In a paper published in Cell, the laboratory of Isha Jain at Gladstone Institutes showed that a small molecule inhibitor can control excess oxygen levels resulting from dysfunctional mitochondria. These results point to a potential new therapeutic strategy for mitochondrial diseases.

Oxygen is well-known to be critical for human life, but too much oxygen can be toxic. Thus, the balance between supply and demand is important. For most of us, that is no problem. However, that careful balance is disrupted in those with some mitochondrial diseases so that excess oxygen is a common feature. Leigh syndrome is the most common pediatric mitochondrial disease.

Since tissue hyperoxia is problematic in these patients, one might wonder if reducing the concentration of oxygen in tissues would be beneficial. A recent study from the laboratory of at Gladstone Institutes and the University of California, San Francisco showed just that. The team, led by Isha Jain, took advantage of mice with a knockout of the Ndufs4 gene (Blume et al., 2025). That mutation results in the loss of an important complex in the electron transport chain that mimics the disease, and these mice are often used as a model for experimentation.

They exposed the mice to a small molecule called HypoxyStat that induces hypoxia by causing oxygen to bind more tightly to hemoglobin, leading to decreased release of oxygen into tissues. Chronic exposure of the mice to the molecule normalized tissue hyperoxia and resulted in significantly longer lifespans in the mice.

Thus, these findings suggest that drugs, such as HypoxyStat, that lower effective oxygen levels might be a promising therapeutic strategy for these diseases in general. Of course, manipulating oxygen levels is challenging, but these results provide valuable insights into mitochondrial diseases.

A video, Science in Seconds, produced by Gladstone tells the story of Jain and her team’s breakthrough, as does an article, Daily Drug Captures Health Benefits of High-Altitude, Low-Oxygen Living, published by Gladstone on the findings.

An interview with Dr. Isha Jain

Do the benefits result from improved mitochondrial function or the reduction of excess oxygen in tissues or both?

Currently, I would say we have the strongest evidence that the benefit occurs due to the alleviation of tissue hyperoxia (excess oxygen) in tissues. Future work is needed to fully understand the mechanism.

You noted that you wanted to determine if you could generalize your results beyond the Ndufs4 mice. What do you see as the next steps in this research?

The next steps include testing whether this compound (or further optimized compounds) work in additional mitochondrial disorders and additionally affected tissues beyond the brain.

Mitochondria have been around for a very long time, and oxygen levels have fluctuated in our atmosphere. Does that mean that mitochondria have adapted to the available oxygen?

It is indeed puzzling that oxygen is both a substrate and a toxin for mitochondrial ATP production. It appears that we have evolved to exist in a very delicate balance of too little or too much oxygen.

The findings are intriguing, but controlling oxygen levels might be a challenge in patients. For example, are those with mitochondrial diseases, such as Leigh syndrome, affected by changes in altitude (e.g., Denver)?

There is anecdotal evidence that this might be the case. However, mitochondrial diseases are rare enough and the altitudes we are talking about are fairly high, so it is difficult to amass enough epidemiological data to make this claim definitively.

You mention pulmonary hypertension as a complication of using drugs, such as these. Are there other potential complications and ways around the problems?

The side effects are the same as living at altitude: things like pulmonary hypertension and increased blood viscosity. A gradual acclimation to the drug (dose escalation) will likely be needed. Many more safety studies are needed before this compound or related compounds can be used in patients.

What initially interested you in the study of mitochondria?

I am broadly interested in developing creative new therapies for metabolic disorders. Of course, mitochondria are where much of metabolism takes place.

 

Reference

Blume SY, Garg A, Martí-Mateos Y, Midha AD, Chew BTL, Lin B, Yu C, Dick R, Lee PS, Situ E, Sarwaikar R, Green E, Ramanan Y, Grotenbreg G, Hoek M, Sinz C, Jain IH (2025) HypoxyStat, a small-molecule form of hypoxia therapy that increases oxygen-hemoglobin affinity. Cell https://doi.org/10.1016/j.cell.2025.01.029.