The mitochondrial calcium uniporter engages UCP1 to form a thermoporter that promotes thermogenesis
The mitochondrial calcium uniporter engages UCP1 to form a thermoporter that promotes thermogenesis
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DOI：
10.1016/j.cmet.2022.07.011
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发表时间：
2022-09-06
期刊：
影响因子：
29
通讯作者：
Qiu, Yifu
中科院分区：
文献类型：
--
作者：
Xue, Kaili;Wu, Dongmei;Qiu, Yifu
解偶联蛋白1（UCP 1）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）招聘UCP 1通过必要的MCU调节器（EMRE），形成一个MCU-EMRE-UCP 1复合物肾上腺素能刺激。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，并提供更多的质子，促进解偶联呼吸，作为产热单向转运体发挥作用。线粒体钙摄取1（MICU 1）可能通过抑制产热单向转运体的形成负调控产热。因此，棕色脂肪细胞中Mcu或Emre的缺失显著损害产热并加重肥胖和代谢功能障碍。值得注意的是，通过Micu 1敲除或表达连接的EMRE-UCP 1增强产热单向转运蛋白的组装导致相反的表型。因此，我们已经发现了一种“热转运体“，它为产热中的UCP 1操作提供了驱动力，这可以用来对抗肥胖和相关的代谢紊乱。
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 in-creases 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 exacer-bates 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 uncov-ered a "thermoporter"that provides a driving force for the UCP1 operation in thermogenesis, which could be leveraged to combat obesity and associated metabolic disorders.