Mitochondrial calcium and the permeability transition in cell death

Abstract

Dysregulation of Ca2+ has long been implicated to be important in cell injury. A Ca2+-linked process important in necrosis and apoptosis (or necrapoptosis) is the mitochondrial permeability transition (MPT). In the MPT, large conductance permeability transition (PT) pores open that make the mitochondrial inner membrane abruptly permeable to solutes up to 1500 Da. The importance of Ca2+ in MPT induction varies with circumstance. Ca2+ overload is sufficient to induce the MPT. By contrast after ischemia-reperfusion to cardiac myocytes, Ca2+ overload is the consequence of bioenergetic failure after the MPT rather than its cause. In other models, such as cytotoxicity from Reye-related agents and storage-reperfusion injury to liver grafts, Ca2+ appears to be permissive to MPT onset. Lastly in oxidative stress, increased mitochondrial Ca2+ and ROS generation act synergistically to product the MPT and cell death. Thus, the exact role of Ca2+ for inducing the MPT and cell death depends on the particular biologic setting.

Role of mitochondrial function in the protective effects of ischaemic postconditioning on ischaemia/reperfusion cerebral damage

“…Mitochondrial swelling is related to the opening of the mitochondrial permeability transition pore, 49 with calcium ion (Ca 2þ ) concentration being proportional to the extent of pore opening. 50,51 Overload of Ca 2þ is a pathological characteristic of ischaemia/reperfusion. 52 Ischaemic postconditioning has been shown to limit Ca 2þ overload via modulating the NCX3 isoform of the sodium/calcium ion (Na þ /Ca 2þ ) exchanger.…”

(+)α-Tocopheryl succinate inhibits the mitochondrial respiratory chain complex I and is as effective as arsenic trioxide or ATRA against acute promyelocytic leukemia in vivo

“…MPT is a Ca 2 þ -dependent permeabilization of the inner mitochondrial membrane, which is caused by diverse stimuli including oxidative stress and is believed to be involved in cell death. In MPT, the inner and outer mitochondrial membranes communicate via high-conductance channels that dissipate Dc and release cytochrome c. 22 However, MPT was not the cause because NB4 cells under the same condition did not release cytochrome c before 12 h treatment (Figure 2c, insert) and isolated rat liver mitochondria did not swell in response to a-TOS (data not shown). Next, we evaluate if this immediate effect on Dc could be explained by the a-TOS action on AKT and NFkB signaling, as these pathways had been described as targets.…”

UCP1 deficiency causes brown fat respiratory chain depletion and sensitizes mitochondria to calcium overload-induced dysfunction

“…The complex I Q site inhibitor rotenone inhibits RET-driven superoxide production during succinate oxidation (29,(34)(35)(36)(37). Critically, mitochondrial ROS has been demonstrated to potentiate calcium-dependent permeability transition (25,38). Moreover, succinate has been shown to generate significant amounts of ROS in BAT, which is exacerbated in the absence of UCP1 (7,8).…”