Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Mol Cell. 2022 Oct 6;82(19):3661-3676.e8. doi: 10.1016/j.molcel.2022.09.006.
Mitochondrial Ca uptake, mediated by the mitochondrial Ca uniporter, regulates oxidative phosphorylation, apoptosis, and intracellular Ca signaling. Previous studies suggest that non-neuronal uniporters are exclusively regulated by a MICU1-MICU2 heterodimer. Here, we show that skeletal-muscle and kidney uniporters also complex with a MICU1-MICU1 homodimer and that human/mouse cardiac uniporters are largely devoid of MICUs. Cells employ protein-importation machineries to fine-tune the relative abundance of MICU1 homo- and heterodimers and utilize a conserved MICU intersubunit disulfide to protect properly assembled dimers from proteolysis by YME1L1. Using the MICU1 homodimer or removing MICU1 allows mitochondria to more readily take up Ca so that cells can produce more ATP in response to intracellular Ca transients. However, the trade-off is elevated ROS, impaired basal metabolism, and higher susceptibility to death. These results provide mechanistic insights into how tissues can manipulate mitochondrial Ca uptake properties to support their unique physiological functions.
线粒体通过线粒体钙单向转运体摄取 Ca2+，调节氧化磷酸化、细胞凋亡和细胞内 Ca2+信号转导。先前的研究表明，非神经元单向转运体仅受 MICU1-MICU2 异二聚体调节。在这里，我们表明骨骼肌和肾脏单向转运体也与 MICU1-MICU1 同源二聚体复合，并且人/鼠心脏单向转运体很大程度上缺乏 MICUs。细胞利用蛋白导入机制来微调 MICU1 同源和异源二聚体的相对丰度，并利用保守的 MICU 亚基间二硫键来保护正确组装的二聚体免受 YME1L1 的蛋白水解。使用 MICU1 同源二聚体或去除 MICU1 可以使线粒体更容易摄取 Ca2+，从而使细胞能够在响应细胞内 Ca2+瞬变时产生更多的 ATP。然而，这一权衡是 ROS 增加、基础代谢受损和更高的死亡易感性。这些结果为组织如何操纵线粒体 Ca2+摄取特性以支持其独特的生理功能提供了机制上的见解。
