Fig. 7: Model of ATF4-dependent and ATF4-independent ISR metabolic outputs.

The ISR increases glutathione and serine synthesis, while diverting glucose and glutamine carbon away from oxidation in mitochondria. Synthesis of aspartate, asparagine and acyl-CoA is maintained via reductive carboxylation of glutamine. These ATF4-dependent changes are accompanied by ATF4-independent inhibition of glycolysis, increased pentose phosphate pathway activity, and increased TG production and accumulation in lipid droplets. Changes in pathway utilization, metabolite abundance and enzyme expression are indicated by color (red = up, blue = down).