Mitochondrial DNA mutations and intercellular mitochondrial transfer in cancer: mechanisms, biological effects, and clinical potential

Mitochondrial DNA (mtDNA) mutations are frequently detected in tumor cells and represent a distinctive aspect of cancer genomics. Common types of mtDNA alterations include single nucleotide variants, insertions and deletions, and copy number changes. These mutations often result in a range of biological effects, encompassing both in situ and ectopic mechanisms. In situ, mutant mtDNA may lead to respiratory chain dysfunction, impairing oxidative phosphorylation and shifting energy production toward glycolysis and other metabolic pathways. This metabolic reprogramming, along with altered glutamine and lipid metabolism, is frequently accompanied by reactive oxygen species accumulation, which can activate pro-tumorigenic signaling cascades and contribute to genomic instability. These changes promote cancer cell proliferation, enhance invasive and metastatic potential, and facilitate immune evasion. Moreover, through mitochondrial transfer mechanisms such as tunneling nanotubes, extracellular vesicles, cell fusion, or gap junction channels, mutant mtDNA can be transmitted to other cells, serving as an important mode of intercellular communication within tumors. This process promotes tumor progression and metastasis, regulates apoptotic pathways, facilitates immune evasion, and enhances therapeutic resistance, allowing mutant mtDNA to exert ectopic effects. Clinically, mtDNA mutations hold substantial potential in oncology, with applications spanning tumor diagnosis, disease monitoring, therapeutic resistance prediction, and prognosis assessment. Analysis of tumor tissue or circulating cell-free mtDNA provides a promising non-invasive approach for these purposes. In addition, the involvement of mtDNA mutations in regulating tumor metabolism and mediating intercellular communication underscores their value as potential therapeutic targets, making them a prominent focus of current cancer research.