Mechanisms and significance of tissue-specific MICU regulation of the mitochondrial calcium uniporter complex

Mitochondrial Ca2+ uptake, mediated by the mitochondrial Ca2+ uniporter, regulates oxidative phosphoryla-tion, apoptosis, and intracellular Ca2+ signaling. Previous studies suggest that non-neuronal uniporters are exclusively regulated by a MICU1-MICU2 heterodimer. Here, we show that skeletal-muscle and kidney uni-porters 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 Ca2+ so that cells can produce more ATP in response to intracellular Ca2+ 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 Ca2+ uptake properties to support their unique physiological functions.

Automated summary

Mitochondrial Ca2+ uptake is regulated by the mitochondrial Ca2+ uniporter and plays important roles in various physiological functions. Skeletal-muscle and kidney uniporters also interact with a MICU1-MICU1 homodimer, while cardiac uniporters mostly lack MICUs. Cells use protein-import machinery to regulate the abundance of MICU1 homo- and heterodimers and protect properly assembled dimers from proteolysis. However, enhancing Ca2+ uptake can lead to increased ATP production, but also elevated ROS levels, impaired basal metabolism, and higher susceptibility to death.