The p53–p66shc–Manganese Superoxide Dismutase (MnSOD) network: A mitochondrial intrigue to generate reactive oxygen species

Once considered as a mere by-product of respiration, mitochondrial generation of reactive oxygen species (ROS) has recently emerged as a genetically controlled phenomenon, involved in complex intracellular signal transduction cascades that directly regulate cell survival and death in responses to environmental stressors. These cascades are involved in the pathogenesis of several major age-related diseases, such as cancer and neurodegeneration, and also appear to somehow regulate the “normal” ageing process.The present short review summarizes recent discoveries on mitochondrial reactive oxygen species regulation by p53, a tumor suppressor protein and p66shc, a protein implicated in the life-span determination. It also outlines the emerging network whereby these molecules cross-talk with each other and with the mitochondrial antioxidant system, namely MnSOD (SOD2), another life-span determining protein, to regulate oxidative stress in the organelle. This molecular circuit, which comprises two genetic determinants of longevity and a major tumor suppressor gene, also provides a theoretical framework connecting senescence and cancer.