| First Author | Vais H | Year | 2020 |
| Journal | Proc Natl Acad Sci U S A | Volume | 117 |
| Issue | 35 | Pages | 21731-21739 |
| PubMed ID | 32801213 | Mgi Jnum | J:295968 |
| Mgi Id | MGI:6454510 | Doi | 10.1073/pnas.2005976117 |
| Citation | Vais H, et al. (2020) Coupled transmembrane mechanisms control MCU-mediated mitochondrial Ca(2+) uptake. Proc Natl Acad Sci U S A 117(35):21731-21739 |
| abstractText | Ca(2+) uptake by mitochondria regulates bioenergetics, apoptosis, and Ca(2+) signaling. The primary pathway for mitochondrial Ca(2+) uptake is the mitochondrial calcium uniporter (MCU), a Ca(2+)-selective ion channel in the inner mitochondrial membrane. MCU-mediated Ca(2+) uptake is driven by the sizable inner-membrane potential generated by the electron-transport chain. Despite the large thermodynamic driving force, mitochondrial Ca(2+) uptake is tightly regulated to maintain low matrix [Ca(2+)] and prevent opening of the permeability transition pore and cell death, while meeting dynamic cellular energy demands. How this is accomplished is controversial. Here we define a regulatory mechanism of MCU-channel activity in which cytoplasmic Ca(2+) regulation of intermembrane space-localized MICU1/2 is controlled by Ca(2+)-regulatory mechanisms localized across the membrane in the mitochondrial matrix. Ca(2+) that permeates through the channel pore regulates Ca(2+) affinities of coupled inhibitory and activating sensors in the matrix. Ca(2+) binding to the inhibitory sensor within the MCU amino terminus closes the channel despite Ca(2+) binding to MICU1/2. Conversely, disruption of the interaction of MICU1/2 with the MCU complex disables matrix Ca(2+) regulation of channel activity. Our results demonstrate how Ca(2+) influx into mitochondria is tuned by coupled Ca(2+)-regulatory mechanisms on both sides of the inner mitochondrial membrane. |
