Systems Biology | Rare Diseases | Common Diseases | Calcium Uniporter
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Mitochondrial Calcium Uniporter  
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Mitochondria uptake and buffer huge amounts of calcium via a channel called the "uniporter."  Calcium uptake into mitochondria activates the TCA cycle and is believed to serve as a key signal for coordinating mitochondrial ATP production with its utilization in the cytosol.  The uniporter has been studied for decades but its molecular composition has remained a complete mystery.  Our laboratory used comparative genomics and proteomics to discover all of the molecular components of the uniporter.  This strategy led initially to the identification of MICU1, which we now understand to be one of the gate-keepers of the uniporter.  Using integrative genomics, we could then discover MCU as the pore-forming subunit.  Although MCU fulfilled all of the criteria for serving as the uniporter’s pore, it was not sufficient for reconstituting uniporter activity.  We then performed an affinity purification of the uniporter holocomplex to identify the remaining distinct component, EMRE, a tiny trans-membrane protein required for activity of MCU and of coupling to the calcium sensing activity of MICU1.  With these components in hand, we achieved the first in vivo reconstitution of this channel complex in yeast, an organism whose mitochondria lack uniporter activity and machinery.  Detailed biophysical studies indicate that the MICU1/MICU2 heterodimer sense calcium in the inter membrane space to serve as an "on-off" switch for trans-membrane protein complex MCU/EMRE, the minimal components required for pore-activity.  Ongoing studies are aimed at a full molecular understanding of this channel complex in health and in disease.

 

 
Selected Publications
arrow MICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake
Perocchi F, Gohil VK, Girgis H, Bao R., McCombs JE, Palmer AE, Mootha VK.
Nature: 467(7313):291-296. 2010
arrow Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter
Baughman J, Perocchi F, Girgis H, Plovanich M, Belcher-Timme CA, Sancak Y, Bao XR, Strittmatter L, Goldberger O, Bogorad RL, Koteliansky V, Mootha VK.
Nature: 476(7360):341-345. 2011
arrow Evolutionary diversity of the mitochondrial calcium uniporter
Bick AG, Calvo SE, Mootha VK.
Science: 336(6083):86. 2012
arrow EMRE is an essential component of the mitochondrial calcium uniporter complex
Sancak Y, Markhard AL, Kitami T, Kovács-Bogdán E, Kamer KJ, Udeshi ND, Carr SA, Chaudhuri D, Clapham DE, Li AA, Calvo SE, Goldberger O, Mootha VK.
Science: 342(6164):1379-1382. 2013
arrow Reconstitution of the mitochondrial calcium uniporter in yeast
Kovacs-Bogdan E, Sancak Y, Kamer KJ, Plovanich M, Jambhekar A, Huber RJ, Myre MA, Blower MD, Mootha VK.
Proceedings of the National Academy of Sciences U.S.A.: 111(24):8985-8990. 2014
arrow The molecular era of the mitochondrial calcium uniporter
Kamer KJ, Mootha VK.
Nature Reviews Molcular Cell Biology: 16(9):545-553. 2015
arrow High-affinity cooperative Ca2+ binding by MICU1-MICU2 serves as an on-off switch for the uniporter
Kamer KJ, Grabarek Z, Mootha VK.
EMBO Reports: e201643748. 2017
arrow Cryo-EM structure of a fungal mitochondrial calcium uniporter
Nguyen NX, Armache J, Lee C, Yang Y, Zeng W, Mootha VK, Cheng Y, Bai X, Jiang Y.
Nature: 2018
 

 

     
   
     
     
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