Abstract
Mitochondrial permeability transition (MPT), which contributes substantially to the regulation of normal mitochondrial metabolism, also plays a crucial role in the initiation of cell death. It is known that MPT is regulated in a tissue-specific manner. The importance of MPT in the pancreatic beta-cell is heightened by the fact that mitochondrial bioenergetics serve as the main glucose-sensing regulator and energy source for insulin secretion. In the present study, using MIN6 and INS-1 beta-cells, we revealed that both Ca(2+)-phosphate- and oxidant-induced MPT is remarkably different from other tissues. Ca(2+)-phosphate-induced transition is accompanied by a decline in mitochondrial reactive oxygen species production related to a significant potential dependence of reactive oxygen species formation in beta-cell mitochondria. Hydroperoxides, which are indirect MPT co-inducers active in liver and heart mitochondria, are inefficient in beta-cell mitochondria, due to the low mitochondrial ability to metabolize them. Direct cross-linking of mitochondrial thiols in pancreatic beta-cells induces the opening of a low conductance ion permeability of the mitochondrial membrane instead of the full scale MPT opening typical for liver mitochondria. Low conductance MPT is independent of both endogenous and exogenous Ca(2+), suggesting a novel type of nonclassical MPT in beta-cells. It results in the conversion of electrical transmembrane potential into DeltapH instead of a decrease in total protonmotive force, thus mitochondrial respiration remains in a controlled state. Both Ca(2+)- and oxidant-induced MPTs are phosphate-dependent and, through the "phosphate flush" (associated with stimulation of insulin secretion), are expected to participate in the regulation in beta-cell glucose-sensing and secretory activity.
Highlights
Mitochondrial permeability transition (MPT), which contributes substantially to the regulation of normal mitochondrial metabolism, plays a crucial role in the initiation of cell death
Calcium Phosphate-induced MPT and Mitochondrial reactive oxygen species (ROS) Production—Because experiments in permeabilized -cells were supplemented with respiratory substrate but not ATP, only mitochondrial Ca2ϩ stores were available under these experimental conditions
Our findings show that in the pancreatic -cell lines MIN6 and INS-1, MPT may function in several distinct modes
Summary
It results in the conversion of electrical transmembrane potential into ⌬pH instead of a decrease in total protonmotive force, mitochondrial respiration remains in a controlled state Both Ca2؉- and oxidant-induced MPTs are phosphate-dependent and, through the “phosphate flush” (associated with stimulation of insulin secretion), are expected to participate in the regulation in -cell glucose-sensing and secretory activity. We demonstrate that mitochondria from both MIN6 and INS-1 cells exhibited novel MPT characteristics as follows: (i) Ca2ϩ-phosphate-induced MPT is associated with reduced (instead of enhanced) mitochondrial ROS formation; (ii) initiation of MPT with hydroperoxides does not happen in intact -cell mitochondria but requires exogenous glutathione peroxidase mimetic activity; and (iii) nonclassical MPT, caused by thiol cross-linking, is entirely independent of mitochondrial Ca2ϩ and causes the interconversion of electrical and chemical components of the mitochondrial protonmotive force. This supports a potential link between insulin-secretory activity and Ca2ϩ- and oxidant-induced MPT in the -cell
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