Figure 2.

DNA damage is linked to mitochondrial physiology. As described earlier, high glucose levels trigger a cascade of events leading to the activation of professional inhibitors of cell cycle proliferation as p53-p21-pRB. The activation of p53 by DNA damage response (DDR) impacts on mitochondrial physiology and energy metabolism. Telomeric shortening negatively influences mitochondrial homeostasis. This mitochondrial failure mostly derives from the p53-mediated repression of peroxisome proliferator-activated receptor gamma co-activator 1α/β gene (PGC-1α/β) expression. Of note, PGC-1 is largely involved in mitochondrial biogenesis and function, including oxidative phosphorylation and reactive oxygen species (ROS) detoxification. Along with PGC-1 activity abrogation, other mitochondrial biogenesis regulators as nuclear respiratory factor (NRF) and SIRT-1 are also impaired. Here again, pathogenic vicious circles are established leading and amplification of cells senescence as a final outcome.