Laterally transferred macrophage mitochondria act as a signaling source promoting cancer cell proliferation

Lateral transfer of mitochondria occurs in many physiological and pathological conditions. Given that mitochondria provide essential energy for cellular activities, mitochondrial transfer is currently thought to promote the rescue of damaged cells. We report that mitochondrial transfer occurs between macrophages and breast cancer cells, leading to increased cancer cell proliferation. Unexpectedly, transferred macrophage mitochondria are dysfunctional, lacking mitochondrial membrane potential. Rather than performing essential mitochondrial activities, transferred mitochondria accumulate reactive oxygen species which activates ERK signaling, indicating that transferred mitochondria act as a signaling source that promotes cancer cell proliferation. We also demonstrate that pro-tumorigenic M2-like macrophages exhibit increased mitochondrial transfer to cancer cells. Collectively, our findings reveal how mitochondrial transfer is regulated and leads to sustained functional changes in recipient cells. One-Sentence Summary Lateral transfer of macrophage mitochondria acts as a ROS signaling source, regulating cancer cell proliferation through ERK signaling. ### Competing Interest Statement University of Utah may license PDxO models to for-profit companies, which may result in tangible property royalties to members of the Welm lab (SDS and ALW). The other authors declare that they have no competing interests.