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Essential MCU regulator (EMRE) in the Mitochondrial Calcium Uniporter (MCU) Complex

Reviewer and Curator: Larry H. Bernstein, MD, FCAP 

UPDSTED on 9/22/2018

J Biol Chem. 2016 Dec 2;291(49):25505-25515. Epub 2016 Oct 28.

CRISPR/Cas9-mediated endogenous C-terminal Tagging of Trypanosoma cruzi Genes Reveals the Acidocalcisome Localization of the Inositol 1,4,5-Trisphosphate Receptor.

Lander N¹, Chiurillo MA², Storey M³, Vercesi AE², Docampo R^4,3.

https://www.ncbi.nlm.nih.gov/pubmed/27793988

The article that follows establishes the essential role that the mitochondria have in calcium-uptake that requires a calcium-binding protein, MICU1 and MICU2  mitochondrial uptake proteins,  the pore forming subunit mitochondrial uniporter (MCU), and occurs through a selective calcium channel MCU regulator in the inner membrane – EMRE, not previously characterized.  This is the case in neural transmission as well as in cardiac contraction.

EMRE Is an Essential Component of the Mitochondrial Calcium Uniporter Complex

Y Sancak1,2, AL Markhard1, T Kitami1,2,*, E Kovács-Bogdán1, et al.

1Department of Molecular Biology, Massachusetts General Hospital, Department of Systems Biology, Harvard Medical School, Boston, MA
2Broad Institute of MIT and Harvard, Cambridge, MA
3Howard Hughes Medical Institute, Department of Cardiology, Children’s Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA
Science 13 Dec 2013; 342 (6164): 1379-1382
http://dx.doi.org/10.1126/science.1242993

ABSTRACT

The mitochondrial uniporter is a highly selective calcium channel in the organelle’s inner membrane. Its molecular components include the EF-hand–containing

• calcium-binding 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-kilodalton, 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.

EDITOR’S SUMMARY

EMRE Emerges

L. Bryan Ray
Sci. Signal. 17 Dec 2013: 6(306), p. ec310.  [DOI: 10.1126/scisignal.2005002]

Concentrations of calcium within mitochondria are tightly regulated and modulate physiological mitochondrial functions,

including control of metabolism and cell death.

Sancak et al. complete the molecular characterization of the mitochondrial calcium uniporter (MCU), the multicomponent channel that allows concentration of calcium within the organelle.

They identified a small protein termed “essential MCU regulator”—or EMRE—which was required for calcium transport activity of the fully assembled uniporter.