Molecular and cellular mechanisms underlying tissue-specific MICU-dimer assembly in the mitochondrial calcium uniporter complex.

Abstract

The mitochondria calcium uniporter is a multi-subunit Ca2+ channel that mediates mitochondrial Ca2+ uptake. It regulates multiple physiological processes including oxidative phosphorylation, intracellular Ca2+ signaling, and apoptosis. The uniporter is activated by Ca2+—It remains closed at resting cellular [Ca2+] and becomes open when stimulated by intracellular Ca2+ signals. Previous work suggests that in non-neuronal cells, such Ca2+ activation is exclusively mediated by a MICU1-2 heterodimer. Here, we find that kidney and skeletal muscle uniporters also complex with a MICU1-1 homodimer. Kinetic analyses show that the uniporter is more readily activated by Ca2+ when complexed with MICU1-1 (K0.5=0.6 µM) than MICU1-2 (K0.5=1.2 µM). Thus, tissues can create specific mitochondrial Ca2+ uptake properties by varying the population of MICU1-1 and MICU1-2. Here, we demonstrate two findings to establish the mechanisms by which cells control the relative abundance of these MICU dimers. Firstly, MICU1 has a >50-fold tendency to dimerize with MICU1 than MICU2; Secondly, mitochondria import MICU2 faster than MICU1 to maintain an excess of MICU2 monomers while the MICU1 monomer is depleted. In several types of cells, due to this MICU2 excess in mitochondria, an imported MICU1 monomer can only encounter MICU2 to form MICU1-2 heterodimers. Other types of cells can produce MICU1-1 by importing MICU1 slightly faster so MICU1 could form homodimers due to its higher tendency to homodimerize. Contradicting previous studies, we show that a conserved MICU intersubunit disulfide is not required for the MICUs to regulate uniporter transport. Instead, this disulfide functions to protect properly assembled MICU dimers from proteolytic degradation by YME1L1. These results shed light on the molecular and cellular mechanisms by which different types of cells can produce unique mitochondrial Ca2+ uptake properties to fulfill their unique physiological functions.