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

Abstract

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.

Keywords: Ca2+ flux; EMRE; MCU complex; MICU1; MICU2; MICU3; pancreatic β-cell.

Figure 1

Mitochondrial Calcium Flux and GSIS in the Pancreatic β-cell. Under high blood glucose conditions, glucose enters the β-cell via the GLUT2 transporter. Glucose is then shunted to glycolysis, the TCA cycle, and the electron transport chain to generate ATP. ATP closes the K_ATP channels, which results in insulin granule exocytosis. Ca²⁺ is shunted to the mitochondria to further stimulate ATP production and cause continued insulin secretion. This figure was created with biorender.com.

Figure 2

Mitochondrial Calcium Uniporter Complex under low and high cytosolic Ca²⁺ conditions. Under low cytosolic Ca²⁺ conditions the MCU is found in a closed state that impedes mitochondrial Ca²⁺ entry. Under elevated cytosolic Ca²⁺ conditions the MCU complex in the inner mitochondrial membrane is opened through Ca²⁺ binding, thus resulting in mitochondrial Ca²⁺ entry. MCU-Mitochondrial Calcium Uniporter, MICU1—Mitochondrial calcium uptake 1, MICU2—Mitochondrial calcium uptake 2, MICU3—Mitochondrial calcium uptake 3, and EMRE-essential MCU regulator. This figure was created with biorender.com.

Figure 3

Mitochondrial Calcium Uniporter and MICU1 interaction under high cytosolic Ca²⁺ conditions. Under high cytosolic Ca²⁺ conditions the MCU complex opens to allow mitochondrial Ca²⁺ influx. The MCU complex opens due to interactions between MCU protein aspartate residues and the cytosolic Ca²⁺. When cytosolic Ca²⁺ is low the MICU1 arginine fingers bind to the MCU protein aspartate residues and closes the MCU complex. MCU-Mitochondrial Calcium Uniporter, MICU1—Mitochondrial calcium uptake 1. This figure was created with biorender.com.

Figure 4

Mitochondrial Calcium Uniporter Complex under high mitochondrial matrix Ca²⁺ conditions. Increased mitochondrial matrix Ca²⁺ interacts with the EMRE tail that extends into the mitochondrial matrix. This interaction causes a conformational change that results in the EMRE tail blocking the MCU complex. This interaction prevents further influx of Ca²⁺ into the mitochondria. MCU-Mitochondrial Calcium Uniporter, MICU1—Mitochondrial calcium uptake 1, MICU2—Mitochondrial calcium uptake 2, MICU3—Mitochondrial calcium uptake 3, and EMRE-essential MCU regulator This figure was created with biorender.com.