EMRE Is an Essential Component of the Mitochondrial Calcium Uniporter Complex

Abstract

The mitochondrial uniporter is a highly selective calcium channel in the organelle’s inner membrane. Its molecular components include the EF-hand containing proteins mitochondrial calcium uptake 1 (MICU1) and MICU2 and the pore forming subunit mitochondrial calcium uniporter (MCU). We sought to achieve a full molecular characterization of the uniporter holocomplex (uniplex). Quantitative mass spectrometry of affinity-purified uniplex recovered MICU1 and MICU2, MCU and its paralog MCUb, and essential MCU regulator (EMRE), a previously uncharacterized protein. EMRE is a 10 kD, metazoan specific protein with a single transmembrane domain. In its absence, uniporter channel activity was lost despite intact MCU expression and oligomerization. EMRE was required for the interaction of MCU with MICU1 and MICU2. Hence, EMRE is essential for in vivo uniporter current and additionally bridges the calcium-sensing role of MICU1 and MICU2 with the calcium conducting role of MCU.

Reduced mitochondrial Ca2+ transients stimulate autophagy in human fibroblasts carrying the 13514A>G mutation of the ND5 subunit of NADH dehydrogenase

“…However, as the defect in mitochondrial Ca 2+ accumulation in Pat#1 cells is also evident in permeabilized cells (Supplementary Figure S3c), we conclude that the assembly of the MCU complex has a major role in lowering mitochondrial Ca 2+ uptake. In particular, Pat#1 and Pat#2 (but not Pat#3 and Pat#4) cells show a significant decrease of MICU1 and EMRE levels, known as positive MCU regulators, [15][16][17][18] and an increase in the expression of MICU2. MICU2 is a negative MCU modulator as it forms the MICU1/ MICU2 heterodimer, thus sequestering MICU1 and preventing the MICU1 homodimer stimulatory activity on MCU, as we recently demonstrated.…”

“…The pore region is composed of MCU, its isoform MCUb 14 and essential MCU regulator (EMRE). 15 The channel is gated by the Ca 2+ -sensitive proteins mitochondrial Ca 2+ uptake 1 (MICU1) and MICU2 [16][17][18][19] and further regulated by the SLC25A23 protein. 20 As to its cellular function, mitochondrial Ca 2+ has been shown to stimulate ATP production by positive regulation of three key dehydrogenases of the tricarboxylic acid cycle 21 and of the ETC.…”

Inseparable tandem: evolution chooses ATP and Ca2+to control life, death and cellular signalling

“…An MCU-encoding gene is found in Trypanosoma [31]. Paramecium also possesses MCU and associated MIUC protein, as well as the MCU regulator, EMRE [176,178]. Accordingly, in Paramecium, during synchronous exocytosis, Ca 2þ rapidly (on a subsecond time scale) flushes into mitochondria; most of the Ca 2þ , however, is released back into the cytosol within seconds, with only a minor fraction remaining in the organelle [109,179].…”

“…This requires rapid crosstalk between the cytosol and the organelle. The key player is the mitochondrial calcium uniporter (MCU) for rapid Ca 2þ influx [176,177]; the MCU and its regulators are present at the protozoan level. An MCU-encoding gene is found in Trypanosoma [31].…”

Metabolic Syndrome in Aging Heart: Molecular Insights

“…The most important contributor to Mito Ca 2+ uptake is the mitochondrial calcium uniporter complex (MCUC) with the MCU serving as a highly selective channel that moves Ca 2+ ions across the IMM dependent on Mito membrane potential (ΔΨm). Recently, integrative genomics methods enabled the discovery of the molecular nature of MCU, and its regulatory subunits, MCUb, MICU1 and 2, and EMRE [22][23][24][25][26][27]. MCU is an integral membrane protein with two transmembrane domains that forms the pore through which Mito Ca 2+ currents are conducted across the IMM [22,23].…”