mTOR: Driving apoptosis and autophagy for neurocardiac complications of diabetes mellitus

Figure 1 Cellular signaling of mechanistic target of rapamycin in diabetes mellitus. mTOR is a component of the protein complexes mTORC1 and mTORC2 with two important targets of p70S6K and 4EBP1 that promote mTOR kinase activity. mTOR signaling is controlled by AMPK that oversees the activity of TSC1/TSC2, an inhibitor of mTORC1. During periods of oxidative stress in DM, EPO uses mTOR to protect cell survival from programmed cell death injury. For example, EPO blocks cell injury in studies of diabetic retinal degeneration, maintains endothelial cell integrity during experimental models of DM, and regulates the detrimental effects of obesity in animal models. AMPK can have dual roles in cell survival. AMPK can limit oxidative stress that can lead to hypertension and reduce insulin resistance through autophagy that can have linked pathways to apoptosis. However, under other circumstances AMPK also can lead to neuroinflammation and cardiac dysfunction. Ultimately, a careful balance in the activities of autophagy and apoptosis is required through mTOR to foster cell survival during DM. mTOR: Mechanistic target of rapamycin; DM: Diabetes mellitus; AMPK: AMP activated protein kinase; EPO: Erythropoietin; p70S6K: p70 ribosomal S6 kinase; 4EBP1: 4E-binding protein 1; mTORC1: mTOR complex 1; TSC1/TSC2: Tuberous sclerosis 1/ tuberous sclerosis 2.