1. Cell Biology
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Hypoxic mitophagy regulates mitochondrial quality and platelet activation and determines severity of I/R heart injury

  1. Weilin Zhang
  2. He Ren
  3. Chunling Xu
  4. Chongzhuo Zhu
  5. Hao Wu
  6. Dong Liu
  7. Jun Wang
  8. Lei Liu
  9. Wei Li
  10. Qi Ma
  11. Lei Du
  12. Ming Zheng
  13. Chuanmao Zhang
  14. Junling Liu
  15. Quan Chen  Is a corresponding author
  1. Chinese Academy of Sciences, China
  2. Peking University, China
  3. Shanghai Jiaotong University, China
Research Article
  • Cited 70
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Cite this article as: eLife 2016;5:e21407 doi: 10.7554/eLife.21407

Abstract

Mitochondrial dysfunction underlies many prevalent diseases including heart disease arising from acute ischemia/reperfusion (I/R) injury. Here, we demonstrate that mitophagy, which selectively removes damaged or unwanted mitochondria, regulated mitochondrial quality and quantity in vivo. Hypoxia induced extensive mitochondrial degradation in a FUNDC1-depenent manner in platelets, and this was blocked by in vivo administration of a cell-penetrating peptide encompassing the LIR motif of FUNDC1 only in wild-type mice. Genetic ablation of Fundc1 impaired mitochondrial quality and increased mitochondrial mass in platelets and rendered the platelets insensitive to hypoxia and the peptide. Moreover, hypoxic mitophagy in platelets protected the heart from worsening of I/R injury. This represents a new mechanism of the hypoxic preconditioning effect which reduces I/R injury. Our results demonstrate a critical role of mitophagy in mitochondrial quality control and platelet activation, and suggest that manipulation of mitophagy by hypoxia or pharmacological approaches may be a novel strategy for cardioprotection.

Article and author information

Author details

  1. Weilin Zhang

    The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. He Ren

    The Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Chunling Xu

    Department of Physiology, Peking University School of Basic Medical Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Chongzhuo Zhu

    The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Hao Wu

    The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Dong Liu

    The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Jun Wang

    The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Lei Liu

    The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Wei Li

    State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7430-6019
  10. Qi Ma

    The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Lei Du

    The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Ming Zheng

    Department of Physiology, Peking University School of Basic Medical Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Chuanmao Zhang

    The Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, College of Life Sciences, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Junling Liu

    Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiaotong University, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  15. Quan Chen

    The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
    For correspondence
    chenq@ioz.ac.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7539-8728

Funding

National Natural Science Foundation of China (31271529)

  • Quan Chen

National Natural Science Foundation of China (81130045)

  • Quan Chen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the Institute of Zoology, Chinese Academy of Sciences. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#08-133) of the Institute of Zoology, Chinese Academy of Sciences. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Institute of Zoology, Chinese Academy of Sciences (Permit Number:2014-31301130). All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.

Reviewing Editor

  1. Hong Zhang, Institute of Biophysics, Chinese Academy of Sciences, China

Publication history

  1. Received: September 13, 2016
  2. Accepted: December 18, 2016
  3. Accepted Manuscript published: December 20, 2016 (version 1)
  4. Version of Record published: January 5, 2017 (version 2)

Copyright

© 2016, Zhang 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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