蛋白尿是慢性肾脏病(CKD)常见且重要的临床表现,是肾脏病进展的独立危险因素。作为肾小球滤过屏障(GFB)的组成部分,足细胞在肾小球疾病和蛋白尿的发病机制中起关键作用。然而,与线粒体功能相关的肾小球疾病的病理生理学尚未完全了解。这里,我们在MTX2中发现了三个新的突变,在线粒体中编码一种膜蛋白,在两名中国患者中与多系统表现相关,包括肾病性蛋白尿和肾损伤。条件性足细胞特异性Mtx2敲除(Pod-Mtx2-KO)小鼠从8周龄到老年出现一系列足细胞和肾小球异常,包括微量白蛋白尿,肾小球系膜增生,足过程的融合和消除。MTX2缺乏在体外损害足细胞功能,表现为附着力的降低,迁移和内吞作用,通过MTX2的过表达进一步恢复。此外,MTX2缺陷导致线粒体结构异常和功能障碍,以复合物I和III的缺陷证明,增加活性氧(ROS)的产生,线粒体膜间间隙桥接(MIB)复合物中Sam50-CHCHD3-Mitofilin轴的蛋白质水平降低,该复合物负责维持线粒体cr的形态。总的来说,这些发现揭示了MTX2在肾小球的正常表达在肾小球粘连中起着重要作用,迁移,内吞作用,足细胞的增殖和其他生理功能,这可以通过维持线粒体的形态结构和功能来实现。MTX2的异常表达可导致足细胞中Sam50-CHCHD3-Mitofilin轴的线粒体功能障碍和结构异常,进一步诱导足细胞损伤,肾小球病变和蛋白尿。
Proteinuria is a common and important clinical manifestation of chronic kidney disease (CKD) and an independent risk factor for the progression of kidney disease. As a component of the glomerular filtration barrier (GFB), podocyte plays a key role in the pathogenesis of glomerular diseases and proteinuria. However, the pathophysiology of glomerular diseases associated with mitochondrial function is incompletely understood. Here, we identified three novel mutations in
MTX2, encoding a membrane protein in mitochondria, associated with multisystem manifestations including nephrotic proteinuria and kidney injury in two Chinese patients. Conditional podocyte-specific
Mtx2 knockout (Pod-
Mtx2-KO) mice present a series of podocyte and glomerular abnormalities from 8 weeks to old age, including microalbuminuria, glomerular mesangial hyperplasia, fusion and effacement of foot process.
MTX2 deficiency impaired podocyte functions in vitro, manifested by reductions of adhesion, migration and endocytosis, which were further restored by overexpression of
MTX2. Moreover,
MTX2 defects led to abnormal mitochondrial structure and dysfunction, evidenced with defects of complex I and III, increased production of reactive oxygen species (ROS), and decreased protein levels of Sam50-CHCHD3-Mitofilin axis in the mitochondrial intermembrane space bridging (MIB) complex which is responsible for maintaining mitochondrial cristae morphology. Collectively, these findings reveal that the normal expression of MTX2 in glomerulus plays an important role in the adhesion, migration, endocytosis, proliferation and other physiological functions of podocytes, which may be realized by maintaining the morphological structure and function of mitochondria. Abnormal expression of MTX2 can lead to mitochondrial dysfunction and structural abnormalities by Sam50-CHCHD3-Mitofilin axis in podocyte, which further induces podocyte injury, glomerular lesions and proteinuria.