Is NADPH Critical to Maintain Redox Homeostasis in Hypoxia-Tolerant Naked Mole-Rat Brain?

Nicotinamide adenine dinucleotide phosphate (NADPH) is a ubiquitous electron donor and a key reducing agent in numerous biochemical reactions. Among other important cellular roles, NADPH activity is central to the maintenance of redox homeostasis in eukaryotic cells. NADPH increases markedly during acute in vivo hypoxia in the brain of naked mole-rats, which are among the most hypoxia-tolerant mammals, and which do not exhibit imbalances in redox homeostasis or increased reactive oxygen species (ROS)-mediated damage during bouts of hypoxia-reoxygenation in brain. Conversely, NADPH does not increase in the brain of hypoxia-intolerant mice, which are prone to deleterious ROS bursts during perturbations in oxygen availability. Although the importance of NADPH in mediating ROS homeostasis has been demonstrated in the brain of other mammals, little is known about the source of NADPH changes in hypoxic naked mole-rat brain, nor about the mechanisms via which NADPH may provide neuroprotection in this species. Elucidating the underlying mechanisms that support the remarkably stable ROS profile in naked mole-rat brain may provide insight into novel mechanisms to ameliorate the deleterious impact of ROS bursts in the brains of hypoxia-intolerant mammals, such as occur during stroke and other diseases. In this review, we discuss what is known regarding the management of ROS and NADPH in naked mole-rat brain, examine potential cellular sources of NADPH that may underlie the large hypoxic increase in this molecule during acute hypoxic exposure, and propose experiments to advance our understanding of the role NADPH has in maintaining naked mole-rat brain redox balance. (First online: December 28, 2022)