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The pore-forming subunit MCU of the mitochondrial Ca2+ uniporter is required for normal glucose-stimulated insulin secretion in vitro and in vivo in mice – published online 29/04/2020

Fig from Georgiadou paper

Eleni Georgiadou, Elizabeth Haythorne, Matthew T. Dickerson, Livia Lopez-Noriega, Timothy J. Pullen, Gabriela da Silva Xavier, Samuel P. X. Davis, Aida Martinez-Sanchez, Francesca Semplici, Rosario Rizzuto, James A. McGinty, Paul M. French, Matthew C. Cane, David A. Jacobson, Isabelle Leclerc, Guy A. Rutter

Impaired Ca2+ signalling in the pancreatic beta cell contributes to deficiencies in insulin secretion in type 2 diabetes. Intramitochondrial oxidative metabolism is thought to be stimulated by increases in cytosolic Ca2+; the mitochondrial uniporter (MCU) complex and its associated regulatory proteins are proposed to be the main driving force of Ca2+ entry into mitochondria. In this issue, Georgiadou et al (https://doi.org/10.1007/s00125-020-05148-x) tested this hypothesis by selectively eliminating Mcu expression in the beta cells of mice. Mitochondrial Ca2+ uptake, ATP production, and insulin secretion in response to glucose stimulation were all substantially impaired, in vitro, in the absence of Mcu. However, the in vivo phenotype of mice lacking Mcu was more complex, with glucose-stimulated insulin release varying depending on test conditions (e.g. time after glucose injection, method of glucose administration and age of animals). The authors conclude that these findings suggest that altered mitochondrial Ca2+ uptake may contribute to defective insulin secretion in some forms of diabetes, and highlight MCU as a potential therapeutic target.

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