| First Author | Yoast RE | Year | 2021 |
| Journal | J Biol Chem | Volume | 297 |
| Issue | 4 | Pages | 101174 |
| PubMed ID | 34499925 | Mgi Jnum | J:314266 |
| Mgi Id | MGI:6787324 | Doi | 10.1016/j.jbc.2021.101174 |
| Citation | Yoast RE, et al. (2021) The Mitochondrial Ca(2+) uniporter is a central regulator of interorganellar Ca(2+) transfer and NFAT activation. J Biol Chem 297(4):101174 |
| abstractText | Mitochondrial Ca(2+) uptake tailors the strength of stimulation of plasma membrane phospholipase C-coupled receptors to that of cellular bioenergetics. However, how Ca(2+) uptake by the mitochondrial Ca(2+) uniporter (MCU) shapes receptor-evoked interorganellar Ca(2+) signaling is unknown. 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. 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. Paradoxically, MCU knockout (MCU-KO) enhanced cytosolic Ca(2+) responses to store depletion. 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. 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. 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. |
