Effective treatments for mitochondrial disease are scarce. A paper in Nature Metabolism from Core Investigator Isha Jain and team offers one, showing that breathing low-oxygen air nearly triples lifespan in a mouse model of HTRA2 deficiency.
HTRA2 is a protease in the mitochondrial intermembrane space. Its loss causes 3-methylglutaconic aciduria, a fatal childhood disorder. The same gene, also known as PARK13, is linked to Parkinson’s, and was among the strongest hits in the team’s earlier screen for genes whose loss can be rescued by low oxygen.
In mice lacking HTRA2 protease activity, continuous 11% oxygen extended median lifespan nearly threefold across two cohorts. It also improved motor function and cleared neuroinflammation in the striatum, a movement-controlling region where these mice develop lesions.
HTRA2 loss destabilizes Complex I, the entry point of the respiratory chain. Low oxygen restored Complex I protein levels but not its enzymatic activity, suggesting the rescue worked through a mechanism other than respiration. With Complex I impaired, mitochondria burn less oxygen, so it accumulates in the tissue and damages oxygen-sensitive iron-sulfur cluster proteins. The team used those proteins as a readout and found that hypoxia cleared the excess oxygen and restored protein levels.
HTRA2 also partners with CLPB, another intermembrane-space protein that causes the same disease when mutated. HTRA2 degrades protein aggregates while CLPB pulls them apart, and losing either destabilizes Complex I. CLPB and HAX1 knockouts were also rescued by low oxygen in the original screen, pointing to a broader class of protein-quality-control diseases that low oxygen might treat.
Reaching patients is an open challenge, since breathing low-oxygen air isn’t yet a viable therapy for humans. To address this, the Jain lab and Maze Therapeutics developed HypoxyStat, a small molecule that lowers tissue oxygen by raising hemoglobin’s oxygen affinity. It extended lifespan in a related mitochondrial disease, and the team is now adapting it to test against disorders like HTRA2 deficiency. (Read more about HypoxyStat here: https://lnkd.in/eMm22qkT)
- Explore the Nature Metabolism paper: https://lnkd.in/g3TQw2ae