Abstract
Significance: Reducing equivalents (NAD(P)H and glutathione [GSH]) are essential for maintaining cellular redox homeostasis and for modulating cellular metabolism. Reductive stress induced by excessive levels of reduced NAD+ (NADH), reduced NADP+ (NADPH), and GSH is as harmful as oxidative stress and is implicated in many pathological processes.Recent Advances: Reductive stress broadens our view of the importance of cellular redox homeostasis and the influences of an imbalanced redox niche on biological functions, including cell metabolism.Critical Issues: The distribution of cellular NAD(H), NADP(H), and GSH/GSH disulfide is highly compartmentalized. Understanding how cells coordinate different pools of redox couples under unstressed and stressed conditions is critical for a comprehensive view of redox homeostasis and stress. It is also critical to explore the underlying mechanisms of reductive stress and its biological consequences, including effects on energy metabolism.Future Directions: Future studies are needed to investigate how reductive stress affects cell metabolism and how cells adapt their metabolism to reductive stress. Whether or not NADH shuttles and mitochondrial nicotinamide nucleotide transhydrogenase enzyme can regulate hypoxia-induced reductive stress is also a worthy pursuit. Developing strategies (e.g., antireductant approaches) to counteract reductive stress and its related adverse biological consequences also requires extensive future efforts.
Highlights
Mammalian cells depend on a series of oxidation and reduction reactions to generate energy (e.g., ATP) and to synthesize essential cellular components from nutrients in support of their biological functions
Enhanced failure in the myocardium of wild-type mice coincided with a decline in NADPH levels and an increase in NADH, H2O2 production, and oxidative damage [69]. These findings suggest that pathological cardiac pressure overload induces NNT reverse functional mode to generate NADH at the expense of NADPH resulting in a high NADH/NAD+ and reductive stress, further promoting reactive oxygen species (ROS) at complex I leading to oxidative injury and cell death (Fig. 6)
Activation of Hypoxia-inducible factor 1a (HIF-1a) signaling by PHD2 deletion under normoxia enhanced glutamine uptake and upregulated glutaminase 1 (GLS1) expression leading to enhanced glutaminolysis and increases in cellular GSH levels and in GSH/GSSG, which correlated with upregulation of antioxidant genes (SOD1, SOD2, catalase, GPx1, and glutathione reductase (GR)) and reduction in cellular and mitochondrial ROS production, indicatives of reductive stress
Summary
Mammalian cells depend on a series of oxidation and reduction (redox) reactions to generate energy (e.g., ATP) and to synthesize essential cellular components (e.g., nucleic acids) from nutrients in support of their biological functions. These findings suggest that pathological cardiac pressure overload induces NNT reverse functional mode to generate NADH at the expense of NADPH resulting in a high NADH/NAD+ and reductive stress, further promoting ROS at complex I leading to oxidative injury and cell death (Fig. 6).
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