AIDA directly connects sympathetic innervation to adaptive thermogenesis by UCP1
AIDA directly connects sympathetic innervation to adaptive thermogenesis by UCP1
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AIDA 通过 UCP1 将交感神经支配与适应性产热直接联系起来。
DOI：
10.1038/s41556-021-00642-9
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发表时间：
2021
影响因子：
21.3
通讯作者：
Lin Sheng-Cai
中科院分区：
文献类型：
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作者：
Shi Meng;Huang Xiao-Yu;Ren Xin-Yi;Wei Xiao-Yan;Ma Yue;Lin Zhi-Zhong;Liu Dong-Tai;Song Lintao;Zhao Tong-Jin;Li Guang;Yao Luming;Zhu Mingxia;Zhang Cixiong;Xie Changchuan;Wu Yaying;Wu Han-Ming;Fan Li-Ping;Ou Jingxing;Zhan Yi-Hong;Lin Shu-Yong;Lin Sheng-Cai
交感神经系统-儿茶酚胺-解偶联蛋白 1 (UCP1) 轴在非颤抖适应性生热过程中发挥着重要作用。然而，是否存在将儿茶酚胺信号传导与 UCP1 物理连接以响应急性寒冷的直接效应器尚不清楚。在此，我们报道位于线粒体外膜的 AIDA 在 S161 处被儿茶酚胺激活蛋白激酶 A (PKA) 磷酸化。磷酸化的 AIDA 易位至膜间隙，与 UCP1 结合并通过促进 UCP1 的半胱氨酸氧化来激活 UCP1 的解偶联活性。 AIDA 的脂肪细胞特异性消耗消除了 UCP1 依赖性生热作用，导致急性冷暴露期间体温过低。与野生型 AIDA 不同，S161A-AIDA 的重新表达无法恢复 Aida 敲除小鼠的急性寒冷反应。 PKA-AIDA-UCP1 轴在哺乳动物（包括冬眠动物）中高度保守。交感神经节后纤维的去神经消除了冷诱导的 AIDA 依赖性生热作用。这些发现揭示了交感神经输入与 UCP1 介导的适应性产热之间的直接机制联系。
The sympathetic nervous system–catecholamine–uncoupling protein 1 (UCP1) axis plays an essential role in non-shivering adaptive thermogenesis. However, whether there exists a direct effector that physically connects catecholamine signalling to UCP1 in response to acute cold is unknown. Here we report that outer mitochondrial membrane-located AIDA is phosphorylated at S161 by the catecholamine-activated protein kinase A (PKA). Phosphorylated AIDA translocates to the intermembrane space, where it binds to and activates the uncoupling activity of UCP1 by promoting cysteine oxidation of UCP1. Adipocyte-specific depletion of AIDA abrogates UCP1-dependent thermogenesis, resulting in hypothermia during acute cold exposure. Re-expression of S161A-AIDA, unlike wild-type AIDA, fails to restore the acute cold response inAida-knockout mice. The PKA–AIDA–UCP1 axis is highly conserved in mammals, including hibernators. Denervation of the sympathetic postganglionic fibres abolishes cold-induced AIDA-dependent thermogenesis. These findings uncover a direct mechanistic link between sympathetic input and UCP1-mediated adaptive thermogenesis.