Mitochondrial clearance of calcium facilitated by MICU2 controls insulin secretion

Vishnu, Neelanjan; Hamilton, Alexander; Bagge, Annika; Wernersson, Anya; Cowan, Elaine; Barnard, H. C.; Sancak, Yasemin; Kamer, Kimberli J.; Sartipy, Peter; Fex, Malin; Tengholm, Anders; Mootha, Vamsi K.; Nicholls, David G.; Mulder, Hindrik

doi:10.1016/j.molmet.2021.101239

Cited by 17 publications

(20 citation statements)

References 83 publications

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“…The requirement for mitochondrial calcium for insulin secretion has been shown in pancreatic cells where knockdown of the Na + -Ca + exchanger altered mitochondrial calcium transport, resulting in delayed glucose-stimulated insulin release without changes in ATP production ( 45 ). Recently, reduced mitochondrial calcium transport has been shown to reduce insulin secretion ( 46 ). Under normal conditions and basal insulin levels, cellular calcium levels were sufficient in the N434S variant mice to meet the demand for insulin secretion.…”

Section: Discussionmentioning

confidence: 99%

A common genetic variant of a mitochondrial RNA processing enzyme predisposes to insulin resistance

et al. 2021

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Mitochondrial energy metabolism plays an important role in the pathophysiology of insulin resistance. Recently, a missense N437S variant was identified in the MRPP3 gene, which encodes a mitochondrial RNA processing enzyme within the RNase P complex, with predicted impact on metabolism. We used CRISPR-Cas9 genome editing to introduce this variant into the mouse Mrpp3 gene and show that the variant causes insulin resistance on a high-fat diet. The variant did not influence mitochondrial gene expression markedly, but instead, it reduced mitochondrial calcium that lowered insulin release from the pancreatic islet  cells of the Mrpp3 variant mice. Reduced insulin secretion resulted in lower insulin levels that contributed to imbalanced metabolism and liver steatosis in the Mrpp3 variant mice on a high-fat diet. Our findings reveal that the MRPP3 variant may be a predisposing factor to insulin resistance and metabolic disease in the human population.

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Section: Discussionmentioning

confidence: 99%

A common genetic variant of a mitochondrial RNA processing enzyme predisposes to insulin resistance

et al. 2021

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“…MICU2 forms a disulfide bond with MICU1 and is involved in Ca 2+ sensing in conjunction with MICU1. β-cell siRNA mediated MICU2 knockdown attenuates GSIS by 41-51 percent [38]. Similarly, mitochondrial Ca 2+ uptake is attenuated, the ETC is not stimulated, and ATP is not transported to the cell membrane to close the K + channels.…”

Section: Micu2 Functionmentioning

confidence: 98%

“…These data indicate that MICU2 is essential for sustained GSIS in the pancreatic β-cell. MICU2 deletion results in Ca 2+ accumulation in the submembrane compartment in the mitochondrial matrix of the β-cell [38].…”

Section: Micu2 Functionmentioning

confidence: 99%

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Ca2+ Sensors Assemble: Function of the MCU Complex in the Pancreatic Beta Cell

Allen

Tessem

2022

Cells

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The Mitochondrial Calcium Uniporter Complex (MCU Complex) is essential for β-cell function due to its role in sustaining insulin secretion. The MCU complex regulates mitochondrial Ca2+ influx, which is necessary for increased ATP production following cellular glucose uptake, keeps the cell membrane K+ channels closed following initial insulin release, and ultimately results in sustained insulin granule exocytosis. Dysfunction in Ca2+ regulation results in an inability to sustain insulin secretion. This review defines the functions, structure, and mutations associated with the MCU complex members mitochondrial calcium uniporter protein (MCU), essential MCU regulator (EMRE), mitochondrial calcium uptake 1 (MICU1), mitochondrial calcium uptake 2 (MICU2), and mitochondrial calcium uptake 3 (MICU3) in the pancreatic β-cell. This review provides a framework for further evaluation of the MCU complex in β-cell function and insulin secretion.

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“…Under basal condition, intramitochondrial calcium ([Ca 2+ ] m ) is low, comparable to that of [Ca 2+ ] c (<100nM) (91). Calcium is transported into mitochondria through voltage-dependent anion channels (VDACs) in the outer mitochondrial membrane and the mitochondrial Ca 2+ uniporter (MCU) (92) in the inner mitochondrial membrane, while calcium exits the mitochondria through the Na + /Ca 2+ exchanger (NCLX) (93). Endoplasmic reticulum is another source of Ca 2+ for mitochondria, and tethering molecules such as GRP75 and mitofusins are present in microdomains between ER and mitochondria to facilitate calcium flow from ER (which has basal calcium concentration of ~5mM) into the mitochondria (94,95).…”

Section: Mitochondrial Calcium Dynamics In B-cellsmentioning

confidence: 99%

Beta-Cell Adaptation to Pregnancy – Role of Calcium Dynamics

Pretorius

Huang

2022

Front. Endocrinol.

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During pregnancy, the mother develops insulin resistance to shunt nutrients to the growing fetus. As a result, the maternal islets of Langerhans undergo several changes to increase insulin secretion in order to maintain glucose homeostasis and prevent the development of gestational diabetes. These changes include an increase in β-cell proliferation and β-cell mass, upregulation of insulin synthesis and insulin content, enhanced cell-to-cell communication, and a lowering of the glucose threshold for insulin secretion, all of which resulting in an increase in glucose-stimulated insulin secretion. Emerging data suggests that a change in intracellular calcium dynamics occurs in the β-cell during pregnancy as part of the adaptive process. Influx of calcium into β-cells is crucial in the regulation of glucose-stimulated insulin secretion. Calcium fluxes into and out of the cytosol, endoplasmic reticulum, and mitochondria are also important in controlling β-cell function and survival. Here, we review calcium dynamics in islets in response to pregnancy-induced changes in hormones and signaling molecules, and how these changes may enhance insulin secretion to stave off gestational diabetes.

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Mitochondrial clearance of calcium facilitated by MICU2 controls insulin secretion

Cited by 17 publications

References 83 publications

A common genetic variant of a mitochondrial RNA processing enzyme predisposes to insulin resistance

A common genetic variant of a mitochondrial RNA processing enzyme predisposes to insulin resistance

Ca2+ Sensors Assemble: Function of the MCU Complex in the Pancreatic Beta Cell

Beta-Cell Adaptation to Pregnancy – Role of Calcium Dynamics

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