MICU1 Interacts with the D-Ring of the MCU Pore to Control Its Ca2+ Flux and Sensitivity to Ru360

• Published in: Molecular cell 2018-11, Vol.72 (4), p.778-785.e3
• Main Authors: Paillard, Melanie, Csordás, György, Huang, Kai-Ting, Várnai, Peter, Joseph, Suresh K., Hajnóczky, György
• Format: Article
• Language: English
• Subjects: Ca2+ uptake; calcium signaling; cooperativity; Life Sciences; mitochondria; oxidative stress; threshold
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2018.09.008

Proper control of the mitochondrial Ca2+ uniporter’s pore (MCU) is required to allow Ca2+-dependent activation of oxidative metabolism and to avoid mitochondrial Ca2+ overload and cell death. The MCU’s gatekeeping and cooperative activation is mediated by the Ca2+-sensing MICU1 protein, which has been proposed to form dimeric complexes anchored to the EMRE scaffold of MCU. We unexpectedly find that MICU1 suppresses inhibition of MCU by ruthenium red/Ru360, which bind to MCU’s DIME motif, the selectivity filter. This led us to recognize in MICU1’s sequence a putative DIME interacting domain (DID), which is required for both gatekeeping and cooperative activation of MCU and for cell survival. Thus, we propose that MICU1 has to interact with the D-ring formed by the DIME domains in MCU to control the uniporter. [Display omitted] •MICU1 controls the RuRed/Ru360 sensitivity of the MCU complex•MICU1’s R440/443 supports a direct interaction with MCU•MICU1 R440/443-dependently competes with RuRed for interacting with the D-ring of MCU•MICU1-MCU interaction is central for MCU gatekeeping and cell survival Paillard et al. report that mitochondrial Ca2+ uptake 1 (MICU1) interacts with the D-ring of MCU, the pore-forming protein of the mitochondrial Ca2+ uniporter, through a DIME interacting domain involving the arginines 440 and 443 to control both the Ca2+ flux and the ruthenium red sensitivity of the MCU complex.