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

ABSTRACT: Mitochondrial Ca²⁺ uptake, mediated by the mitochondrial Ca²⁺ uniporter, regulates oxidative phosphorylation, 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 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 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.

SUBMITTER: Tsai CW 

PROVIDER: S-EPMC9557913 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature