Receptor-mediated mitophagy regulates EPO production and protects against renal anemia.
Receptor-mediated mitophagy regulates EPO production and protects against renal anemia.
复制标题
受体介导的线粒体自噬调节 EPO 产生并预防肾性贫血
作者：
Geng G;Liu J;Xu C;Pei Y;Chen L;Mu C;Wang D;Gao J;Li Y;Liang J;Zhao T;Zhang C;Zhou J;Chen Q;Zhu Y;Shi L
促红细胞生成素（EPO）驱动红细胞生成，主要由肾在缺氧或贫血应激时分泌。肾促红细胞生成素细胞（REPs）缺乏促红细胞生成素导致肾性贫血，这是慢性肾病最常见的并发症之一。虽然线粒体功能障碍在一些肾脏和造血疾病中普遍存在，但线粒体质量控制影响肾性贫血的机制尚不清楚。在这项研究中，我们发现有丝分裂受体FUNDC1在应激诱导的epo驱动的红细胞生成中起关键作用。从机制上讲，应激条件下Fundc1-/-小鼠的REPs中EPO的产生受到损害，这种损害是由受损线粒体的积累引起的，从而导致活性氧（ROS）水平升高，并通过上调促炎细胞因子引发炎症反应。这些炎症因子促进REPs的肌成纤维转化，导致EPO的产生减少。因此，我们提供了异常线粒体自噬和肾性贫血中EPO生成不足之间的联系。我们的研究结果还表明，线粒体质量控制可以保护应激下的rep，这可能是治疗肾性贫血的潜在治疗策略。
Erythropoietin (EPO) drives erythropoiesis and is secreted mainly by the kidney upon hypoxic or anemic stress. The paucity of EPO production in renal EPO-producing cells (REPs) causes renal anemia, one of the most common complications of chronic nephropathies. Although mitochondrial dysfunction is commonly observed in several renal and hematopoietic disorders, the mechanism by which mitochondrial quality control impacts renal anemia remains elusive. In this study, we showed that FUNDC1, a mitophagy receptor, plays a critical role in EPO-driven erythropoiesis induced by stresses. Mechanistically, EPO production is impaired in REPs in Fundc1-/- mice upon stresses, and the impairment is caused by the accumulation of damaged mitochondria, which consequently leads to the elevation of the reactive oxygen species (ROS) level and triggers inflammatory responses by up-regulating proinflammatory cytokines. These inflammatory factors promote the myofibroblastic transformation of REPs, resulting in the reduction of EPO production. We therefore provide a link between aberrant mitophagy and deficient EPO generation in renal anemia. Our results also suggest that the mitochondrial quality control safeguards REPs under stresses, which may serve as a potential therapeutic strategy for the treatment of renal anemia.