MitoNEET-Parkin effects in pancreatic α- and β-cells, cellular survival, and intrainsular cross talk

Mitochondrial metabolism plays an integral role in glucose-stimulated insulin secretion (GSIS) in β-cells. In addition, the diabetogenic role of glucagon released from α-cells plays a major role in the etiology for both type 1 and type 2 diabetes, since un-opposed hyperglucagonemia is a pertinent contributor to diabetic hyperglycaemia. Titrating expression levels of the mitochondrial protein mitoNEET is a powerful approach to fine-tune mitochondrial capacity of cells. Mechanistically, β-cell-specific mitoNEET induction causes hyperglycaemia and glucose intolerance due to activation of a Parkin-dependent mitophagic pathway, leading to the formation of vacuoles and uniquely structured mitophagosomes. Induction of mitoNEET in α-cells leads to fasting-induced hypoglycaemia and hypersecretion of insulin during GSIS. MitoNEET challenged α-cells exert potent anti-apoptotic effects on β-cells and prevent cellular dysfunction associated with mitoNEET overexpression in β-cells. These observations identify that reduced mitochondrial function in α-cells exerts potently protective effects on β-cells, preserving β-cell viability and mass.