Role of Forkhead Transcription Factors in Diabetes-Induced Oxidative Stress

Figure 2

Oxidative stress and insulin signaling affect mitochondrial function via FOXO. ROS induce IRS serine phosphorylation which inhibits IRS activation by insulin signalling. As a result of reduced IRS activity, Akt activity is reduced. Reduced Akt reduces negative signalling of FOXO so that FOXO1 is left in an activated state since it is not exported out of the nucleus by 14-3-3. Meanwhile, ROS activate MST1 and JNK which induce FOXO nuclear translocation by disrupting the complex of FOXO and 14-3-3. PP2A activates FOXO by dephosphorylation of FOXO and by Akt dephosphorylation. FOXO nuclear translocation will induce HMOX1 gene expression which inhibits mitochondrial function by affecting like fatty acid oxidation, ATP, and oxidative respiration (arrow indicates stimulatory event; bar indicates inhibitory event).