Figure 3.

Cytosolic reducing equivalents supporting the mitochondrial redox balance during metastatic dissemination. Glucose and glutamine metabolisms are attenuated during metastatic dissemination to mitigate the accumulation of mitochondrial reactive oxygen species (ROS). Glutamine goes through reductive carboxylation, where isocitrate dehydrogenase 1 (IDH1) consumes NADPH from the cytosol, and citrate generated in this process enters into the mitochondria to support NAPDH production via isocitrate dehydrogenase 2 (IDH2) and fortify the ROS defense. Glucose is metabolized through the pentose phosphate pathway to provide cytosolic NAPDH needed by IDH1. Oxaloacetate (OAA) produced via reductive carboxylation is metabolized by malate dehydrogenase 1 (MDH1) in the cytosol to produce NAD⁺ to support the glycolytic flux. α-KG, α-ketoglutarate; Asp, aspartate.