Mechanisms of Oxygen Toxicity

PROJECT SUMMARY/ABSTRACT Excess oxygen or “hyperoxia” is toxic across all three domains of life. A range of pathologies arise from states of hyperoxia – hyperoxic lung injury, bronchopulmonary dysplasia, retinopathy of prematurity, etc. More recently, we found that mitochondrial disorders are also characterized by pathological tissue hyperoxia. By normalizing this brain hyperoxia (using inhaled hypoxia), we can rescue disease and increase lifespan of multiple mitochondrial disease mouse models. Additionally, we have developed a small molecule form of hypoxia. Before we can translate this approach to patients, we must understand the mechanisms of hyperoxia toxicity and hypoxia rescue. We have recently identified the exact molecular pathways that are damaged in hyperoxia – diphthamide synthesis, de novo purine synthesis and the mitochondrial electron transport chain. Notably, each of these pathways has an essential step that is catalyzed by an iron-sulfur cluster (ISC)-containing protein complex. We now (Aim 1) propose testing whether diphthamide and purine synthesis are necessary and sufficient for impaired cell fitness in hyperoxia. Additionally, we will investigate the downstream consequences of these defects to motivate novel therapies. Furthermore, we (Aim 2) set out to identify the weakest link in oxygen toxicity – that is, the first ISC-containing protein that is affected in hyperoxia and triggers a cycle of damage. If we can identify the weakest link, this will serve as an ideal therapeutic target. Finally, we propose (Aim 3) studying the relevance of our findings to hyperoxic tissue pathologies in multiple models of mitochondrial disease. Additionally, we will test whether therapeutic hypoxia ameliorates this damage.