Mitochondrial damage activates the STING pathway to promote chronic kidney disease

Fibrosis of the kidney is the final common pathway leading to end stage renal failure. By analyzing kidneys of patients and animal models with fibrosis we observed a significant mitochondrial defect, including the loss of the mitochondrial transcription factor A (TFAM) in kidney tubule cells. Here, we generated mice with tubule-specific deletion of TFAM (Ksp-Cre/Tfam flox/flox). While these mice developed severe mitochondrial loss and energetic deficit (ATP level decline) by 6 weeks of age, kidney fibrosis, immune cell infiltration and progressive azotemia causing death was only observed around 12 weeks of age. Mechanistic studies demonstrated that in the TFAM KO mice aberrant packaging of the mitochondrial DNA (mtDNA) resulted in escape of the mtDNA into the cytosol of the renal cells, activation of the cytosolic cGAS-STING (Stimulator of interferon genes) DNA sensing pathway, and thus cytokine expression and immune cell recruitment. Genetic deletion or pharmacological inhibition of STING ameliorated kidney fibrosis in mouse models of chronic kidney disease, demonstrating that in addition to its essential role in metabolism TFAM sequesters mtDNA to prevent the activation of innate immune pathways and fibrosis. RNA-seq of kidneys of 12 weeks old control mice (Tfam flox/flox without Ksp cre) and Kspcre Tfam flox/flox mice肾脏纤维化是引发终末期肾衰竭的最终共同通路。通过分析纤维化患者及动物模型的肾脏组织，我们观察到显著的线粒体功能缺陷，包括肾小管细胞中线粒体转录因子A（TFAM）的丢失。本研究构建了肾小管特异性敲除TFAM的小鼠模型（Ksp-Cre/Tfam flox/flox）。该模型小鼠在6周龄时即出现严重的线粒体丢失与能量代谢缺陷（ATP水平下降），但肾脏纤维化、免疫细胞浸润及引发死亡的进行性氮质血症仅在12周龄左右才出现。机制研究表明，在TFAM敲除小鼠中，线粒体DNA（mtDNA）的异常包装导致其逃逸至肾细胞胞浆，激活胞质内cGAS-STING（干扰素基因刺激因子，Stimulator of interferon genes）DNA感知通路，进而诱导细胞因子表达与免疫细胞招募。对慢性肾病小鼠模型进行STING的基因敲除或药物抑制，可减轻肾脏纤维化，这表明除了在代谢中的核心作用外，TFAM还通过隔离线粒体DNA以防止先天免疫通路激活及肾脏纤维化的发生。本研究对12周龄对照小鼠（仅携带Tfam flox/flox等位基因，无Ksp cre）与Kspcre Tfam flox/flox小鼠的肾脏组织开展了RNA测序（RNA-seq）。