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bioRxiv · 10.1101/781161

The mitochondrial Ca2+ uniporter MCU is required for normal glucose-stimulated insulin secretion in vitro and in vivo

Haythorne, E.·Georgiadou, E.·Dickerson, M.·Lopez Noriega, L.·Pullen, T. J.·da Silva Xavier, G.·Davis, S.·Martinez-Sanchez, A.·Semplici, F.·Rizzuto, R.·McGinty, J. A.·French, P. M.·Cane, M. C.·Jacobson, D. A.·Leclerc, I.·Rutter, G. A.
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Abstract

Mitochondrial oxidative metabolism is central to glucose-stimulated insulin secretion (GSIS). Whether Ca2+ uptake into pancreatic {beta}-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 Ca2+ transport across the inner mitochondrial membrane, its role in {beta}-cells has not previously been examined in vivo. Here, we inactivated the pore-forming subunit MCUa (MCU) selectively in the {beta}-cell in mice using Ins1Cre-mediated recombination. Glucose-stimulated mitochondrial Ca2+ accumulation, ATP production and insulin secretion were strongly (p<0.05 and p<0.01) inhibited in MCU null animals ({beta}MCU-KO) in vitro. Interestingly, cytosolic Ca2+ concentrations increased (p<0.001) whereas mitochondrial membrane depolarisation improved in {beta}MCU-KO animals. Male {beta}MCU-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 {beta}MCU-KO (<12 weeks), but not older animals. We conclude that MCU is crucial for mitochondrial Ca2+ uptake in pancreatic {beta}-cells and is required for normal GSIS. The apparent compensatory mechanisms which maintain glucose tolerance in {beta}MCU-KO mice remain to be established.

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Haythorne, E., Georgiadou, E., Dickerson, M., Lopez Noriega, L., Pullen, T. J., da Silva Xavier, G., Davis, S., Martinez-Sanchez, A., Semplici, F., Rizzuto, R., McGinty, J. A., French, P. M., Cane, M. C., Jacobson, D. A., Leclerc, I., Rutter, G. A.. 2019-09-25. The mitochondrial Ca2+ uniporter MCU is required for normal glucose-stimulated insulin secretion in vitro and in vivo. https://doi.org/10.1101/781161

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