The mitochondrial Ca2+uniporter MCU is required for normal glucose-stimulated insulin secretionin vitroandin vivo

Mitochondrial oxidative metabolism is central to glucose-stimulated insulin secretion (GSIS). Whether Ca 2+ uptake into pancreatic β-cell mitochondria potentiates or antagonises this process is still a matter of debate. Although the mitochondrial importer (MCU) complex is thought to represent the main route for Ca 2+ transport across the inner mitochondrial membrane, its role in β-cells has not previously been examined in vivo . Here, we inactivated the pore-forming subunit MCUa (MCU) selectively in the β-cell in mice using Ins1 Cre-mediated recombination. Glucose-stimulated mitochondrial Ca 2+ accumulation, ATP production and insulin secretion were strongly (p<0.05 and p<0.01) inhibited in MCU null animals (βMCU-KO) in vitro . Interestingly, cytosolic Ca 2+ concentrations increased (p<0.001) whereas mitochondrial membrane depolarisation improved in βMCU-KO animals. Male βMCU-KO mice displayed impaired in vivo insulin secretion at 5 (p<0.001) but not 15 min. post intraperitoneal (IP) injection of glucose while the opposite phenomenon was observed following an oral gavage at 5 min. Unexpectedly, glucose tolerance was improved (p<0.05) in young βMCU-KO (<12 weeks), but not older animals. We conclude that MCU is crucial for mitochondrial Ca 2+ uptake in pancreatic β-cells and is required for normal GSIS. The apparent compensatory mechanisms which maintain glucose tolerance in βMCU-KO mice remain to be established.