Mitochondrial Metabolism-Related Candidate Signatures in Calcific Aortic Valve Disease Spectrum: An Exploratory Integrative Bioinformatics Study.

Abstract

​Calcific aortic valve disease (CAVD) is a progressive valvular disorder in which the role of mitochondrial metabolism remains incompletely understood. This exploratory study aimed to identify mitochondrial metabolism-related genes (MIMMRGs) associated with CAVD-spectrum valve remodeling. GSE83453 was used as the training dataset, and GSE51472 was used for expression-direction validation. Both datasets contain biologically and phenotypically heterogeneous groups of diseased valves. CAVD-associated differentially expressed genes (DEGs) were integrated with MIMMRGs, followed by functional enrichment analysis, least absolute shrinkage and selection operator (LASSO), and support vector machine-recursive feature elimination (SVM-RFE), expression validation, immune infiltration analysis, transcription factor analysis, drug and compound prediction, and molecular docking. A total of 909 DEGs and 1,234 MIMMRGs were identified, yielding 67 candidate genes enriched in metabolic and biosynthetic processes. ACADL and TDO2 were identified as candidate biomarkers and exhibited consistent expression differences between CAVD and normal samples in both datasets. Gene set enrichment analysis indicated the involvement of chemokine-related and immune-regulatory pathways. Four immune cell types differed between the CAVD and normal groups, and ACADL and TDO2 exhibited opposite correlations with naive B cells. HNF4A, STAT3, and AR were predicted to be common transcriptional regulators. Molecular docking indicated favorable in silico interactions between doxorubicin and ACADL and between dexamethasone and TDO2. In conclusion, ACADL and TDO2 are candidate biomarkers associated with mitochondrial metabolism and immune-related processes in heterogeneous CAVD-spectrum valve lesions. These findings are exploratory and hypothesis-generating and require independent clinical and experimental validation.