Mitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression

• Published in: Nature communications Vol. 15; no. 1; pp. 3653 - 18
• Main Authors: Guan, Bingjie, Liu, Youdong, Xie, Bowen, Zhao, Senlin, Yalikun, Abudushalamu, Chen, Weiwei, Zhou, Menghua, Gu, Qi, Yan, Dongwang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.04.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 42; 42/109; 42/89; 49; 49/109; 49/15; 49/22; 49/39; 49/91; 631/67/1504/1885/1393; 631/67/2327; 631/67/327; 96; Animals; Biomarkers; Cell interactions; Cell Line, Tumor; Colon - metabolism; Colon - pathology; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Crosstalk; Deoxyribonucleic acid; Disease Progression; DNA; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; Electron transport; Epithelial cells; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelium; Extracellular vesicles; Extracellular Vesicles - metabolism; Female; Gene Expression Regulation, Neoplastic; Genome, Mitochondrial; Genomes; Humanities and Social Sciences; Humans; Male; Metabolic Reprogramming; Metabolism; Mice; Middle Aged; Mitochondria - metabolism; Mitochondrial DNA; multidisciplinary; Nuclear transport; Paracrine signalling; Reactive oxygen species; Reactive Oxygen Species - metabolism; Science; Science (multidisciplinary); Signal Transduction; Smad protein; Therapeutic targets; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Translocation; Tumors; Vesicles
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48100-y

Although nontumor components play an essential role in colon cancer (CC) progression, the intercellular communication between CC cells and adjacent colonic epithelial cells (CECs) remains poorly understood. Here, we show that intact mitochondrial genome (mitochondrial DNA, mtDNA) is enriched in serum extracellular vesicles (EVs) from CC patients and positively correlated with tumor stage. Intriguingly, circular mtDNA transferred via tumor cell-derived EVs (EV-mtDNA) enhances mitochondrial respiration and reactive oxygen species (ROS) production in CECs. Moreover, the EV-mtDNA increases TGFβ1 expression in CECs, which in turn promotes tumor progression. Mechanistically, the intercellular mtDNA transfer activates the mitochondrial respiratory chain to induce the ROS-driven RelA nuclear translocation in CECs, thereby transcriptionally regulating TGFβ1 expression and promoting tumor progression via the TGFβ/Smad pathway. Hence, this study highlights EV-mtDNA as a major driver of paracrine metabolic crosstalk between CC cells and adjacent CECs, possibly identifying it as a potential biomarker and therapeutic target for CC. The interaction between colon cancer cells and colonic epithelial cells (CECs) is critical yet not well-known. Here, the authors show that tumor extracellular vesicles mediate mitochondrial DNA transfer to CECs, initiating mitochondrial activation and RelA-induced TGFβ1 expression, leading to tumor progression.