Protein kinase C beta and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66(Shc)

The 66-kD isoform of the growth factor adapter Shc (p66Shc) translates oxidative damage into cell death by acting as reactive oxygen species (ROS) producer within mitochondria. However, the signalling link between cellular stress and mitochondrial pro-apoptotic activity of p66Shc was not known. We demonstrate that Protein Kinase C , activated by oxidative conditions in the cell, induces phosphorylation of p66Shc and triggers mitochondrial accumulation of the protein after it is recognised by the prolyl-isomerase Pin1. Once imported, p66Shc causes alterations of mitochondrial Ca2+ responses and three-dimensional structure, thus inducing apoptosis. These data identify a signalling route that activates an apoptotic inducer shortening the lifespan and could be a potential target of pharmacological approaches to inhibit aging.