Mitochondrial FIS1 As a Novel Drug Target for the Treatment of Erectile Dysfunction: A Multi-Omic and Epigenomic Association Study

Purpose: Mitochondrial dysfunction may impact male erectile function, but the underlying genetic mechanisms remain unclear. The study aims to investigate the causal role for genetically regulated mitochondrial function in erectile dysfunction (ED) and to identify potential drug targets for the treatment of ED.

Materials and methods: The data of gene methylation, gene expression and protein level related to mitochondria were extracted from the corresponding genome-wide association studies (GWAS) database. Discovery and validation datasets for ED were sourced from research by Bovijn et al, the FinnGen database, and the UK Biobank. We performed summary-data-based Mendelian randomization analysis, colocalization analysis, as well as molecular prediction and molecular docking analysis to assess the association between mitochondrial dysfunction and ED. We also identified relevant targets and potential molecules for the treatment of ED.

Results: Through the integration of multi-omics results, we identified an inverse relationship between the expression of the mitochondrial-related gene FIS1 and the risk of ED (odds ratio [OR]: 0.89, 95% confidence interval [CI]: 0.81-0.97, p-value of summary-data-based Mendelian randomization analysis [PSMR]=1.01×10^-2). In FIS1, methylation of cg19802458 and cg08601038 was related to high expression of the FIS1 gene, which is consistent with the protective effects of cg19802458 and cg08601038 methylation against ED. Additionally, elevated levels of FIS1 protein displayed a negative association with ED risk (OR: 0.71, 95% CI: 0.55-0.92, PSMR=1.00×10^-2). Molecular prediction and molecular docking analysis revealed that resveratrol and quercetin had protective effects against ED by targeting FIS1, and had good affinity and binding mode with FIS1, respectively.

Conclusions: This study demonstrated the causal relationship between the mitochondrial FIS1 gene and ED risk and found that resveratrol and quercetin may have therapeutic effects on ED. These discoveries offer fresh perspectives on the pathogenesis of ED and propose preliminary candidate targets and drugs for future treatment of ED.