Transferred mitochondria accumulate reactive oxygen species, promoting proliferation
- University of Utah, United States
- Case Western Reserve University, United States
- University of Washington, United States
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.
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Macrophage and MDA-MB-231 coculture and mitochondrial transferNCBI Gene Expression Omnibus, GSE181410.
Article and author information
Author details
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.
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.
Reviewing Editor
- Lydia W S Finley, Memorial Sloan Kettering Cancer Center, United States
Publication history
- Preprint posted: August 10, 2021 (view preprint)
- Received: December 10, 2022
- Accepted: March 1, 2023
- Accepted Manuscript published: March 6, 2023 (version 1)
- 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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Transferred mitochondria accumulate reactive oxygen species, promoting proliferation
eLife 12:e85494.
https://doi.org/10.7554/eLife.85494
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