Receptor-mediated mitophagy regulates EPO production and protects against renal anemia

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.

Automated summary

Erythropoietin (EPO) is crucial for erythropoiesis, and mitochondrial quality control, specifically through the mitophagy receptor FUNDC1, plays a significant role in EPO-driven erythropoiesis. Impaired FUNDC1 function leads to the accumulation of damaged mitochondria, elevated ROS levels, inflammatory responses, and decreased EPO production in renal anemia. This study suggests that targeting mitochondrial quality control mechanisms could be a potential therapeutic strategy for treating renal anemia.