Causal role of mitochondrial proteins in aortic aneurysms: Evidence from Mendelian randomization, transcriptomic...

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.