Intercellular Mitochondrial Transfer between Fibroblasts and Macrophages: An Extrinsic Mechanism for Organelle Quality Control

Abstract

Mitochondrial quality control is traditionally viewed as a cell-autonomous process mediated by intracellular surveillance and mitophagy. Here, I show that fibroblasts can also export mitochondrial material that is selectively acquired by neighboring macrophages under steady-state conditions. Using in vitro co-culture systems, flow cytometry, live-cell imaging, mitochondrial DNA analysis, and quantitative PCR, I found that mitochondrial transfer occurred rapidly, was enriched in macrophages over lymphocytes, and displayed specificity for mitochondria relative to other organelles. Mechanistically, efficient transfer was not recapitulated by conditioned medium or physically separated co-culture, but imaging supported a vesicle-mediated route, and perturbation of mitochondrial quality-control pathways showed that export was regulated by mitochondrial stress and BNIP3/NIX-dependent programs. In vivo lineage tracing further demonstrated transfer of fibroblast-derived mitochondrial material to myeloid cells across multiple tissues. Together, these findings identify fibroblast-to-macrophage mitochondrial transfer as a selective and regulated tissue-level mechanism of organelle handling beyond cell-autonomous mitophagy.