Zhu Tianle, Gao Pan, Ma Yukuai, Yang Peng, Cao Zhi, Gao Jingjing, Du Junhua, Jiang Hui, Zhang Xiansheng
Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Department of Urology, Peking University First Hospital, Beijing, China.
World J Mens Health. 2024 Oct 16. doi: 10.5534/wjmh.240131.
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.
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.
Through the integration of multi-omics results, we identified an inverse relationship between the expression of the mitochondrial-related gene 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). In FIS1, methylation of cg19802458 and cg08601038 was related to high expression of the 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). 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.
This study demonstrated the causal relationship between the mitochondrial 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.
线粒体功能障碍可能影响男性勃起功能，但其潜在的遗传机制尚不清楚。本研究旨在探讨基因调控的线粒体功能在勃起功能障碍（ED）中的因果作用，并确定治疗ED的潜在药物靶点。
从相应的全基因组关联研究（GWAS）数据库中提取与线粒体相关的基因甲基化、基因表达和蛋白质水平的数据。ED的发现和验证数据集来自Bovijn等人的研究、芬兰基因数据库和英国生物银行。我们进行了基于汇总数据的孟德尔随机化分析、共定位分析以及分子预测和分子对接分析，以评估线粒体功能障碍与ED之间的关联。我们还确定了治疗ED的相关靶点和潜在分子。
通过整合多组学结果，我们发现线粒体相关基因的表达与ED风险呈负相关（优势比[OR]：0.89，95%置信区间[CI]：0.81 - 0.97，基于汇总数据的孟德尔随机化分析的p值[PSMR]=1.01×10）。在FIS1中，cg19802458和cg08601038的甲基化与该基因的高表达相关，这与cg19802458和cg08601038甲基化对ED的保护作用一致。此外，FIS1蛋白水平升高与ED风险呈负相关（OR：0.71，95% CI：0.55 - 0.92，PSMR=1.00×10）。分子预测和分子对接分析表明，白藜芦醇和槲皮素通过靶向FIS1对ED具有保护作用，并且分别与FIS1具有良好的亲和力和结合模式。
本研究证明了线粒体基因与ED风险之间的因果关系，并发现白藜芦醇和槲皮素可能对ED具有治疗作用。这些发现为ED的发病机制提供了新的视角，并为未来ED的治疗提出了初步的候选靶点和药物。
