Functional and clinical impact of mitochondrial DNA variants in ovarian and colorectal cancer

Mitochondrial DNA (mtDNA) mutations are frequently reported across several solid tumors. Despite recent progress, the functional characterization of mtDNA variants in cancer and their impact on patients’ clinical outcome remain poorly understood. In the present study, we characterized the mitochondrial genome in two distinct cohorts: women with ovarian cancer (OC) and patients with colorectal cancer (CRC). We identified 110 mtDNA variants in the OC cohort and 81 mtDNA variants in the CRC cohort. We examined their abundance, described their molecular features, and investigated their functional implications at both transcriptomic and tissue levels, revealing alterations in key pathways related to metabolism, cell motility and proliferation. We further assessed the association between mtDNA variants and clinical outcomes, finding that nearly homoplasmic variants were linked to improved survival in epithelial ovarian cancer (EOC) patients, but showed no significant prognostic effect in CRC. To gain mechanistic insight, we employed advanced genetic engineering approaches to generate murine CRC experimental models and evaluate the molecular and metabolic impact of variants targeting Mt-Nd5, a subunit of Complex I encoded in the mitochondrial genome. In this context, we demonstrated a pronounced antiproliferative effect induced by BAY-402234, a dihydroorotate dehydrogenase (DHODH) inhibitor, which occurred independently of Mt-Nd5 mutational status. Collectively, this thesis reveals that mtDNA variants could be considered as potential prognostic biomarkers in ovarian cancer and preliminary evidence suggests that mitochondrial dysfunction may contribute to a less invasive tumor phenotype with more favorable immune landscape.