Prohibitin 1 regulates mtDNA release and downstream inflammatory responses
Prohibitin 1 regulates mtDNA release and downstream inflammatory responses
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抑制素 1 调节 mtDNA 释放和下游炎症反应
DOI：
10.15252/embj.2022111173
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发表时间：
2022-10-17
期刊：
影响因子：
11.4
通讯作者：
Feng，Du
中科院分区：
文献类型：
--
作者：
Liu，Hao;Fan，Hualin;Feng，Du
线粒体DNA（mtDNA）暴露于胞质溶胶激活先天免疫应答。但线粒体DNA穿过线粒体内膜的机制尚不清楚。在这里，我们发现，线粒体内膜蛋白抑制素1（PHB 1）通过调节线粒体内膜的渗透性在mtDNA释放中起着关键作用。PHB 1的丢失导致线粒体完整性和功能的改变。PHB 1缺陷型巨噬细胞、骨髓特异性PHB 1 KO（Phb 1 MyeKO）小鼠的血清和新生儿败血症患者的外周血单核细胞显示白细胞介素-1 β（IL-1β）水平升高。PHB 1 KO小鼠也不能耐受脂多糖休克。Phb 1耗尽的巨噬细胞显示线粒体DNA的细胞质释放和炎症反应增加。这一过程被环孢菌素A和VBIT-4抑制，它们抑制线粒体通透性转换孔（mPTP）和VDAC寡聚化。炎症应激下调巨噬细胞中PHB 1的表达水平。在正常生理条件下，线粒体内膜蛋白AFG 3L 2和SPG 7与PHB 1连接以抑制mPTP开放。PHB 1的下调导致AFG 3L 2和SPG 7之间的相互作用增强，mPTP开放，mtDNA释放和下游炎症反应。
Exposure of mitochondrial DNA (mtDNA) to the cytosol activates innate immune responses. But the mechanisms by which mtDNA crosses the inner mitochondrial membrane are unknown. Here, we found that the inner mitochondrial membrane protein prohibitin 1 (PHB1) plays a critical role in mtDNA release by regulating permeability across the mitochondrial inner membrane. Loss of PHB1 results in alterations in mitochondrial integrity and function. PHB1‐deficient macrophages, serum from myeloid‐specific PHB1 KO (Phb1MyeKO) mice, and peripheral blood mononuclear cells from neonatal sepsis patients show increased interleukin‐1β (IL‐1β) levels. PHB1 KO mice are also intolerant of lipopolysaccharide shock. Phb1‐depleted macrophages show increased cytoplasmic release of mtDNA and inflammatory responses. This process is suppressed by cyclosporine A and VBIT‐4, which inhibit the mitochondrial permeability transition pore (mPTP) and VDAC oligomerization. Inflammatory stresses downregulate PHB1 expression levels in macrophages. Under normal physiological conditions, the inner mitochondrial membrane proteins, AFG3L2 and SPG7, are tethered to PHB1 to inhibit mPTP opening. Downregulation of PHB1 results in enhanced interaction between AFG3L2 and SPG7, mPTP opening, mtDNA release, and downstream inflammatory responses.