FIG. 9.

A schematic of the signaling events. Our model shows that in diabetes, decreased expression of Sirt1 increases H3K9 acetylation at p66Shc promoter and p53 transcription factor binding, which subsequently increases p66Shc expression. Cytosolic accumulation of p66Shc leads to increase in its binding with Grb2 and releasing Sos1 from Sos1–Grb2 complex. Sos1, thus, by replacing GDP with GTP, activates Rac1 and consequently induces Nox2-mediated cytosolic ROS production. In addition, increased p66Shc phosphorylation (p-p66Shc) facilitates its Pin1-mediated isomerization and mitochondrial localization. In mitochondria, it oxidizes Cyt c, generates ROS, and damages mitochondrial DNA and membranes. Cyt c release in the cytoplasm is increased, activating the apoptotic machinery, and ultimately, the development of retinopathy. Cyt c, cytochrome c; GDP, guanosine diphosphate; GTP, guanosine triphosphate; Nox, NADPH oxidase.