Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA.
Center for Metabolism and Mitochondrial Medicine, Division of Cardiology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Cell Metab. 2019 Oct 1;30(4):784-799.e5. doi: 10.1016/j.cmet.2019.08.003. Epub 2019 Aug 29.
Fibrosis is the final common pathway leading to end-stage renal failure. By analyzing the 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). While these mice developed severe mitochondrial loss and energetic deficit by 6 weeks of age, kidney fibrosis, immune cell infiltration, and progressive azotemia causing death were only observed around 12 weeks of age. In renal cells of TFAM KO (knockout) mice, aberrant packaging of the mitochondrial DNA (mtDNA) resulted in its cytosolic translocation, activation of the cytosolic cGAS-stimulator of interferon genes (STING) DNA sensing pathway, and thus cytokine expression and immune cell recruitment. Ablation of STING ameliorated kidney fibrosis in mouse models of chronic kidney disease, demonstrating how TFAM sequesters mtDNA to limit the inflammation leading to fibrosis.
纤维化是导致终末期肾衰竭的共同途径。通过分析纤维化患者和动物模型的肾脏，我们观察到一个显著的线粒体缺陷，包括肾小管细胞中线粒体转录因子 A (TFAM) 的缺失。在这里，我们生成了小管特异性缺失 TFAM 的小鼠 (Ksp-Cre/Tfam)。虽然这些小鼠在 6 周龄时就出现了严重的线粒体丢失和能量不足，但只有在 12 周龄左右才观察到肾纤维化、免疫细胞浸润和进行性氮血症导致死亡。在 TFAM KO (敲除) 小鼠的肾细胞中，线粒体 DNA (mtDNA) 的异常包装导致其在细胞质中的易位，激活细胞质 cGAS-干扰素基因刺激物 (STING) DNA 感应途径，从而导致细胞因子表达和免疫细胞募集。STING 的消融改善了慢性肾脏病小鼠模型的肾纤维化，证明了 TFAM 如何隔离 mtDNA 来限制导致纤维化的炎症。
