The mechanism of micu-dependent gating of the mitochondrial ca2+ uniporter

Vivek Garg, Junji Suzuki, Ishan Paranjpe, Tiffany Unsulangi, Liron Boyman, Lorin S. Milescu, W. Jonathan Lederer, Yuriy Kirichok

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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 insight. 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.

Original languageEnglish
Article numbere69312
StatePublished - Aug 2021


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