Uncoupling protein 1 (UCP1)-mediated adaptive thermogenesis protects mammals against hypothermia and metabolic dysregulation. Whether and how mitochondrial calcium regulates this process remains unclear. Here, we show that mitochondrial calcium uniporter (MCU) recruits UCP1 through essential MCU regulator (EMRE) to form an MCU-EMRE-UCP1 complex upon adrenergic stimulation. This complex formation increases mitochondrial calcium uptake to accelerate the tricarboxylic acid cycle and supply more protons that promote uncoupled respiration, functioning as a thermogenic uniporter. Mitochondrial calcium uptake 1 (MICU1) negatively regulates thermogenesis probably through inhibiting thermogenic uniporter formation. Accordingly, the deletion of Mcu or Emre in brown adipocytes markedly impairs thermogenesis and exacerbates obesity and metabolic dysfunction. Remarkably, the enhanced assembly of the thermogenic uniporter via Micu1 knockout or expressing linked EMRE-UCP1 results in opposite phenotypes. Thus, we have uncovered a “thermoporter” that provides a driving force for the UCP1 operation in thermogenesis, which could be leveraged to combat obesity and associated metabolic disorders.

解偶联蛋白 1 (UCP1) 介导的适应性产热保护哺乳动物免受体温过低和代谢失调。线粒体钙是否以及如何调节这一过程仍不清楚。在这里，我们表明线粒体钙单向转运体 (MCU) 通过必需的 MCU 调节器 (EMRE) 募集 UCP1，在肾上腺素能刺激下形成 MCU-EMRE-UCP1 复合物。这种复合物的形成增加了线粒体钙的摄取，以加速三羧酸循环并提供更多促进非耦合呼吸的质子，起到产热单向转运体的作用。线粒体钙摄取 1 (MICU1) 可能通过抑制产热单向转运体的形成负调节产热。因此，删除MCU或Emre在棕色脂肪细胞中显着损害产热并加剧肥胖和代谢功能障碍。值得注意的是，通过Micu1敲除或表达连接的 EMRE-UCP1 增强的产热单向转运体组装导致相反的表型。因此，我们发现了一种“热转运蛋白”，它为产热中的 UCP1 操作提供驱动力，可用于对抗肥胖和相关的代谢紊乱。