Ankur Garg, a young scientist in San Francisco, was studying something strange in his lab: mice that breathed low-oxygen air lived much longer than mice breathing normal air. The finding was so surprising that even Garg couldn't quite believe it at first.
"We kept checking the data to make sure it was real," Garg said.
But it was real. Garg, a postdoctoral fellow at Gladstone Institutes, and his team found that mice with a rare genetic disease lived three times longer when they breathed air with less oxygen. The study, published in the journal Nature Metabolism, could eventually help children with devastating brain diseases.
The research focuses on tiny power plants inside our cells called mitochondria. Every time we breathe, about 90% of the oxygen we take in goes straight to these microscopic machines, which turn it into energy for our bodies. But sometimes the mitochondria malfunction, and instead of being useful, the oxygen becomes toxic to our tissues.
Garg and his team zeroed in on a protein called HTRA2. When this protein doesn't work properly, it teams up with another protein called CLPB to try to keep the mitochondria running smoothly. Think of them as a tiny cleanup crew inside every cell, making sure the cellular machinery doesn't get clogged with broken proteins.
When both proteins are defective, the cleanup crew fails. The mitochondria start producing toxic oxygen instead of useful energy, leading to brain damage. This problem shows up in several terrible diseases, including Leigh syndrome (the most common mitochondrial disease in children), Parkinson's disease, and a rare condition called 3-MGA that often kills children before they reach adolescence.
To test a potential treatment, the scientists bred mice that lacked the HTRA2 protein—giving them the same flaw seen in some human patients. Some mice breathed normal air (about 21% oxygen), while others breathed air with much less oxygen. The mice breathing low oxygen lived three times longer and showed less brain inflammation.
The team didn't stop there. They scanned 75 genes linked to mitochondrial diseases to see which patients might benefit from this kind of treatment. The hope is that someday, children with these conditions might breathe specially formulated air as medicine.
"This protein is linked to many other conditions, so our findings suggest that hypoxia therapy could be transformative for treating many neurological diseases," said Isha Jain, the study's lead researcher at Gladstone.
The research was a collaboration between scientists at Gladstone Institutes in San Francisco, the University of Pennsylvania, and UC San Francisco. The team says the next step is to better understand exactly why low oxygen helps—and whether the same approach could work in humans.