Receptor-mediated mitophagy regulates EPO production and protects against renal anemia
- Nankai University, China
- Institute of Hematology and Blood Diseases Hospital, China
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.
Data availability
RNA-Sequencing data is deposited at GEO Accession number GSE 158361. Information on replicates is presented in Materials and Methods as well as in figure legend. Replicate numbers are mentioned in figure legends. All data generated or analysed during this study are included in the manuscript and supporting files
Article and author information
Author details
Funding
National Key Research and Development Program of China (2019YFA0508601,2017YFA0103102,2016YFA0102300)
- Quan Chen
National Natural Science Foundation of China (91849201,31790404)
- Quan Chen
National Key Research and Development Program of China (2019YFA0508603)
- Yushan Zhu
National Natural Science Foundation of China (32030026)
- Yushan Zhu
National Natural Science Foundation of China (81870089,81890990,81700105)
- Lihong Shi
The CAMS innovation Fund for Medical Sciences (2016-I2M-3-002,2019-I2M-1-006,2016-I2M-1-018 and 2017-I2M-1-015)
- Lihong Shi
The authors declare that there was no funding for this work
Reviewing Editor
- Jian Xu, University of Texas Southwestern Medical Center, United States
Ethics
Animal experimentation: Mice were maintained in the animal core facility of College of Life Sciences , Nankai University, Tianjin, China. All experiments involving animals were reviewed and approved by the Animal Care and Use Committee of Nankai University and were performed in accordance with the university guidelines (NO. 2021-SYDWLL-000410).
Version history
- Received: October 30, 2020
- Accepted: May 2, 2021
- Accepted Manuscript published: May 4, 2021 (version 1)
- Version of Record published: May 14, 2021 (version 2)
Copyright
© 2021, Geng et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Receptor-mediated mitophagy regulates EPO production and protects against renal anemia
eLife 10:e64480.
https://doi.org/10.7554/eLife.64480
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