The mitochondrial Ca 2+ uniporter MCU is required for normal glucose-stimulated insulin secretion in vitro and in vivo
The mitochondrial Ca 2+ uniporter MCU is required for normal glucose-stimulated insulin secretion in vitro and in vivo
Abstract Mitochondrial oxidative metabolism is central to glucose-stimulated insulin secretion (GSIS). Whether Ca2+ 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 Ca2+ 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 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 (βMCU-KO) in vitro. Interestingly, cytosolic Ca2+ 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 Ca2+ 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.
Haythorne Elizabeth、Dickerson Matthew T.、McGinty James A.、Jacobson David A.、Leclerc Isabelle、Davis Samuel P.X.、Martinez-Sanchez Aida、Rizzuto Rosario、da Silva Xavier Gabriela、French Paul M.、Rutter Guy A.、Semplici Francesca、Cane Matthew C.、Lopez-Noriega Livia、Georgiadou Eleni、Pullen Timothy J.
Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College LondonDepartment of Molecular Physiology and Biophysics, Vanderbilt UniversityPhotonics Group, Department of Physics, Imperial College LondonDepartment of Molecular Physiology and Biophysics, Vanderbilt UniversitySection of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College LondonPhotonics Group, Department of Physics, Imperial College LondonSection of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College LondonDepartment of Biomedical Sciences, University of PadovaSection of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College LondonPhotonics Group, Department of Physics, Imperial College LondonSection of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College LondonSection of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College LondonSection of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College LondonSection of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College LondonSection of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College LondonSection of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London
基础医学生理学生物化学
Haythorne Elizabeth,Dickerson Matthew T.,McGinty James A.,Jacobson David A.,Leclerc Isabelle,Davis Samuel P.X.,Martinez-Sanchez Aida,Rizzuto Rosario,da Silva Xavier Gabriela,French Paul M.,Rutter Guy A.,Semplici Francesca,Cane Matthew C.,Lopez-Noriega Livia,Georgiadou Eleni,Pullen Timothy J..The mitochondrial Ca 2+ uniporter MCU is required for normal glucose-stimulated insulin secretion in vitro and in vivo[EB/OL].(2025-03-28)[2025-04-28].https://www.biorxiv.org/content/10.1101/781161.点此复制
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