Cx43 acts as a mitochondrial calcium regulator that promotes obesity by inducing the polarization of macrophages in adipose tissue.
Cx43 acts as a mitochondrial calcium regulator that promotes obesity by inducing the polarization of macrophages in adipose tissue.
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DOI：
10.1016/j.cellsig.2023.110606
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发表时间：
2023-01
影响因子：
4.8
通讯作者：
Qing Zhou;Yuyan Wang;Zongshi Lu;Chengkang He;Li Li-Li;Mei You;Lijuan Wang;T. Cao;Yu Zhao;Qiang Li;Aidi Mou;Wentao Shu;H. He;Z. Zhao;Daoyan Liu;Zhiming Zhu;Peng Gao;Zhencheng Yan
中科院分区：
文献类型：
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作者：
Qing Zhou;Yuyan Wang;Zongshi Lu;Chengkang He;Li Li-Li;Mei You;Lijuan Wang;T. Cao;Yu Zhao;Qiang Li;Aidi Mou;Wentao Shu;H. He;Z. Zhao;Daoyan Liu;Zhiming Zhu;Peng Gao;Zhencheng Yan
巨噬细胞的代谢重编程引发促炎巨噬细胞的极化，从而加剧脂肪细胞功能障碍和肥胖。线粒体 Ca2+ 稳态失衡会损害线粒体功能并促进炎症。 Connexin 43 (Cx43) 是一种普遍存在的间隙连接蛋白，已被证明可以调节细胞内 Ca2+ 稳态。在这里，我们探讨了巨噬细胞Cx43是否通过调节巨噬细胞的极化来影响肥胖过程。 HFD 治疗诱导肥胖并加剧巨噬细胞浸润，巨噬细胞 Cx43 上调。巨噬细胞特异性敲除 Cx43 可通过减轻脂肪组织炎症来减少 HFD 诱导的肥胖，同时减少促炎性 M1 巨噬细胞浸润。一致地，抑制或敲低 Cx43 可改善棕榈酸 (PA) 诱导的线粒体功能障碍，如氧化磷酸化 (OXPHOS) 改善、线粒体相关膜 (MAM) 形成减少和线粒体 Ca2+ 过载所示。从机制上讲，Cx43 与线粒体 Ca2+ 单向转运蛋白 (MCU) 相互作用，敲低 Cx43 通过降低 MCU 介导的线粒体 Ca2+ 摄取来减轻 PA 诱导的琥珀酸脱氢酶 (SDH) 氧化，从而促进促炎性 M1 巨噬细胞的极化。因此，本研究确定 Cx43 是一种线粒体 Ca2+ 调节剂，可通过促进巨噬细胞极化为 M1 促炎表型来加剧肥胖，并表明 Cx43 可能是对抗肥胖的有前景的治疗靶点。
Metabolic reprogramming of macrophages initiates the polarization of pro-inflammatory macrophages that exacerbates adipocyte dysfunction and obesity. The imbalance of mitochondrial Ca2+homeostasis impairs mitochondrial function and promotes inflammation. Connexin 43 (Cx43), a ubiquitous gap junction protein, has been demonstrated to regulate intracellular Ca2+homeostasis. Here we explored whether macrophage Cx43 affects the obesity process by regulating the polarization of macrophage. HFD treatment induced obesity and exacerbated macrophages infiltration with upregulation of macrophages Cx43. Macrophage-specific knockout of Cx43 reduced HFD-induced obesity by alleviating inflammation in adipose tissue, with less pro-inflammatory M1 macrophage infiltration. Consistently, inhibition or knockdown of Cx43 improved palmitic acid (PA) induced mitochondrial dysfunction, as indicated by improved oxidative phosphorylation (OXPHOS), reduced formation of mitochondria-associated membranes (MAM) and mitochondrial Ca2+overload. Mechanistically, Cx43 interacted with the mitochondrial Ca2+uniporter (MCU) and knockdown of Cx43 alleviated PA-induced succinate dehydrogenase (SDH) oxidation by lowering MCU-mediated mitochondrial Ca2+uptake, which then, promoting the polarization of pro-inflammatory M1 macrophages. Thus, this study identified Cx43 as a mitochondrial Ca2+regulator that aggravates obesity via promoting macrophages polarized to M1 pro-inflammatory phenotype and suggests that Cx43 might be a promising therapeutic target antagonizing obesity.