Abodulikemu Adilai, Li Li, Juaiti Mukamengjiang
Department of Coronary Care Unit, Traditional Chinese Medical Hospital of Xinjiang Uygur Autonomous Region, The Affiliated Hospital of Traditional Chinese Medicine of Xinjiang Medical University, Urumqi, China.
Department of Cardiology, Changsha Institute of Cardiovascular Medicine, Changsha Fourth Hospital, Changsha, China.
Medicine (Baltimore). 2025 Mar 7;104(10):e41757. doi: 10.1097/MD.0000000000041757.
Mitochondrial dysfunction has been implicated in the pathogenesis of aortic aneurysms (AA); however, the causal role of mitochondrial-related proteins remains unclear. This study employs a Mendelian randomization (MR) approach to investigate the potential causal relationship between mitochondrial proteins and AA. Genetic instruments for mitochondrial proteins were obtained from the IEU Open genome-wide association study database, while AA-related genetic data were sourced from the FinnGen biobank. Inverse-variance weighting (IVW) served as the primary MR method, with MR-Egger and weighted median approaches utilized as complementary methods. Sensitivity analyses, including Cochran Q test, MR-Egger intercept, and MR-PRESSO, were performed to assess heterogeneity and pleiotropy. Reverse MR analysis was conducted to exclude the possibility of reverse causation. To enhance the robustness of the findings, replication was carried out using genome-wide association study Catalog data, and a meta-analysis was performed by integrating discovery and replication datasets. Gene expression validation was conducted using the Gene Expression Omnibus dataset, and gene set enrichment analysis (GSEA) was applied to explore relevant biological pathways. Additionally, in vitro experiments employing platelet-derived growth factor-BB-induced human aortic smooth muscle cells were performed to validate the expression patterns of mitochondrial-related proteins at both mRNA and protein levels. Through rigorous genetic variant selection, MR analysis using IVW, sensitivity analyses, replication, and meta-analysis, we identified iron-sulfur cluster assembly enzyme (ISCU), 39S ribosomal protein L14 (MRPL14), and mitochondrial peptide methionine sulfoxide reductase (MSRA) as mitochondrial proteins associated with AA. Sensitivity analyses confirmed the robustness of these findings, with no evidence of heterogeneity or pleiotropy. Reverse MR analysis ruled out reverse causation. Gene expression analysis demonstrated that ISCU was significantly upregulated, whereas MRPL14 and MSRA were downregulated in AA tissues. GSEA revealed that these proteins are involved in pathways related to inflammation, immune response, and vascular remodeling. In vitro experiments further corroborated these findings, demonstrating consistent expression patterns in platelet-derived growth factor-BB-induced human aortic smooth muscle cells. This study provides robust genetic and experimental evidence supporting the causal role of ISCU, MRPL14, and MSRA in AA pathogenesis. These mitochondrial proteins may serve as potential biomarkers and therapeutic targets for AA, warranting further investigation.
线粒体功能障碍与主动脉瘤（AA）的发病机制有关；然而，线粒体相关蛋白的因果作用仍不清楚。本研究采用孟德尔随机化（MR）方法来研究线粒体蛋白与AA之间的潜在因果关系。线粒体蛋白的遗传工具来自IEU开放全基因组关联研究数据库，而AA相关的遗传数据则来自芬兰生物银行。逆方差加权（IVW）作为主要的MR方法，MR-Egger和加权中位数方法作为补充方法。进行了敏感性分析，包括Cochran Q检验、MR-Egger截距和MR-PRESSO，以评估异质性和多效性。进行了反向MR分析以排除反向因果关系的可能性。为了增强研究结果的稳健性，使用全基因组关联研究目录数据进行了重复验证，并通过整合发现和重复数据集进行了荟萃分析。使用基因表达综合数据集进行基因表达验证，并应用基因集富集分析（GSEA）来探索相关的生物学途径。此外，进行了体外实验，采用血小板衍生生长因子-BB诱导的人主动脉平滑肌细胞，以验证线粒体相关蛋白在mRNA和蛋白质水平上的表达模式。通过严格的遗传变异选择、使用IVW的MR分析、敏感性分析、重复验证和荟萃分析，我们确定铁硫簇组装酶（ISCU）、39S核糖体蛋白L14（MRPL14）和线粒体肽甲硫氨酸亚砜还原酶（MSRA）为与AA相关的线粒体蛋白。敏感性分析证实了这些发现的稳健性，没有异质性或多效性的证据。反向MR分析排除了反向因果关系。基因表达分析表明，ISCU在AA组织中显著上调，而MRPL14和MSRA则下调。GSEA显示这些蛋白参与了与炎症、免疫反应和血管重塑相关的途径。体外实验进一步证实了这些发现，在血小板衍生生长因子-BB诱导的人主动脉平滑肌细胞中显示出一致的表达模式。本研究提供了有力的遗传和实验证据，支持ISCU、MRPL14和MSRA在AA发病机制中的因果作用。这些线粒体蛋白可能作为AA的潜在生物标志物和治疗靶点，值得进一步研究。
