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 homeostasis. 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 networks. 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.

Document Details

Document Type
Pub Defense Publication
Publication Date
Mar 06, 2023
Source ID
10.7554/elife.85494

Entities

People

  • Alana L Welm
  • Chelsea U. Kidwell
  • Daniel Greiner
  • Defne Bayik
  • Dionysios C Watson
  • Gregory S Olson
  • Jared Rutter
  • Jarrod S. Johnson
  • Joseph Casalini
  • Justin D. Lathia
  • Minna Roh‐Johnson
  • Sandra D. Scherer
  • Soorya Pradeep
  • Thomas A. Zangle

Organizations

  • Case Comprehensive Cancer Center
  • Case Western Reserve University
  • Cleveland Clinic Lerner Research Institute
  • Howard Hughes Medical Institute
  • Mary Kay Foundation
  • National Institutes of Health
  • The Breast Cancer Research Foundation
  • United States Department of Defense
  • University Hospitals of Cleveland
  • University of Utah
  • University of Washington

Tags

Fields of Study

  • Biology

Readers

  • Molecular Photonics/Laser Physics
  • Molecular and Cellular Biology