MITOCHONDRIAL ACTIVATIONS IN PANCREATIC BETA–CELLS: Ca2+- AND REDOX- DEPENDENT SIGNAL TRANSDUCTION

The pancreatic beta-cells possess a unique signal transduction system linking metabolism of nutrients to the secretion of insulin. Mitochondria play a crucial role in this process through the generation of ATP and other factors, raising intracellular Ca2+ for the stimulation of insulin secretion. Here we have compared the signals generated by glucose and the mitochondrial complex-II substrate methylsuccinate, in pancreatic INS-1E beta-cells. Glucose and methylsuccinate promoted distinct patterns of oxygen consumption and induced nutrient-stimulated insulin secretion. Surprisingly, only glucose was able to initiate intracellular [Ca2+] rises. In contrast, methylsuccinate-stimulated INS-1E cells showed little Ca2+ rises and even depression of the signals. Glucose was further associated with an increase in the autofluorescence of NAD(P)H. Consistently, the redox-sensitive roGFP1 signal revealed a net reduction of the mitochondrial matrix in response to glucose. This redox response was less pronounced following methylsuccinate stimulation, demonstrating a less reduced matrix redox state. Our findings suggest a possible involvement of methylsuccinate-dependent electron flux through complex-I/complex-II in insulin secretion. We propose that, in addition to the classical Ca2+-dependent signal transduction, redox-sensitive proteins associated with mitochondria may promote insulin secretion without the need for large cytosolic Ca2+ rises.