MTG2 as a Causal and Druggable Target in Uveal Melanoma via Mitochondrial DNA Dynamics: Evidence From Functional Validation and DMSA Identification.

Purpose: Mitochondrial dysfunction is increasingly recognized as a pivotal factor in cancer pathogenesis. We thus explored the causal role of mitochondrial-related genes (MRGs) in uveal melanoma (UM) and the underlying mechanisms. Methods: We performed Mendelian randomization (MR) analysis using 1693 cis-expression quantitative trait loci (cis-eQTLs) of MRGs as instrumental variables and genome-wide association data (GWAS) of UM. Colocalization analysis assessed whether gene expression and UM risk shared a common causal variant. Further, mediation MR and in vitro functional assays were used to validate key findings and explore their biological relevance. A molecular docking-based virtual screening strategy, followed by experimental validation, was used to identify potential therapeutic compounds. Results: MR analysis identified 57 MRGs significantly associated with UM risk after Bonferroni correction (P < 0.05/1693). Among them, MTG2 or GTPBP5, encoding a mitochondrial ribosome-associated GTPase, showed strong colocalization with UM susceptibility (PP.H4 = 75%). Silencing MTG2 in UM cell lines induced PARP cleavage and markedly suppressed cell proliferation and colony formation. Mediation analysis revealed that mitochondrial DNA (mtDNA) heteroplasmy at chrM:567 (A:ACCCCCC) partially mediates MTG2's effect on UM (4%). Moreover, both genetically driven analysis and qPCR confirmed a positive association between MTG2 expression and mtDNA copy number. Notably, dimercaptosuccinic acid (DMSA), identified as a potential MTG2 inhibitor, reduced MTG2 levels and promoted apoptosis in UM cells. Conclusions: Our integrative genomic and experimental approach uncovers MTG2 as a causal contributor to UM pathogenesis, potentially through modulation of mtDNA heteroplasmy and copy number. DMSA emerges as a promising therapeutic agent targeting mitochondrial dysregulation in UM.