The characterization of mitochondrial permeability transition in clonal pancreatic beta-cells. Multiple modes and regulation.
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.
Koshkin
Vasilij
V
Departments of Physiology and Medicine, University of Toronto, Toronto M5S 1A8, Canada.
Bikopoulos
George
G
Chan
Catherine B
CB
Wheeler
Michael B
MB
D000818:Animals; D002130:Calcium Phosphates / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000648:ultrastructure*; D008564:Membrane Potentials; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D016877:Oxidants / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
D002130:Calcium Phosphates; D016877:Oxidants; D017382:Reactive Oxygen Species; C020243:calcium phosphate; D006861:Hydrogen Peroxide