Figure 3. NO-mediated effects on cellular metabolism via S-nitrosation and signaling pathways.

NO, in the presence of oxygen postranslationally modifies proteins via S-nitrosation. S-nitrosation can lead to either enhanced or repressed metabolic pathway activity. Excess NO inactivates antioxidant GSH, which leads to build up of ROS and subsequently induces HIF-1α. HIF-1α initiates a signaling cascade that regulates glycolytic enzymes such as HK, LDH and MCT. NO inhibits the electron transport chain activity and subsequently mitochondrial respiration by interacting with complex IV. NO enhances lipid metabolism by inhibiting ACO and upregulating FASN to redirect citrate into lipogenic acetyl-CoA. NO also affects TCA cycle fluxes by increasing GLS activity, which enhances glutamine utilization by the TCA cycle.

ROS, Reactive oxygen species; GSH, glutathione; GSSG, reduced glutathione; HIF, hypoxia inducible factor; GLUT4, Glucose transporter type 2; HK, Hexokinase; ENO, Enolase; PKM, pyruvate kinase; LDH, Lactate dehydrogenase; MCT, Monocarboxylate transporters; GLS, glutaminase; GLUD, glutamate dehydrogenase; ACO: aconitase; SDH, succinate dehydrogenase; MDH, malate dehydrogenase