Transferred mitochondria accumulate reactive oxygen species, promoting proliferation

Abstract

Recent studies reveal that lateral mitochondrial transfer, the movement of mitochondria from one cell to another, can affect cellular and tissue homeostasis1,2. Most of what we know about mitochondrial transfer stems from bulk cell studies and have led to the paradigm that functional transferred mitochondria restore bioenergetics and revitalize cellular functions to recipient cells with damaged or non-functional mitochondrial networks3. However, we show that mitochondrial transfer also occurs between cells with functioning endogenous mitochondrial networks, but the mechanisms underlying how transferred mitochondria can promote such sustained behavioral reprogramming remain unclear. We report that unexpectedly, transferred macrophage mitochondria are dysfunctional and accumulate reactive oxygen species in recipient cancer cells. We further discovered that reactive oxygen species accumulation activates ERK signaling, promoting cancer cell proliferation. Pro-tumorigenic macrophages exhibit fragmented mitochondrial networks, leading to higher rates of mitochondrial transfer to cancer cells. Finally, we observe that macrophage mitochondrial transfer promotes tumor cell proliferation in vivo. Collectively these results indicate that transferred macrophage mitochondria activate downstream signaling pathways in a ROS-dependent manner in cancer cells, and provide a model of how sustained behavioral reprogramming can be mediated by a relatively small amount of transferred mitochondria in vitro and in vivo.

Data availability

The code for QPI analysis is available on GitHub (https://github.com/Zangle-Lab/Macrophage_tumor_mito_transfer) for Figure 1.Single-cell RNA-sequencing data are available in GEO accession number GSE181410. The code for single-cell RNA-sequencing analysis is available on GitHub (https://github.com/rohjohnson-lab/kidwell_casalini_2021) for Figure 1.

The following data sets were generated

Article and author information

Author details

  1. Chelsea U Kidwell

    Department of Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4269-2503
  2. Joseph R Casalini

    Department of Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Soorya Pradeep

    Department of Chemical Engineering, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sandra D Scherer

    Department of Oncological Sciences, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7943-8595
  5. Daniel Greiner

    Department of Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Defne Bayik

    Department of Cardiovascular and Metabolic Sciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Dionysios C Watson

    Department of Cardiovascular and Metabolic Sciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Gregory S. Olson

    Medical Scientist Training Program, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Justin D Lathia

    Department of Cardiovascular and Metabolic Sciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jarrod S Johnson

    Department of Pathology, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7355-5240
  11. Jared Rutter

    Department of Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2710-9765
  12. Alana L Welm

    Department of Oncological Sciences, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Thomas A Zangle

    Department of Chemical Engineering, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Minna Roh-Johnson

    Department of Biochemistry, University of Utah, Salt Lake City, United States
    For correspondence
    roh-johnson@biochem.utah.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3961-4547

Funding

National Institutes of Health (R37CA247994)

  • Minna Roh-Johnson

VeloSano Bike Ride

  • Defne Bayik
  • Dionysios C Watson
  • Justin D Lathia

U.S. Department of Defense (W81XWH1910065)

  • Thomas A Zangle

National Institutes of Health (U54CA224076)

  • Alana L Welm

Breast Cancer Research Foundation

  • Alana L Welm

U.S. Department of Defense (W81XWH-20-1-0591)

  • Minna Roh-Johnson

The Mary Kay Foundation (10-19)

  • Minna Roh-Johnson

National Institutes of Health (R00CA190836)

  • Chelsea U Kidwell
  • Minna Roh-Johnson

National Institutes of Health (F31CA250317)

  • Joseph R Casalini

National Institutes of Health (K99 CA248611)

  • Defne Bayik

National Institutes of Health (TL1 TR002549)

  • Dionysios C Watson

Lerner Research Institute, Cleveland Clinic

  • Justin D Lathia

Case Comprehensive Cancer Center, Case Western Reserve University

  • Justin D Lathia

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

Reviewing Editor

  1. Lydia W S Finley, Memorial Sloan Kettering Cancer Center, United States

Ethics

Animal experimentation: All animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of Utah (PHS Assurance Registration Number: A3031-01; USDA Registration Number: 87-R-0001; protocol #19-12001) and at the Cleveland Clinic (protocol #2179). In accordance to approved protocol, all animals were anesthetized appropriately to assure maximum comfort throughout the duration of procedures. When tumors were grown to approved volumes, mice were humanely euthanized with slow C02 gas exchange for 5 minutes.

Version history

  1. Preprint posted: August 10, 2021 (view preprint)
  2. Received: December 10, 2022
  3. Accepted: March 1, 2023
  4. Accepted Manuscript published: March 6, 2023 (version 1)
  5. Version of Record published: March 27, 2023 (version 2)

Copyright

© 2023, Kidwell 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. Chelsea U Kidwell
  2. Joseph R Casalini
  3. Soorya Pradeep
  4. Sandra D Scherer
  5. Daniel Greiner
  6. Defne Bayik
  7. Dionysios C Watson
  8. Gregory S. Olson
  9. Justin D Lathia
  10. Jarrod S Johnson
  11. Jared Rutter
  12. Alana L Welm
  13. Thomas A Zangle
  14. Minna Roh-Johnson
(2023)
Transferred mitochondria accumulate reactive oxygen species, promoting proliferation
eLife 12:e85494.
https://doi.org/10.7554/eLife.85494

Share this article

https://doi.org/10.7554/eLife.85494

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