The mechanism of MICU-dependent gating of the mitochondrial Ca2+uniporter

Ca2+ entry into mitochondria is through the mitochondrial calcium uniporter complex (MCUcx), a Ca2+-selective channel composed of five subunit types. Two MCUcx subunits (MCU and EMRE) span the inner mitochondrial membrane, while three Ca2+-regulatory subunits (MICU1, MICU2, and MICU3) reside in the...

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Published in:eLife 2021-08, Vol.10
Main Authors: Garg, Vivek, Suzuki, Junji, Paranjpe, Ishan, Unsulangi, Tiffany, Boyman, Liron, Milescu, Lorin S, Lederer, W Jonathan, Kirichok, Yuriy
Format: Article
Language:English
Subjects:
Binding sites
Calcium (mitochondrial)
Calcium influx
calcium signaling
Channel gating
CRISPR
Experiments
Genes
ion channels
Mitochondria
mitochondrial calcium uniporter
mouse embryonic fibroblasts
patch clamp
Regulatory subunits
Structural Biology and Molecular Biophysics
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Summary:Ca2+ entry into mitochondria is through the mitochondrial calcium uniporter complex (MCUcx), a Ca2+-selective channel composed of five subunit types. Two MCUcx subunits (MCU and EMRE) span the inner mitochondrial membrane, while three Ca2+-regulatory subunits (MICU1, MICU2, and MICU3) reside in the intermembrane space. Here, we provide rigorous analysis of Ca2+ and Na+ fluxes via MCUcx in intact isolated mitochondria to understand the function of MICU subunits. We also perform direct patch clamp recordings of macroscopic and single MCUcx currents to gain further mechanistic insights. This comprehensive analysis shows that the MCUcx pore, composed of the EMRE and MCU subunits, is not occluded nor plugged by MICUs during the absence or presence of extramitochondrial Ca2+ as has been widely reported. Instead, MICUs potentiate activity of MCUcx as extramitochondrial Ca2+ is elevated. MICUs achieve this by modifying the gating properties of MCUcx allowing it to spend more time in the open state.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.69312