Hao Jianheng, Liu Liying, Chang Boya, Zhao Yuemeng, Lai Yuanyuan, Tian Chunhui, Xu Huichao, Wang Haijun, Ji Laixi, Yang Jie
The Second Clinical College, Shanxi University of Chinese Medicine, Jinzhong 030619, China; College of acupuncture and massage, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China.
College of acupuncture and massage, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China.
Exp Gerontol. 2025 Sep;208:112825. doi: 10.1016/j.exger.2025.112825. Epub 2025 Jul 10.
Mitochondrial dysfunction is a key hallmark of aging, and blood-based biomarkers related to mitochondrial genes provide an effective means to assess ovarian aging progression. In this study, we aimed to explore the role of mitochondrial dysfunction-related genetic variations in determining the natural age at menopause (ANM) by applying both Mendelian randomization (MR) and summary data-based Mendelian randomization (SMR) approaches, complemented by experimental validation in animal models.
Summary statistics on ANM, gene expression, DNA methylation, and protein abundance quantitative trait loci (eQTL, mQTL, pQTL) were obtained from public databases. Genetic variations associated with mitochondrial dysfunction were selected as instrumental variables, and SMR analysis was performed to investigate causal relationships with ANM. MR methods were also used to evaluate the causal effect of mitochondrial DNA copy number (mtDNA-CN) on ANM, with preliminary validation through animal experiments.
SMR and meta-analysis results identified NSUN4 as a critical regulator of ANM at both the gene expression and DNA methylation levels. A preliminary causal relationship between reduced mtDNA-CN and increased ANM risk was found, though further validation with larger datasets is needed. Animal experiments indicated that NSUN4 levels in blood reflect ovarian function decline and may correlate with its expression in ovarian tissue.
The findings suggest that NUSN4 levels detected in the blood could serve as a potential biomarker for ovarian aging. This provides new insights into the role of mitochondrial dysfunction in reproductive age-related traits and may inform future targeted interventions to slow ovarian aging.
线粒体功能障碍是衰老的关键标志，与线粒体基因相关的血液生物标志物为评估卵巢衰老进程提供了一种有效手段。在本研究中，我们旨在通过应用孟德尔随机化（MR）和基于汇总数据的孟德尔随机化（SMR）方法，并辅以动物模型的实验验证，来探索线粒体功能障碍相关基因变异在确定自然绝经年龄（ANM）中的作用。
从公共数据库中获取关于ANM、基因表达、DNA甲基化和蛋白质丰度数量性状位点（eQTL、mQTL、pQTL）的汇总统计数据。选择与线粒体功能障碍相关的基因变异作为工具变量，并进行SMR分析以研究与ANM的因果关系。还使用MR方法评估线粒体DNA拷贝数（mtDNA-CN）对ANM的因果效应，并通过动物实验进行初步验证。
SMR和荟萃分析结果确定NSUN4在基因表达和DNA甲基化水平上均为ANM的关键调节因子。发现mtDNA-CN降低与ANM风险增加之间存在初步因果关系，不过需要用更大的数据集进行进一步验证。动物实验表明，血液中的NSUN4水平反映卵巢功能下降，并且可能与其在卵巢组织中的表达相关。
研究结果表明，血液中检测到的NUSN4水平可能作为卵巢衰老的潜在生物标志物。这为线粒体功能障碍在生殖年龄相关性状中的作用提供了新的见解，并可能为未来减缓卵巢衰老的靶向干预提供依据。
