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.

需要适当控制线粒体 Ca ²⁺单向转运蛋白孔 (MCU)，以允许 Ca ²⁺依赖性氧化代谢激活，并避免线粒体 Ca ²⁺过载和细胞死亡。 MCU 的守门和协同激活是由 Ca ²⁺感应 MICU1 蛋白介导的，该蛋白已被提议形成锚定到 MCU 的 EMRE 支架上的二聚体复合物。我们意外地发现，MICU1 抑制了钌红/Ru360 对 MCU 的抑制，钌红/Ru360 与 MCU 的 DIME 基序（选择性过滤器）结合。这使我们在 MICU1 的序列中识别出一个假定的 DIME 相互作用域 (DID)，它是 MCU 的看门和协作激活以及细胞生存所必需的。因此，我们建议 MICU1 必须与 MCU 中 DIME 域形成的 D 环相互作用来控制单向转运蛋白。