Atypical peripheral actin band formation via overactivation of RhoA and Non-muscle myosin II in Mitofusin 2 deficient cells
- Purdue University West Lafayette, United States
- Loyola University Chicago, United States
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
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.
Reviewing Editor
- Jonathan A Cooper, Fred Hutchinson Cancer Research Center, United States
Version history
- Preprint posted: October 4, 2022 (view preprint)
- Received: April 21, 2023
- Accepted: September 19, 2023
- Accepted Manuscript published: September 19, 2023 (version 1)
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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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
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