Oxygen is vital for life, but too much can be harmful. When cells can't use oxygen properly, it can become toxic. This can lead to severe brain and mitochondrial diseases.
Scientists at Gladstone Institutes are exploring a surprising solution: lowering oxygen levels. This "hypoxia therapy" might protect the brain.
The Problem with Too Much Oxygen
Excess oxygen in the brain is linked to several serious conditions. These include 3-MGA, a rare childhood disorder, and Leigh syndrome, the most common pediatric mitochondrial disease. It's also connected to Parkinson's disease and premature aging.
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Start Your News DetoxIsha Jain, a Gladstone Investigator, has studied this for ten years. Her research shows that oxygen levels similar to high altitudes can help with Leigh syndrome, diabetes, and tumors. The big question was if this approach could work for more mitochondrial and neurological disorders.
How a Faulty Protein Causes Oxygen Buildup
The researchers found that a protein called HTRA2 can cause too much oxygen to build up in tissues. They studied mice with motor neuron degeneration due to defective HTRA2. When these mice breathed air with less oxygen, they lived much longer and their brain function improved.
Jain noted that HTRA2 is linked to many conditions. This suggests that hypoxia therapy could be a game-changer for many neurological diseases.
Mitochondria and Oxygen
Mitochondria are the powerhouses of cells, using oxygen to create energy. Their largest internal machine is called Complex 1.
Ankur Garg, a postdoctoral fellow in Jain's lab, explained that 90% of the oxygen we breathe goes to our mitochondria. If Complex 1 doesn't work right, mitochondria can't burn off oxygen at normal rates. This leads to oxygen buildup, which can damage the brain in some diseases. The team wanted to see if less oxygen could fix this.
Finding the Key Protein
The scientists looked at old data from an experiment. This experiment identified genes that made cells struggle in normal air but thrive in low oxygen. They compared these results with known genetic disorders. This gave them a list of 75 disease-linked genes that might respond to hypoxia therapy.
HTRA2 stood out. Further tests showed it works with another protein, CLPB, to protect Complex 1. These two proteins act like a "clean-up crew" inside mitochondria. They stop misfolded proteins from clogging the machinery.
When HTRA2 or CLPB were missing or faulty, this protective system failed. Misfolded proteins built up, and a key part of Complex 1 stopped working.
Low Oxygen Triples Mouse Survival
Next, the researchers tested reduced oxygen on living mice that lacked HTRA2.
The mice breathed air with less oxygen than the usual 21% found in the atmosphere. They lived three times longer. Hypoxia therapy also reduced inflammation in the striatum, a brain area important for movement.
Garg said this study shows that low oxygen can treat a wide range of conditions affecting mitochondrial Complex 1. This could lead to using "turning the oxygen dial" for many diseases, from rare genetic ones to common neurological conditions.
While the mice breathed less oxygen, Jain's team is developing a drug called HypoxyStat. This drug could create the same effects through a pill or injection.
Jain hopes hypoxia therapy can treat many genetic mitochondrial conditions, as there are currently no widespread treatments. The team is working to make it a practical treatment for people.
Deep Dive & References
Hypoxia rescues complex 1-associated disease caused by proteostatic defects - Nature Metabolism, 2026
