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Involvement of Ca 2+ and ROS in α‐tocopheryl succinate‐induced mitochondrial permeabilization
Author(s) -
Gogvadze Vladimir,
Norberg Erik,
Orrenius Sten,
Zhivotovsky Boris
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25204
Subject(s) - mitochondrion , cytochrome c , mitochondrial permeability transition pore , apoptosis , mitochondrial apoptosis induced channel , microbiology and biotechnology , reactive oxygen species , biology , mitochondrial ros , inner mitochondrial membrane , membrane potential , jurkat cells , cytochrome , biochemistry , programmed cell death , immunology , immune system , t cell , enzyme
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, α‐tocopheryl succinate (α‐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 α‐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, α‐TOS stimulates rapid Ca 2+ entry into the cells with subsequent accumulation of Ca 2+ in mitochondria—a prerequisite step for MPT induction. Alteration of mitochondrial Ca 2+ buffering capacity was observed as early as 8 hr after incubation with α‐TOS, when no activation of Bax was yet detected. Ca 2+ accumulation in mitochondria was important for apoptosis progression, since inhibition of mitochondrial Ca 2+ uptake significantly mitigated the apoptotic response. Importantly, Ca 2+ ‐induced mitochondrial destabilization might cooperate with Bax‐mediated mitochondrial outer membrane permeabilization to induce cytochrome c release from mitochondria.