Introduction: 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.
Approaches: We use a combination of comparative metabolism, functional genomics and computational toolsets to systematically define the “Oxygen Ledger” and understand the fundamentals of how the body senses and adapts to changes in oxygen tensions.
Biomedical Relevance: (1) Mechanistic understanding and therapies for diseases of hypoxia (stroke, MI, etc.). (2) Mechanistic understanding and therapies for diseases of relative hyperoxia (mitochondrial disease, neurodegenerative diseases). (3) Metabolic susceptibilities of tumor hypoxia and novel chemotherapies.