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

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

  1. Guangfeng Geng

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Jinhua Liu

    Chinese Academy of Medical Sciences, Institute of Hematology and Blood Diseases Hospital, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Changlu Xu

    Chinese Academy of Medical Sciences, Institute of Hematology and Blood Diseases Hospital, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1581-7027
  4. Yandong yan Pei

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Linbo Chen

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Chenglong Mu

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Ding Wang

    Chinese Academy of Medical Sciences, Institute of Hematology and Blood Diseases Hospital, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Jie Gao

    Chinese Academy of Medical Sciences, Institute of Hematology and Blood Diseases Hospital, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Yue Li

    Chinese Academy of Medical Sciences, Institute of Hematology and Blood Diseases Hospital, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Jing Liang

    Chinese Academy of Medical Sciences, Institute of Hematology and Blood Diseases Hospital, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Tian Zhao

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Chuanmei Zhang

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Jiaxi Zhou

    Chinese Academy of Medical Sciences, Institute of Hematology and Blood Diseases Hospital, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Quan Chen

    College of Life Sciences, Nankai University, Tianjin, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7539-8728
  15. Yushan Zhu

    College of Life Sciences, Nankai University, Tianjin, China
    For correspondence
    zhuys@nankai.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5648-0416
  16. Lihong Shi

    Chinese Academy of Medical Sciences, Institute of Hematology and Blood Diseases Hospital, Tianjin, China
    For correspondence
    shilihongxys@ihcams.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8876-0802

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

  1. 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

  1. Received: October 30, 2020
  2. Accepted: May 2, 2021
  3. Accepted Manuscript published: May 4, 2021 (version 1)
  4. 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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  1. Guangfeng Geng
  2. Jinhua Liu
  3. Changlu Xu
  4. Yandong yan Pei
  5. Linbo Chen
  6. Chenglong Mu
  7. Ding Wang
  8. Jie Gao
  9. Yue Li
  10. Jing Liang
  11. Tian Zhao
  12. Chuanmei Zhang
  13. Jiaxi Zhou
  14. Quan Chen
  15. Yushan Zhu
  16. Lihong Shi
(2021)
Receptor-mediated mitophagy regulates EPO production and protects against renal anemia
eLife 10:e64480.
https://doi.org/10.7554/eLife.64480

Share this article

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

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