Oxygen isn’t always good. Of course, humans and most living things cannot live without it. However, oxygen is highly toxic and can also have serious health effects.
In the brain, toxic levels of oxygen are associated with a rare and often fatal childhood condition known as 3-MGA, Leigh syndrome (the most common childhood mitochondrial disease), Parkinson’s disease, and premature aging. Now, scientists at the Gladstone Institute are focusing on an approach that could help treat all of these: hypoxia therapy.
Hypoxia therapy, which involves reducing the amount of oxygen available to the body, is a topic of ongoing research for Gladstone researcher Dr Isha Jain. For the past decade, she has studied how the hypoxic conditions found at high altitudes have beneficial effects on conditions such as Leigh syndrome, diabetes, and solid tumors.
An important question is whether this therapeutic approach also extends to other rare and common forms of mitochondrial dysfunction and neurological conditions. So Jain’s lab set out to expand the scope of hypoxic therapy.
To achieve this goal, they collaborated with Dr. James Shorter, professor of biochemistry and biophysics at the University of Pennsylvania, and Dr. Daniel Southworth, professor of biochemistry and biophysics at the University of California, San Francisco. natural metabolism.
They showed that when a protein called HTRA2 malfunctions, it causes a dangerous accumulation of excess oxygen in tissues. They found that breathing air with reduced oxygen levels dramatically extended lifespans and improved brain function in mice suffering from motor neuron degeneration, a disorder caused by a deficiency in HTRA2.
“Because this protein is associated with many other conditions, our findings suggest that hypoxic therapy may be transformative in the treatment of many neurological diseases,” says Jain, who is also a principal investigator at the Ark Institute.
when oxygen becomes toxic
At the center of every cell are tiny power plants called mitochondria that consume oxygen to produce the energy your body needs to function. And the largest cellular machinery within the mitochondria is called complex 1.
“Every time we breathe, 90 percent of the oxygen we consume goes to the mitochondria,” says Dr. Ankur Garg, a postdoctoral fellow in Jain’s lab and lead author of the study. “But when complex 1 becomes dysfunctional, the mitochondria are unable to burn oxygen at their normal rate.”
When this happens, excess oxygen builds up in the tissues, which can eventually become toxic and cause brain damage associated with certain mitochondrial and neurological diseases. Scientists wanted to see if hypoxic therapy could be used to counteract that effect.
Reanalyzing a large-scale previous experiment, the researchers discovered a gene that, when missing, causes cells to struggle in normal air, but allows them to grow fully in low-oxygen air. They then cross-referenced their findings with a directory of known genetic diseases. This allowed us to evaluate 75 genes directly related to diseases in which patients may benefit from hypoxic therapy.
One of the top hits was a protein called HTRA2. They showed that complex 1 interacts closely with another protein (CLPB) to keep it intact.
“Together, these two proteins act like scavengers within the mitochondria, preventing the machinery from becoming clogged with clumps of misfolded proteins,” Jain says.
Jain and her team showed that if HTRA2 and CLPB were missing or defective, cleaning crews would not be able to do their jobs properly and critical parts of Complex 1’s machinery would fail.
Hypoxia therapy testing
To investigate whether hypoxia therapy was beneficial to the organism, scientists studied mice lacking the HTRA2 protein.
By reducing the amount of oxygen the mice breathed, compared to normal atmospheric oxygen, which is about 21 percent, the mice lived three times longer. The research team also found that hypoxia therapy helped reduce inflammation in a part of the brain called the striatum.
“By showing that these mice can be successfully treated with hypoxia, our study expands the potential of hypoxia therapy to a wide range of conditions that directly or indirectly affect mitochondrial complex 1, as in the case of HTRA2 deficiency,” Garg says. “This will facilitate a wide range of applications for ‘turning the oxygen dial’, from rare genetic diseases to common neurological disorders and beyond.”
The study involved mice inhaling hypoxia, but Jain and his colleagues are now developing a drug called HypoxyStat that can have the same effect as a pill or injection.
“Currently, there are no universally available treatments for mitochondrial diseases. Hypoxia therapy gives us hope that we may be able to treat many of these genetic diseases, not just one,” Jain says. “We are working hard to make this a practical treatment for human patients in the clinic.”
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DOI: 10.1038/s42255-026-01566-0
