Open AccessStructure and mechanism of the mitochondrial Ca2+ uniporter holocomplex
Author(s) -
Meiqiang Fan,
Jinru Zhang,
Chen-Wei Tsai,
Benjamin J. Orlando,
Madison Rodriguez,
Yan Xu,
Maofu Liao,
Ming-Feng Tsai,
Liang Feng
Publication year - 2020
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-020-2309-6
Subject(s) - uniporter , cytosol , mitochondrion , microbiology and biotechnology , protein subunit , gating , calcium signaling , gradualism , mechanism (biology) , chemistry , biophysics , biology , biochemistry , signal transduction , genetics , enzyme , physics , quantum mechanics , gene
Mitochondria take up Ca 2+ through the mitochondrial calcium uniporter complex to regulate energy production, cytosolic Ca 2+ signalling and cell death 1,2 . In mammals, the uniporter complex (uniplex) contains four core components: the pore-forming MCU protein, the gatekeepers MICU1 and MICU2, and an auxiliary subunit, EMRE, essential for Ca 2+ transport 3-8 . To prevent detrimental Ca 2+ overload, the activity of MCU must be tightly regulated by MICUs, which sense changes in cytosolic Ca 2+ concentrations to switch MCU on and off 9,10 . Here we report cryo-electron microscopic structures of the human mitochondrial calcium uniporter holocomplex in inhibited and Ca 2+ -activated states. These structures define the architecture of this multicomponent Ca 2+ -uptake machinery and reveal the gating mechanism by which MICUs control uniporter activity. Our work provides a framework for understanding regulated Ca 2+ uptake in mitochondria, and could suggest ways of modulating uniporter activity to treat diseases related to mitochondrial Ca 2+ overload.