Oxygen is such a simple molecule, but our entire life would be impossible without it. The human organism is highly sensitive to changes in oxygen levels. You might have noticed it by yourself if you ever been high in the mountains or had a hot air balloon ride. People respond to high altitudes differently. Some may experience headaches, confusion, dizziness, or other symptoms. It happens because of the low amount of oxygen in the air at high elevation, leading to the deprivation of adequate oxygen supply in the body called hypoxia. However, we know that if we go up gradually, our body starts slowly adjusting to the changes reducing risks to the minimum.
Hypoxia may also be local when it affects only a part of the body. The brain is the most susceptible to hypoxia organ. The mechanisms underlying the sensitivity of the brain to hypoxia are incompletely understood. Oxygen is required to produce energy for the vital activity of cells. In addition, hypoxia induces the accumulation of hydrogen sulfide (H2S), a gas that has the odor of rotten eggs. It also slowers down cells’ essential functions. Significant changes in the brain may occur within 2–3 minutes of the onset of severe hypoxia. Persistent lack of oxygen beyond a few minutes irreversibly damages neurons. This happens during ischemic stroke when the blood supply to part of the brain is interrupted, leading to the oxygen deprivation of that area.
A research group from the Massachusetts General Hospital identified a mechanism that protects the brain from the effects of hypoxia. They noticed that repeated hydrogen sulfide breathing increased tolerance to this gas in mice. Breathing H2S depresses metabolism and decreases the body temperature of rodents. But after five days of such practice, mice became tolerant to those effects. It turns out that an enzyme called sulfide:quinone oxidoreductase (SQOR) was responsible for the first step of recycling the harmful gas. Repeated exposure to H2S led to the increased level of the enzyme in the brain, which minimized the repressing effects of the gas. In addition, those mice exhibited noticeable tolerance to severe hypoxia (5% O2).
SQOR is strongly expressed in the liver, heart, lung, skeletal muscle, and colon. However, the level of SQOR is low in the brains of most mammals, including mice, rats, and humans what makes them very sensitive to sulfide accumulation and, therefore, hypoxia. Previous studies also demonstrated a difference in brain SQOR levels between male and female mice. The majority of female mice tolerated breathing 5% O2 for at least 1 hour, whereas all male mice died in less than 10 minutes. It was explained by the dependence of the enzyme levels on estrogen, a female sex hormone produced by ovaries. Surgical removal of ovaries decreased SQOR levels in the brain and abolished hypoxia tolerance. At the same time, estrogen supplementation was able to restore this ability.
Scientists also used gene therapy to investigate the dependence between SQOR and tolerance to oxygen deprivation. As expected, silencing the SQOR gene increased the brain’s sensitivity to hypoxia. In contrast, neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and brain damage. Unfortunately, such a genetic approach is technically complex and not practical at this point. However, this study is thought to be a cornerstone in developing methods to treat diseases like ischemic stroke or other brain damage related to oxygen deprivation.