Mitochondrial genome transfer drives metabolic reprogramming in adjacent colonic epithelial cells promoting TGFβ1-mediated tumor progression.
Bingjie GuanYoudong LiuBowen XieSenlin ZhaoAbudushalamu YalikunWeiwei ChenMenghua ZhouQi GuDongwang YanPublished in: Nature communications (2024)
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.
Keyphrases
- mitochondrial dna
- copy number
- poor prognosis
- transforming growth factor
- reactive oxygen species
- oxidative stress
- induced apoptosis
- genome wide
- long non coding rna
- cell cycle arrest
- epithelial mesenchymal transition
- cell death
- end stage renal disease
- dna damage
- dna methylation
- newly diagnosed
- chronic kidney disease
- endoplasmic reticulum stress
- ulcerative colitis
- peritoneal dialysis
- binding protein
- cell adhesion