WHY IS TOO LITTLE OR TOO MUCH OXYGEN TOXIC?
Oxygen deprivation (hypoxia) and excess (hyperoxia) are both toxic to humans. Oxygen deprivation contributes to 3 of the 5 leading causes of mortality in developed nations -- heart attack, stroke, and respiratory failure. On the other hand, hyperoxia is toxic to nearly all organisms and contributes to the pathology of ischemia-reperfusion injury, mitochondrial disease and hyperoxic lung injury. However, the molecular mechanisms underlying hypoxia and hyperoxia toxicity remain unknown. By deciphering these mechanisms, we strive to nominate novel therapeutic candidates. Our recent work highlights such mechanisms of hyperoxia toxicity and the cycle of damage caused by destabilization of specific iron-containing protein complexes (Baik*, Haribowo*, Chen* et al., 2023, Molecular Cell).
HOW DOES THE BODY SENSE AND ADAPT TO VARYING OXYGEN LEVELS?
Mammals are capable of sensing and adapting to moderate variations in oxygen tensions . For example, over 1 million individuals reside permanently at altitudes above 4500m altitude (where there is half the amount of oxygen as sea level). The most well-known hypoxia adaptive pathway centers around the HIF transcription factors. This work let to countless clinical advances and the 2019 Nobel Prize. We set out to more comprehensively understand -- how do organisms sense and adapt to both hypoxia and hyperoxia (Jain*, Calvo* et al., 2020 Cell)? Beyond HIF, can we identify additional metabolic rewiring that enables survival in such conditions. Along these lines, we recently demonstrated that fuel sources are differentially redistributed across organs in acute and chronic hypoxia (Midha*, Zhou* et al., 2023 Cell Metabolism).
WHICH DISEASES CAN BE TREATED BY TURNING THE OXYGEN DIAL?
We recently demonstrated that chronically lowering inhaled oxygen tensions can extend the life of a mitochondrial disease mouse model by five-fold (Jain et al., 2016 Science, Jain et al., 2019 Cell Metabolism). Moreover, starting late-stage disease treatment can not only prevent, but even reverse the disease (Ferrari*, Jain* et al., 2017 PNAS). 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, including aging and age-associated damage.