Na Ki Ryang, Jeong Jin Young, Shin Jin Ah, Chang Yoon-Kyung, Suh Kwang-Sun, Lee Kang Wook, Choi Dae Eun
Department of Nephrology, Chungnam National University School of Medicine, Daejeon 35015, Korea.
Department of Medical Science, Chungnam National University School of Medicine, Daejeon 35015, Korea.
Int J Mol Sci. 2021 May 2;22(9):4827. doi: 10.3390/ijms22094827.
Recent studies have implicated mitochondrial disruption in podocyte dysfunction, which is a characteristic feature of primary and diabetic glomerular diseases. However, the mechanisms by which primary mitochondrial dysfunction in podocytes affects glomerular renal diseases are currently unknown. To investigate the role of mitochondrial oxidative phosphorylation (OxPhos) in podocyte dysfunction, glomerular function was examined in mice carrying a loss of function mutation of the gene encoding CR6-interacting factor-1 (CRIF1), which is essential for intramitochondrial production and the subsequent insertion of OxPhos polypeptides into the inner mitochondrial membrane. Homozygotic deficiency of CRIF1 in podocytes resulted in profound and progressive albuminuria from 3 weeks of age; the CRIF1-deficient mice also developed glomerular and tubulointerstitial lesions by 10 weeks of age. Furthermore, marked glomerular sclerosis and interstitial fibrosis were observed in homozygous CRIF1-deficient mice at 20 weeks of age. In cultured mouse podocytes, loss of CRIF1 resulted in OxPhos dysfunction and marked loss or abnormal aggregation of F-actin. These findings indicate that the OxPhos status determines the integrity of podocytes and their ability to maintain a tight barrier and control albuminuria. Analyses of the glomerular function of the podocyte-specific primary OxPhos dysfunction model mice demonstrate a link between podocyte mitochondrial dysfunction, progressive glomerular sclerosis, and tubulointerstitial diseases.
近期研究表明，线粒体功能紊乱与足细胞功能障碍有关，而足细胞功能障碍是原发性和糖尿病性肾小球疾病的一个特征性表现。然而，足细胞原发性线粒体功能障碍影响肾小球疾病的机制目前尚不清楚。为了研究线粒体氧化磷酸化（OxPhos）在足细胞功能障碍中的作用，研究人员检测了携带编码CR6相互作用因子-1（CRIF1）基因功能缺失突变的小鼠的肾小球功能，CRIF1对于线粒体内的产物生成以及随后氧化磷酸化多肽插入线粒体内膜至关重要。足细胞中CRIF1纯合缺失导致3周龄时出现严重且进行性的蛋白尿；CRIF1缺陷小鼠在10周龄时还出现了肾小球和肾小管间质病变。此外，在20周龄的纯合CRIF1缺陷小鼠中观察到明显的肾小球硬化和间质纤维化。在培养的小鼠足细胞中，CRIF1缺失导致氧化磷酸化功能障碍以及F-肌动蛋白显著丢失或异常聚集。这些发现表明，氧化磷酸化状态决定了足细胞的完整性及其维持紧密屏障和控制蛋白尿的能力。对足细胞特异性原发性氧化磷酸化功能障碍模型小鼠的肾小球功能分析表明，足细胞线粒体功能障碍、进行性肾小球硬化和肾小管间质疾病之间存在联系。
