Gong Binbin, Yang Feixiang, Zhang Ning, Wu Zhengyang, Liu Tianrui, Wang Kun, Zhang Xiangyu, Zhang Yangyang, Song Zhengyao, Liang Chaozhao
Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Institute of Urology, Anhui Medical University, Hefei, China.
Front Genet. 2025 Aug 22;16:1609933. doi: 10.3389/fgene.2025.1609933. eCollection 2025.
Prostatic diseases, consisting of prostatitis, benign prostatic hyperplasia (BPH), and prostate cancer (PCa), pose significant health challenges. While single-omics studies have provided valuable insights into the role of mitochondrial dysfunction in prostatic diseases, integrating multi-omics approaches is essential for uncovering disease mechanisms and identifying therapeutic targets.
A genome-wide meta-analysis was conducted for prostatic diseases using the genome-wide association studies (GWAS) data from FinnGen and UK Biobank. Mitochondrial dysfunction-related genes were reviewed based on MitoCarta 3.0, with a library containing 1,244 mitochondrial genes. We integrated multi-omics through quantitative trait loci (QTL) across gene expression (eQTLs), protein abundance (pQTLs), and DNA methylation (mQTLs). We prioritized prostatic disease-related mitochondrial genes into three confidence tiers: Tier 1 (two eQTLs + pQTL + mQTL); Tier 2 (two eQTLs + pQTL/mQTL); and Tier 3 (eQTL + pQTL/mQTL). Further mediation analyses were performed to explore potential mediating pathways for the interaction between mitochondrial dysfunction and prostatic diseases, with 1,400 metabolomics and 731 immunomics.
We identified DCXR as the gene with Tier 1 evidence for BPH, validated by multi-omics integration through transcriptomic, proteomic, and methylomic signatures. We revealed two Tier 2 genes (NOA1 and ELAC2) and one Tier 3 gene (ACAT1) for BPH, two Tier 3 genes (TRMU and SFXN5) for prostatitis, and six Tier 3 genes (MRPL24, NDUFS6, PUS1, NBR1, GLOD4, and PCBD2) for PCa. We also explored the mediating pathways of mitochondrial genes (within the 3-tiers evidence) on prostatic diseases, and identified 8, 4, and 13 metabolites mediating the interaction between mitochondrial genes and BPH, prostatitis, and PCa, respectively, without the involvement of immune characters.
These findings highlight the roles of mitochondrial dysfunction-related genes in prostatic diseases and identify key genes and pathways for potential therapeutic targets.
前列腺疾病，包括前列腺炎、良性前列腺增生（BPH）和前列腺癌（PCa），对健康构成重大挑战。虽然单组学研究为线粒体功能障碍在前列腺疾病中的作用提供了有价值的见解，但整合多组学方法对于揭示疾病机制和确定治疗靶点至关重要。
利用来自芬兰基因库（FinnGen）和英国生物银行（UK Biobank）的全基因组关联研究（GWAS）数据，对前列腺疾病进行全基因组荟萃分析。基于包含1244个线粒体基因的MitoCarta 3.0对线粒体功能障碍相关基因进行了综述。我们通过跨基因表达（eQTL）、蛋白质丰度（pQTL）和DNA甲基化（mQTL）的数量性状位点（QTL）整合多组学。我们将与前列腺疾病相关的线粒体基因分为三个置信等级：1级（两个eQTL + pQTL + mQTL）；2级（两个eQTL + pQTL/mQTL）；3级（eQTL + pQTL/mQTL）。利用1400个代谢组学数据和731个免疫组学数据进行了进一步的中介分析，以探索线粒体功能障碍与前列腺疾病相互作用的潜在中介途径。
我们将DCXR鉴定为BPH的具有1级证据的基因，并通过转录组学、蛋白质组学和甲基化组学特征的多组学整合进行了验证。我们揭示了BPH的两个2级基因（NOA1和ELAC2）和一个3级基因（ACAT1），前列腺炎的两个3级基因（TRMU和SFXN5），以及PCa的六个3级基因（MRPL24、NDUFS6、PUS1、NBR1、GLOD4和PCBD2）。我们还探索了线粒体基因（在3级证据范围内）对前列腺疾病的中介途径，并分别确定了8种、4种和13种代谢物介导线粒体基因与BPH、前列腺炎和PCa之间的相互作用，且不涉及免疫特征。
这些发现突出了线粒体功能障碍相关基因在前列腺疾病中的作用，并确定了潜在治疗靶点的关键基因和途径。
