Regulatory effects of the mitochondrial energetic status on mitochondrial p66Shc

p66^Shc promotes apoptosis and controls the intracellular redox balance. A fraction of p66^Shc exists within mitochondria, where it oxidizes cytochrome c to form hydrogen peroxide, which in turn induces mitochondrial permeability and apoptosis. However, cells tolerate p66 ^Shc expression and accumulate oxidative damage under normal conditions, implying that the p66^Shc functions must be tightly regulated. Here we review available knowledge on the regulation of p66 ^Shc transcription, protein stabilization and post-translational modifications. In addition, we report novel investigations into the role of the mitochondrial import machinery on p66^Shc activation, which highlight the energetic status of mitochondria as a crucial determinant of p66 ^Shc function.