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.

中文翻译：

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抑制素 1 调节 mtDNA 释放和下游炎症反应

线粒体 DNA (mtDNA) 暴露于细胞质中会激活先天免疫反应。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 (PHB1) 通过调节线粒体内膜的通透性，在 mtDNA 释放中发挥关键作用。PHB1 的缺失会导致线粒体完整性和功能的改变。PHB1 缺陷型巨噬细胞、骨髓特异性 PHB1 KO (Phb1MyeKO) 小鼠的血清以及新生儿脓毒症患者的外周血单核细胞显示白细胞介素 1β (IL-1β) 水平升高。PHB1 KO 小鼠也不耐受脂多糖休克。Phb1 耗尽的巨噬细胞显示 mtDNA 的细胞质释放和炎症反应增加。该过程被环孢菌素 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 PHB1 的表达水平。在正常生理条件下，线粒体内膜蛋白 AFG3L2 和 SPG7 与 PHB1 结合以抑制 mPTP 打开。PHB1 的下调导致 AFG3L2 和 SPG7 之间的相互作用增强、mPTP 打开、mtDNA 释放和下游炎症反应。