Modulation of NAD metabolism by oxygen availability

Reduced oxygen availability (hypoxia) can result in decreased energy levels, perturbed redox homeostasis and permanent cellular damage. Efficient hypoxic stress responses and the induction of protective adaptations are crucial to prevent hypoxic damage and can be targeted to improve cellular resilience and health. Nicotinamide adenine dinucleotide (NAD) metabolism is highly sensitive to changes in oxygen availability and interacts with other stress pathways, such as the oxygen-regulated transcription factors hypoxia-inducible factors (HIFs), to orchestrate cellular responses and adaptations to hypoxia. We evaluate what is known about this interaction, how it may be modulated and which benefits could be expected from related therapeutic interventions. We further discuss, which future research is needed to develop therapeutic strategies targeting the hypoxic response-NAD axis.