Atypical peripheral actin band formation via overactivation of RhoA and Non-muscle myosin II in Mitofusin 2 deficient cells

Abstract

Cell spreading and migration play central roles in many physiological and pathophysiological processes. We have previously shown that MFN2 regulates the migration of human neutrophil-like cells via suppressing Rac activation. Here, we show that in mouse embryonic fibroblasts, MFN2 suppresses RhoA activation and supports cell polarization. After initial spreading, the wild-type cells polarize and migrate, whereas the Mfn2-/- cells maintain a circular shape. Increased cytosolic Ca2+ resulting from the loss of Mfn2 is directly responsible for this phenotype, which can be rescued by expressing an artificial tether to bring mitochondria and ER to close vicinity. Elevated cytosolic Ca2+ activates Ca2+/calmodulin-dependent protein kinase II, RhoA, and Myosin light-chain kinase, causing an over-activation of non-muscle Myosin II, leading to a formation of a prominent F-actin ring at the cell periphery and increased cell contractility. The peripheral actin band alters cell physics and is dependent on substrate rigidity. Our results provide a novel molecular basis to understand how MFN2 regulates distinct signaling pathways in different cells and tissue environments, which is instrumental in understanding and treating MFN2-related diseases.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1-5, 7 and Figure 5-figure Supplement 1.

Article and author information

Author details

  1. Yueyang Wang

    Department of Biological Sciences, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Lee D Troughton

    Cell and Molecular Physiology, Loyola University Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Fan Xu

    Weldon School of Biomedical Engineering, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6298-5587
  4. Aritra Chatterjee

    Weldon School of Biomedical Engineering, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5318-3459
  5. Chang Ding

    Department of Biological Sciences, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Han Zhao

    Davidson School of Chemical Engineering, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Laura P Cifuentes

    Department of Biological Sciences, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ryan B Wagner

    School of Mechanical Engineering, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4111-8027
  9. Tianqi Wang

    Department of Biological Sciences, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Shelly Tan

    Department of Biological Sciences, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Jingjuan Chen

    Department of Animal Sciences, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Linlin Li

    Weldon School of Biomedical Engineering, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9667-2965
  13. David Umulis

    Department of Agricultural and Biological Engineering, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1913-2284
  14. Shihuan Kuang

    Department of Animal Sciences, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9180-3180
  15. Daniel M Suter

    Department of Biological Sciences, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5230-7229
  16. Chongli Yuan

    Davidson School of Chemical Engineering, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3765-0931
  17. Deva Chan

    Weldon School of Biomedical Engineering, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1508-1045
  18. Fang Huang

    Weldon School of Biomedical Engineering, Purdue University West Lafayette, West Lafayette, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Patrick W Oakes

    Cell and Molecular Physiology, Loyola University Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9951-1318
  20. Qing Deng

    Department of Biological Sciences, Purdue University West Lafayette, West Lafayette, United States
    For correspondence
    deng67@purdue.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9254-9951

Funding

National Institute of General Medical Sciences (R35GM119787)

  • Qing Deng

National Cancer Institute (P30CA023168)

  • Qing Deng

National Science Foundation (2120200)

  • Deva Chan

National Institute of General Medical Sciences (R01GM132501)

  • David Umulis

National Institute of Mental Health (R35GM119785)

  • Fang Huang

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

Copyright

© 2023, Wang 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. Yueyang Wang
  2. Lee D Troughton
  3. Fan Xu
  4. Aritra Chatterjee
  5. Chang Ding
  6. Han Zhao
  7. Laura P Cifuentes
  8. Ryan B Wagner
  9. Tianqi Wang
  10. Shelly Tan
  11. Jingjuan Chen
  12. Linlin Li
  13. David Umulis
  14. Shihuan Kuang
  15. Daniel M Suter
  16. Chongli Yuan
  17. Deva Chan
  18. Fang Huang
  19. Patrick W Oakes
  20. Qing Deng
(2023)
Atypical peripheral actin band formation via overactivation of RhoA and Non-muscle myosin II in Mitofusin 2 deficient cells
eLife 12:e88828.
https://doi.org/10.7554/eLife.88828

Share this article

https://doi.org/10.7554/eLife.88828

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