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

Guangfeng Geng,Jing Liang,Ding Wang,Yue Li,Changlu Xu,Jinhua Liu,Linbo Chen,Yushan Zhu,Jiaxi Zhou,Jie Gao,Quan Chen,Lihong Shi,Tian Zhao,Yandong Pei,Chenglong Mu,Chuanmei Zhang

doi:10.7554/elife.64480

Guangfeng Geng, Jing Liang + Show 14 more

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https://doi.org/10.7554/elife.64480

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Abstract

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.

Highlights

Erythropoiesis is a highly dynamic and tightly regulated process in which red blood cells are generated from immature progenitors in the bone marrow (An et al, 2015; Nandakumar et al, 2016)
Previous studies have shown that BNIP3L, an important mitophagy receptor, is involved in mitochondrial elimination in reticulocytes and proper functions in red blood cells (Kundu et al, 2008; Mortensen et al, 2010; Honda et al, 2014; Nishida et al, 2009; Sandoval et al, 2008)
Our current study showed that FUN14 domain containing 1 (FUNDC1) is required for EPO production upon PHZ-induced stresses (Figure 6M)

Summary

Introduction

Erythropoiesis is a highly dynamic and tightly regulated process in which red blood cells are generated from immature progenitors in the bone marrow (An et al, 2015; Nandakumar et al, 2016). This process is mainly driven by the cytokine glycoprotein erythropoietin (EPO) (Kuhrt and Wojchowski, 2015). Prior studies have demonstrated that defects in mitochondrial removal are linked to the dysfunction of red blood cells and can lead to anemia

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