heart, and liver.
• Sulfide scavenging preserved mitochondrial function and conferred hypoxia resistance.

Conclusions:

• Sulfide catabolism via SQOR is crucial for energy homeostasis during hypoxia.
• SQOR activity dictates brain resistance to oxygen deprivation.
• Targeting sulfide catabolism offers a potential therapeutic strategy for ischemic brain injury.