Involvement of Ca2+ and ROS in α-tocopheryl succinate-induced mitochondrial permeabilization

Release of mitochondrial proteins such as cytochrome c, AIF, Smac/Diablo etc., plays a crucial role in apoptosis induction. A redox-silent analog of vitamin E, a-tocopheryl succinate (alpha-TOS), was shown to stimulate cytochrome c release via production of reactive oxygen species (ROS) and Bax-mediated permeabilization of the outer mitochondrial membrane. Here we show that a-TOS facilitates mitochondrial permeability transition (MPT) in isolated rat liver mitochondria, Tet21N neuroblastoma cells and Jurkat T-lymphocytes. In particular, in addition to ROS production, a-TOS stimulates rapid Ca2+ entry into the cells with subsequent accumulation of Ca2+ in mitochondria-a prerequisite step for MPT induction. Alteration of mitochondrial Ca2+ buffering capacity was observed as early as 8 hr after incubation with a-TOS, when no activation of Bax was yet detected. Ca2+ accumulation in mitochondria was important for apoptosis progression, since inhibition of mitochondrial Ca2+ uptake significantly mitigated the apoptotic response. Importantly, Ca2+-induced mitochondrial destabilization might cooperate with Bax-mediated mitochondrial outer membrane permeabilization to induce cytochrome c release from mitochondria.