1. Cell Biology
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Miga mediated endoplasmic reticulum-mitochondria contact sites regulate neuronal homeostasis

  1. Lingna Xu
  2. Xi Wang
  3. Jia Zhou
  4. Yunyi Qiu
  5. Weina Shang
  6. Jun-Ping Liu
  7. Liquan Wang
  8. Chao Tong  Is a corresponding author
  1. Zhejiang University, China
  2. Hangzhou Normal University College of Medicine, China
  3. Zhejiang University, China
Research Article
  • Cited 6
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Cite this article as: eLife 2020;9:e56584 doi: 10.7554/eLife.56584

Abstract

Endoplasmic reticulum (ER)–mitochondria contact sites (ERMCSs) are crucial for multiple cellular processes such as calcium signaling, lipid transport, mitochondrial dynamics, and autophagosome biogenesis. However, the molecular organization, functions, and regulation of ERMCS are not fully understood in higher eukaryotes. Also, the physiological roles of altered ERMCSs are not well defined. In this study, we found that Miga, a mitochondrion located protein, markedly increases ERMCSs and causes severe neurodegeneration upon overexpression in fly eyes. Miga interacts with an ER protein Vap33 through its FFAT-like motif and an amyotrophic lateral sclerosis (ALS) disease related Vap33 mutation considerably reduces its interaction with Miga. Multiple serine residues inside and near the Miga FFAT motif were phosphorylated, which is required for its interaction with Vap33 and Miga mediated ERMCS formation. The interaction between Vap33 and Miga promoted further phosphorylation of upstream serine/threonine clusters, which fine-tuned Miga activity. Protein kinases CKI and CaMKII contribute to Miga hyperphosphorylation. MIGA2, encoded by the miga mammalian ortholog, has conserved functions in mammalian cells. We propose a model that shows Miga interacts with Vap33 to mediate ERMCSs and excessive ERMCSs lead to neurodegeneration.

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All data generated or analyzed during this study are included in the manuscript and supporting files

Article and author information

Author details

  1. Lingna Xu

    Life sciences Institute, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Xi Wang

    Life sciences Institute, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Jia Zhou

    Life sciences Institute, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Yunyi Qiu

    Life sciences Institute, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Weina Shang

    Life sciences Institute, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Jun-Ping Liu

    Institute of Ageing Research, Hangzhou Normal University College of Medicine, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Liquan Wang

    The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
    Competing interests
    The authors declare that no competing interests exist.
  8. Chao Tong

    Life sciences Institute, Zhejiang University, Hangzhou, China
    For correspondence
    ctong@zju.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6521-5465

Funding

National Natural Science Foundation of China (91754103)

  • Chao Tong

National Natural Science Foundation of China (31622034)

  • Chao Tong

National Natural Science Foundation of China (31571383)

  • Chao Tong

National key research and developmental program of China (2017YFC1001100)

  • Chao Tong

National key research and developmental program of China (2017YFC1001500)

  • Chao Tong

Natural Science Foundation of Zhejiang Province (LR16C070001)

  • Chao Tong

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

Reviewing Editor

  1. Benoît Kornmann, University of Oxford, United Kingdom

Publication history

  1. Received: March 3, 2020
  2. Accepted: July 9, 2020
  3. Accepted Manuscript published: July 10, 2020 (version 1)
  4. Version of Record published: July 23, 2020 (version 2)

Copyright

© 2020, Xu 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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