Impact of Mitochondrial‐Associated Proteins on Erectile Dysfunction: Insights From Mendelian Randomization Analysis

Background: Mitochondrial dysfunction is implicated in the pathogenesis of erectile dysfunction (ED); establishing a causal relationship remains a challenge. This study employed a two‐sample Mendelian randomization (MR) approach to investigate the potential causal associations between mitochondria‐associated proteins and ED. Methods: Association data on mitochondria‐associated proteins from the IEU OpenGWAS database were used for exposure, whereas ED association data from the UK Biobank and FinnGen databases served as the outcome. MR analyses were conducted separately, primarily employing the inverse‐variance weighted (IVW) method and supplemented by the MR‐Egger, weighted median, simple mode, and weighted mode methods. Sensitivity analyses included Cochran’s Q test, MR‐Egger test, leave‐one‐out analysis, and MR‐PRESSO. A meta‐analysis of both databases was conducted to enhance the credibility of the results. Results: Meta‐analysis revealed a significant causal relationship between five mitochondria‐related proteins and ED: 39S ribosomal protein L33 (RPL33; p = 0.013; odds ratio [OR] = 0.94; 95% confidence interval [CI]: 0.90–0.99), mitochondrial ubiquitin ligase activator of NFKB‐1 (MULAN1; p = 0.039; OR = 1.08; 95% CI: 1.00–1.16), nucleoside diphosphate‐linked moiety X motif ‐8 (NUDT8; p = 0.035; OR = 0.92; 95% CI: 0.84–0.99), pyruvate dehydrogenase (acetyl‐transferring) kinase isozyme‐1 (PDK1; p = 0.047; OR = 1.07; 95% CI: 1.00–1.14), and serine‐tRNA ligase (SerRS; p = 0.005; OR = 1.18; 95% CI: 1.05–1.33). Sensitivity analyses revealed no abnormalities. Conclusion: RPL33 and NUDT8 exhibited potential protective effects against ED, whereas MULAN1, PDK1, and SerRS may increase the risk of developing ED. These findings offer new insights into the role of mitochondrial dysfunction in ED pathogenesis and may guide the development of future therapeutic strategies.