Speakers - 2027

Title: Mitochondria and malignant neoplasms: the impact of mtdna variations on carcinogenesis

Abstract

Mitochondria play a crucial role in cellular oxidation and eukaryotic cell function, possessing their own genome (mtDNA) that encodes polypeptides of the respiratory chain complexes. While the pathogenesis of neoplasms is highly complex, the role of mtDNA alterations in carcinogenesis remains incompletely understood. Numerous studies suggest that specific mtDNA polymorphisms may either predispose individuals to or protect against certain cancers. This study investigated the potential relationship between specific mtDNA polymorphisms, mutations, and the development of brain gliomas and breast cancer in Polish Caucasian patients. Gliomas, particularly grades 3 and 4, are the most common primary malignant brain tumors with a poor prognosis, while breast cancer is the most frequently diagnosed malignancy in women. Within the glioma cohort, mitochondrial haplogroup H was the most prevalent in patients with glioblastoma multiforme, whereas haplogroup K was specifically associated with grade III astrocytoma. The CYB gene, the D-loop, and the ND5 gene emerged as mutational "hot spots". In the breast cancer cohort, specific co-occurring polymorphisms (e.g., A4769G, A4727G, and position 8860) were identified. These polymorphisms most frequently affected subunit 2 of Complex I of the OXPHOS system, and mutations in cytochrome c oxidase subunit III were observed in 38% of patients. Importantly, both cohorts exhibited polymorphisms associated with mitochondrial subgroups other than the Caucasian subgroup (e.g., L0-3, Z7, D, M), suggesting a potential link between these polymorphisms and cancer susceptibility. Both homoplasmic and heteroplasmic changes were detected. The diversity of mutations and the presence of heteroplasmy likely reflect cellular adaptation to the tumor microenvironment. The strong correlation between missense and synonymous polymorphisms suggests that the cellular phenotype is influenced by their specific arrangement rather than the mutation type alone. Crucially, the coexistence of these mitochondrial polymorphisms leads to oxidative phosphorylation (OXPHOS) dysfunction. This bioenergetic impairment likely drives the metabolic reprogramming, facilitating the shift towards aerobic glycolysis. By promoting this metabolic adaptation, mtDNA mutations may significantly contribute to tumour formation and progression. Despite existing discrepancies in the literature, the multitude of mtDNA alterations identified in this study strongly justifies further research into mitochondrial metabolism in oncology.