Mpv17 in mitochondria protects podocytes against mitochondrial dysfunction and apoptosis in vivo and in vitro
Mpv17 in mitochondria protects podocytes against mitochondrial dysfunction and apoptosis in vivo and in vitro
复制标题
DOI：
10.1152/ajprenal.00608.2013
复制
发表时间：
2014-06-01
影响因子：
4.2
通讯作者：
Bottinger, Erwin P.
中科院分区：
文献类型：
--
作者：
Casalena, Gabriela;Krick, Stefanie;Bottinger, Erwin P.
人们越来越认识到线粒体功能障碍会导致肾小球疾病，包括继发于线粒体 DNA (mtDNA) 突变和缺失的肾小球疾病。线粒体维持细胞氧化还原和能量稳态，是细胞内活性氧（ROS）产生的主要来源。线粒体 ROS 积累可能导致应激诱导的线粒体功能障碍和细胞凋亡，从而导致肾小球硬化。在小鼠中，编码 Mpv17 的基因缺失与肾小球硬化症相关，但其潜在机制仍不清楚。在这里，我们报道 Mpv17 定位于足细胞的线粒体，并且其表达在几种肾小球损伤模型和人类局灶节段性肾小球硬化症 (FSGS) 中减少，但在微小病变性疾病中没有减少。使用Mpv17（-/-）野生型（WT）和Mpv17（-/-）敲除小鼠的轻度或重度肾毒性血清肾炎（NTSN）模型，我们发现与WT相比，Mpv17缺陷导致蛋白尿（轻度NTSN）和肾功能不全（重度NTSN）增加。这些损伤与线粒体 ROS 生成增加和线粒体损伤（例如氧化 DNA 损伤）有关。在体外，Mpv17 功能丧失的足细胞的特征是对细胞凋亡和 ROS 损伤的敏感性增加，包括线粒体功能下降、mtDNA 含量丧失和线粒体构型变化。总之，足细胞中的线粒体内膜蛋白 Mpv17 对于维持线粒体稳态至关重要，并在体外和体内保护足细胞免受氧化应激诱导的损伤。
Mitochondrial dysfunction is increasingly recognized as contributing to glomerular diseases, including those secondary to mitochondrial DNA ( mtDNA) mutations and deletions. Mitochondria maintain cellular redox and energy homeostasis and are a major source of intracellular reactive oxygen species (ROS) production. Mitochondrial ROS accumulation may contribute to stress-induced mitochondrial dysfunction and apoptosis and thereby to glomerulosclerosis. In mice, deletion of the gene encoding Mpv17 is associated with glomerulosclerosis, but the underlying mechanism remains poorly defined. Here we report that Mpv17 localizes to mitochondria of podocytes and its expression is reduced in several glomerular injury models and in human focal segmental glomerulosclerosis (FSGS) but not in minimal change disease. Using models of mild or severe nephrotoxic serum nephritis (NTSN) in Mpv17(-/-) wild-type (WT) and Mpv17(-/-) knockout mice, we found that Mpv17 deficiency resulted in increased proteinuria (mild NTSN) and renal insufficiency (severe NTSN) compared with WT. These lesions were associated with increased mitochondrial ROS generation and mitochondrial injury such as oxidative DNA damage. In vitro, podocytes with loss of Mpv17 function were characterized by increased susceptibility to apoptosis and ROS injury including decreased mitochondrial function, loss of mtDNA content, and change in mitochondrial configuration. In summary, the inner mitochondrial membrane protein Mpv17 in podocytes is essential for the maintenance of mitochondrial homeostasis and protects podocytes against oxidative stress-induced injury both in vitro and in vivo.