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Activation of IP 3R channels located in the ER causes ER Ca 2+ store depletion. Such microdomains include the mitochondria-associated membranes (MAMs) where the endoplasmic reticulum (ER) membrane is within 10 to 30 nm from the outer mitochondrial membrane and Ca 2+ is transferred to mitochondria through closely apposed inositol-1,4,5-trisphosphate receptor (IP 3R) channels within ER membranes ( 19).Īctivation of plasma membrane (PM) receptors that couple to isoforms of phospholipase C by hormones, neurotransmitters, and growth factors causes the breakdown of membrane-associated phosphatidylinositol-4,5-bisphosphate into two second messengers: the membrane-bound diacylglycerol and the diffusible IP 3 ( 20). As such, mitochondrial Ca 2+ uptake is thought to take place at specialized microdomains where cytosolic Ca 2+ concentrations are high.
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The gatekeeping of MCU channel activity by MICU1/2 is relieved only when cytosolic Ca 2+ concentration is high (above ∼1.3 μM and above 500 nM when only MICU1 is present ( 13), but see also ( 14) where calculated Kd for Ca 2+ binding to MICU1/2 dimers is ∼650 nM). Ca 2+ extrusion from the mitochondrial matrix to the cytosol occurs through independent transporters, which include the mitochondrial Na +/Ca 2+ exchanger (NCLX) ( 17) and possibly the Ca 2+/H + exchanger Letm1 ( 18). Increased Ca 2+ concentration in the vicinity of MCU and Ca 2+ binding to the EF-hand domains of MICU1/2 disinhibits MCU channels and enhances mitochondrial Ca 2+ uptake ( 13, 14).
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MICU1/2 dimers keep the MCU channel closed under resting levels of free cytosolic Ca 2+. MCU forms a Ca 2+-selective tetrameric channel in the inner mitochondrial membrane that is regulated by the gate-keeping function of Ca 2+-binding MICU1/2 protein dimers ( 11, 12, 13, 14, 15, 16). Mitochondrial Ca 2+ uptake, which is driven by the steep voltage gradient across the inner mitochondrial membrane, occurs through a protein complex containing the pore-forming mitochondrial Ca 2+ uniporter (MCU) protein ( 9, 10). In particular, mitochondria are active participants in cellular Ca 2+ signaling ( 3, 4, 5, 6, 7, 8). In addition to their well-established role in cellular energy production and metabolism, mitochondria play a critical role in cellular signaling pathways that regulate gene transcription, cell survival, and function ( 1, 2). These findings highlight the critical dual function of the MCU not only in the acute Ca 2+ buffering by mitochondria but also in shaping endoplasmic reticulum and cytosolic Ca 2+ signals that regulate cellular transcription and function. Our data show that MCU has dual counterbalancing functions at the cytosol–mitochondria interface, whereby the cell-specific MCU-dependent cytosolic Ca 2+ clearance and buffering capacity of mitochondria reciprocally regulate interorganellar Ca 2+ transfer and nuclear factor for activated T cells nuclear translocation during receptor-evoked signaling. Physiological agonist stimulation in MCU-KO cells led to enhanced frequency of cytosolic Ca 2+ oscillations, endoplasmic reticulum Ca 2+ refilling, nuclear translocation of nuclear factor for activated T cells transcription factors, and cell proliferation, without altering inositol-1,4,5-trisphosphate receptor activity. Paradoxically, MCU knockout (MCU-KO) enhanced cytosolic Ca 2+ responses to store depletion. MCU activity sustains cytosolic Ca 2+ signaling by preventing Ca 2+-dependent inactivation of store-operated Ca 2+ release–activated Ca 2+ channels and by inhibiting Ca 2+ extrusion. Here, we used CRISPR/Cas9 gene knockout, subcellular Ca 2+ imaging, and mathematical modeling to show that MCU is a universal regulator of intracellular Ca 2+ signaling across mammalian cell types. However, how Ca 2+ uptake by the mitochondrial Ca 2+ uniporter (MCU) shapes receptor-evoked interorganellar Ca 2+ signaling is unknown. Mitochondrial Ca 2+ uptake tailors the strength of stimulation of plasma membrane phospholipase C–coupled receptors to that of cellular bioenergetics.