Mitochondrial Ca2+ signaling

Abstract

Mitochondrial Ca²⁺ regulation is crucial for bioenergetics and cellular signaling. The mechanisms controlling mitochondrial calcium homeostasis have been recently unraveled with the discovery of mitochondrial inner membrane proteins that regulate mitochondrial Ca²⁺ uptake and extrusion. Mitochondrial Ca²⁺ uptake depends on a large complex of proteins centered around the Ca²⁺ channel protein, mitochondrial Ca²⁺ uniporter (MCU) in close interactions with several regulatory subunits (MCUb, EMRE, MICU1, MICU2). Mitochondrial Ca²⁺ extrusion is mainly mediated by the mitochondrial Na⁺/Ca²⁺/Li⁺ exchanger (NCLX). Here, we review the major players of mitochondrial Ca²⁺ homeostasis and their physiological functions.

Keywords: Ca(2+) signaling; Cell metabolism; MCU; Mitochondria associated membranes; NCLX; Reactive oxygen species; physiology of mitochondrial Ca(2+).

Figure 1:. Mitochondrial Ca²⁺ homeostasis: Ca²⁺ cycling between the cytosol, ER, and mitochondria.

Activation of phospholipase C (PLC)-coupled agonists produce the soluble cytosolic second messenger inositol-1,4,5 trisphosphate (ΓΡ3) which binds to its receptor, the IP₃R, and cause Ca²⁺ release from the ER to the cytosol. Through mitochondria associated membranes (MAMs), Ca²⁺ released from IP₃R crosses the OMM through VDAC and enters the intermembrane space (IMS) before reaching the mitochondrial matrix through MCU. Depletion of ER Ca²⁺ concentration also triggers the activation of store-operated Ca²⁺ entry (SOCE) into the cytosol across the plasma membrane through ORAI1 channels. Ca²⁺ entry through SOCE is buffered back into the ER by the action of sarcoplasmic/endoplasmic reticulum ATPase (SERCA) pumps or can be taken up by mitochondria through MCU.VDAC resides in the outer mitochondrial membrane (OMM) and brings Ca²⁺ in the intermembrane space (IMS) of mitochondria. Once Ca²⁺ concentration in the IMS is high, it is sensed by the gatekeeper proteins MICU1/MICU2 which disinhibit MCU allowing Ca²⁺ uptake into the mitochondrial matrix. Matrix Ca²⁺ is pumped back to the IMS through the Na⁺/Ca²⁺ exchange (NCLX) and Letml.

Figure 2:. Components of the MCU complex and its regulation by Ca²⁺.

A) MCU, MICU1/2/3, EMRE, MCUR1, and MCUb form the Uniporter complex. When the Ca²⁺ concentration in mitochondrial intermembrane space (IMS) is low, MICU2 inhibits MCU activity. B) When the IMS Ca²⁺ concentration is high, Ca²⁺ binds to MICU1 and activates MCU to cause Ca²⁺ uptake into the mitochondrial matrix. EMRE is an essential subunit that is required for MCU function and helps tether MICU1/MICU2 to the MCU complex. The yellow dots represent Ca²⁺.