The Oxygen Ledger of the Cell
Oxygen is the substrate for over 400 known biochemical reactions, surpassing even ATP and NADH. Thus, it is not surprising that almost all organisms have evolved the ability to sense variations in oxygen levels and adapt accordingly. When oxygen levels fall below a tissue’s buffering capacity, there are devastating effects on health and survival. Notably, the leading causes of death in developed nations are due to impaired oxygenation – heart disease, stroke, and respiratory disease. While the underlying cause of disease may vary, the ultimate pathology results from impaired oxidative metabolism. Our goal is to understand which metabolic processes fail as a function of oxygen tension and which pathways are successfully rewired to cope with variations in oxygen levels.
Turning the Oxygen Dial as a Therapy
We recently demonstrated that chronically lowering inhaled oxygen tensions can extend the life of a mitochondrial disease mouse model by five-fold. Moreover, starting late-stage disease treatment can not only prevent, but even reverse the disease. MRI-detectable lesions are completely cured within weeks of breathing chronic hypoxia. This work has already led to a phase 1 clinical trial for healthy human hypoxia exposure. We believe that this paradoxical finding is just the tip of the iceberg. While small molecules and biologics are the most common forms of therapy, we believe we have uncovered a new mode of treating metabolic disorders. We now hope to extend our findings to additional inborn errors of metabolism, as well as more common metabolic disorders.