1. Cell Biology
Download icon

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 0
  • Views 1,490
  • Annotations
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.

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.

Metrics

  • 1,490
    Page views
  • 322
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cell Biology
    2. Developmental Biology
    Neta Erez et al.
    Research Article

    A hallmark of aging is loss of differentiated cell identity. Aged Drosophila midgut differentiated enterocytes (ECs) lose their identity, impairing tissue homeostasis. To discover identity regulators, we performed an RNAi screen targeting ubiquitin-related genes in ECs. Seventeen genes were identified, including the deubiquitinase Non-stop (CG4166). Lineage tracing established that acute loss of Non-stop in young ECs phenocopies aged ECs at cellular and tissue levels. Proteomic analysis unveiled that Non-stop maintains identity as part of a Non-stop identity complex (NIC) containing E(y)2, Sgf11, Cp190, (Mod) mdg4, and Nup98. Non-stop ensured chromatin accessibility, maintaining the EC-gene signature, and protected NIC subunit stability. Upon aging, the levels of Non-stop and NIC subunits declined, distorting the unique organization of the EC nucleus<strong>.</strong> Maintaining youthful levels of Non-stop in wildtype aged ECs safeguards NIC subunits, nuclear organization, and suppressed aging phenotypes. Thus, Non-stop and NIC, supervise EC identity and protects from premature aging.

    1. Cell Biology
    Ahmad F Alghanem et al.
    Research Article

    The endothelium responds to numerous chemical and mechanical factors in regulating vascular tone, blood pressure and blood flow. The endothelial volume regulatory anion channel (VRAC) has been proposed to be mechano-sensitive and thereby sense fluid flow and hydrostatic pressure to regulate vascular function. Here, we show that the Leucine Rich Repeat Containing Protein 8a, LRRC8A (SWELL1) is required for VRAC in human umbilical vein endothelial cells (HUVECs). Endothelial LRRC8A regulates AKT-eNOS signaling under basal, stretch and shear-flow stimulation, forms a GRB2-Cav1-eNOS signaling complex, and is required for endothelial cell alignment to laminar shear flow. Endothelium-restricted Lrrc8a KO mice develop hypertension in response to chronic angiotensin-II infusion and exhibit impaired retinal blood flow with both diffuse and focal blood vessel narrowing in the setting of Type 2 diabetes (T2D). These data demonstrate that LRRC8A regulates AKT-eNOS in endothelium and is required for maintaining vascular function, particularly in the setting of T2D.