p66SHC promotes T cell apoptosis by inducing mitochondrial dysfunction and impaired Ca2+ homeostasis

p66Shc, a redox enzyme that enhances reactive oxygen species (ROS) production by mitochondria, promotes T cell apoptosis. We have addressed the mechanisms regulating p66Shc-dependent apoptosis in T cells exposed to supraphysiological increases in [Ca 2+ ] c . p66Shc expression resulted in profound mitochondrial dysfunction in response to the Ca 2+ ionophore A23187, as revealed by dissipation of mitochondrial transmembrane potential, cytochrome c release and decreased ATP levels. p66Shc expression also caused a dramatic alteration in the cells’ Ca 2+ -handling ability, which resulted in Ca 2+ overload after A23187 treatment. The impairment in Ca 2+ homeostasis was ROS dependent and caused by defective Ca 2+ extrusion due at least in part to decreased plasma membrane ATPase (PMCA) expression. Both effects of p66Shc required Ca 2+ -dependent serine-36 phosphorylation. The mitochondrial effects of p66Shc were potentiated by but not strictly dependent on the rise in [Ca 2+ ] c . Thus, Ca 2+ -dependent p66Shc phosphorylation causes both mitochondrial dysfunction and impaired Ca 2+ homeostasis, which synergize in promoting T cell apoptosis.