Journal of Energy Bioscience 2025, Vol.16, No.1, 31-41 http://bioscipublisher.com/index.php/jeb 35 maintain redox balance and support various synthetic reactions (Xiao et al., 2018). NADPH oxidase (NOX) is also involved in regulation. It produces reactive oxygen species (ROS) as part of cell signaling and also affects NADPH levels (Ewald, 2018; Ryoo and Kwak, 2018). Figure 2 NADPH in regulating cellular redox homeostasis (Adopted from Liu et al., 2020) Image caption: NADPH is used as a reducing power in GR- or TR1/2-mediated antioxidant reactions. GR reduces GSSG to GSH, which is then used as a co-factor by GPXs, and GSH is re-oxidized to GSSG. In addition, the oxidation of GSH to GSSG is coupled with the reduction of glutaredoxin disulfide Grx-S2 to glutaredoxin thiol Grx-(SH2), which can conduct thiol–disulfide exchange reactions with protein disulfides (P’SSP), generating reduced protein thiols (P′-SH/P-SH). Cytosolic TR1 or mitochondrial TR2 catalyzes the reduction of thioredoxin disulfide Trx-S2 to thioredoxin thiols Trx-(SH)2, which in turn promote the reduction of peroxiredoxin disulfide Prx-S2 to peroxiredoxin thiols Prx-(SH)2. Prx-(SH)2 may directly detoxify ROS or reduce protein disulfide by thiol-disulfide exchange. Transmembrane enzymes NOXs primarily catalyze the formation of superoxide anion O2 -, which is rapidly converted to H2O2 by SOD3. In addition, NADPH binds to catalase converting H2O2 toH2O. Proteins are indicated in purple. GR: glutathione reductase; TR1/2: thioredoxin reductase 1/2; SOD2/3: superoxide dismutase 2/3; NOXs: NADPH oxidases; ROOH: alkyl hydroperoxide; ROH: alkyl alcohol; P’SSP: protein disulfide; P′-SH/P-SH: protein thiol (Adopted from Liu et al., 2020) 5.2 Impact of nutrient availability and environmental stress on NADPH production NADPH production is affected by nutritional conditions and environmental stress. When cells are under oxidative stress, they increase NADPH production to enhance antioxidant capacity. This process is mainly accomplished by activating G6PD in PPP, and this pathway is regulated by both oxidative stress and nutritional signals. In particular, the amount of glucose is very important for NADPH homeostasis. Glucose metabolism can provide NADPH and is its main source. Therefore, when glucose levels fluctuate, NADPH production will also be affected (Tao et al., 2017). Environmental stress, such as hypoxia, can also change the activity of enzymes that produce NADPH or affect redox reactions in cells, thereby affecting NADPH levels (Xiao et al., 2018). These changes allow cells to respond flexibly to external stress and help them survive in adversity (Blacker and Duchen, 2016). 5.3 Role of NADPH in aging and disease NADPH is important in regulating redox balance and metabolism in cells, and therefore plays a key role in aging and various diseases. NADPH levels tend to decrease with age. This can induce more oxidative stress and cause cell damage. The cause of this decline may be related to the reduced activity of enzymes related to NADPH synthesis and the deterioration of mitochondrial function. In some animal experiments, if cells are allowed to produce more NADPH, such as overexpressing synthases, life span can be extended. This suggests that there may be a positive correlation between NADPH levels and life span (Bradshaw, 2019). In terms of disease, NADPH homeostasis is particularly closely related to cancer. Cancer cells adjust their metabolism and need more NADPH to support antioxidant and anabolic reactions. Therefore, targeting NADPH metabolism in cancer cells may be a
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