Scientists Discover a Surprising Way To Protect the Brain: Less Oxygen

New research suggests that low oxygen levels may help alleviate disease caused by defects in mitochondrial quality control. Oxygen is essential for people—and most other organisms—but more is not always better. When oxygen accumulates beyond what cells can safely use, it can become toxic and contribute to serious health problems. In the brain, excess oxygen [...]

New research suggests that low oxygen levels may help alleviate disease caused by defects in mitochondrial quality control. Oxygen is essential for people—and most other organisms—but more is not always better. When oxygen accumulates beyond what cells can safely use, it can become toxic and contribute to serious health problems.

In the brain, excess oxygen has been associated with 3-MGA, a rare and often fatal childhood disorder, along with Leigh syndrome (the most common pediatric mitochondrial disease), Parkinson’s disease, and premature aging. Scientists at Gladstone Institutes are now investigating whether hypoxia therapy, which deliberately lowers the body’s oxygen supply, could help address these conditions. Gladstone Investigator Isha Jain, PhD, has studied this approach for the past decade.

Her research has examined how oxygen levels similar to those found at high altitudes can produce beneficial effects in Leigh syndrome, diabetes, and solid tumors. The unresolved question was whether the same strategy might work across a broader range of rare and common mitochondrial disorders and neurological diseases. Jain’s lab therefore set out to identify additional conditions that could respond to reduced oxygen.

For the study, published in Nature Metabolism, the researchers worked with James Shorter, PhD, professor of biochemistry and biophysics at the University of Pennsylvania, and Daniel Southworth, PhD, professor of biochemistry and biophysics at UC San Francisco. A faulty protein leaves oxygen behind The researchers found that a malfunctioning protein called HTRA2 can cause excess oxygen to accumulate dangerously in tissues. In mice with motor neuron degeneration caused by defective HTRA2, breathing air with less oxygen substantially extended lifespan and improved brain function.

“This protein is linked to many other conditions, so our findings suggest that hypoxia therapy could be transformative for treating many neurological diseases,” says Jain, who is also a core investigator at Arc Institute. Mitochondria explain the oxygen buildup Mitochondria, the structures that supply cells with energy, consume oxygen to keep the body functioning. Their largest internal molecular machine is known as Complex 1.

“Every time we breathe, 90 percent of the oxygen we consume goes to our mitochondria,” says Ankur Garg, PhD, postdoctoral fellow in Jain’s lab and first