Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China.
Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
Cell Metab. 2022 Sep 6;34(9):1325-1341.e6. doi: 10.1016/j.cmet.2022.07.011. Epub 2022 Aug 16.
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）介导的适应性产热可保护哺乳动物免受体温过低和代谢失调的影响。线粒体钙是否以及如何调节这一过程尚不清楚。在这里，我们表明，线粒体钙单向转运蛋白（MCU）通过必需的 MCU 调节剂（EMRE）募集 UCP1，在肾上腺素刺激下形成 MCU-EMRE-UCP1 复合物。这种复合物的形成增加了线粒体钙摄取，以加速三羧酸循环并提供更多质子，促进解偶联呼吸，作为产热单向转运蛋白发挥作用。线粒体钙摄取 1（MICU1）通过抑制产热单向转运蛋白的形成来负调节产热。因此，棕色脂肪细胞中 Mcu 或 Emre 的缺失会显著损害产热作用，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 增强产热单向转运蛋白的组装会导致相反的表型。因此，我们发现了一种“热载体”，为 UCP1 在产热中的作用提供了驱动力，这可能被利用来对抗肥胖和相关的代谢紊乱。
