Unraveling key genes and mitochondrial-related mechanisms of atherosclerosis severity: explorations based on interpretable machine learning

BACKGROUND: Dysfunctional mitochondria increase oxidative stress and inflammation, driving atherosclerosis. Understanding gene expression and regulatory mechanisms is crucial. OBJECTIVE: This study aims to identify key mitochondrial dysfunction-related genes (MitoDEGs) associated with atherosclerotic plaque severity, elucidate their molecular mechanisms and immune-regulatory roles in disease progression, and validate pivotal biomarkers to provide mechanistic insights for personalized therapeutic strategies. METHODS: We utilized eight atherosclerotic plaque datasets (human samples) from GEO and mitochondrial gene data from MitoCarta3.0. Lasso Regression and the Shap algorithm were employed to identify key differentially expressed mitochondrial genes (MitoDEGs) for model construction. Enriched pathways were analyzed using GO and KEGG databases, and protein–protein interactions were explored with STRING and Cytoscape. Experimental validation was conducted using atherosclerosis mouse models and HUVEC cell models. RESULTS: This study identified distinct and shared mitochondrial dysfunction-related genes (MitoDEGs) in carotid and peripheral atherosclerotic plaques. Key carotid-specific MitoDEGs included HK3 and BID, while peripheral-specific ones included RAC2 and TCL1A. Two common MitoDEGs, GZMB and PMAIP1, were found in both plaque types. Enrichment analyses revealed novel associations with mitochondrial pathways including apoptosis, p53 signaling, hexose metabolism, and protein serine/threonine kinase regulation. Importantly, these MitoDEGs are mechanistically linked to mitochondrial outer membrane integrity and metabolic reprogramming. Experimental validation confirmed the upregulation of core MitoDEGs (CASP1, BID, PMAIP1, and GZMB), highlighting their critical roles in mitochondrial dysfunction during atherosclerosis progression. CONCLUSION: This study underscores the critical role of mitochondrial dysfunction, mediated by specific MitoDEGs, in atherosclerosis progression. The identified genes modulate both mitochondrial apoptotic pathways and immune cell infiltration, contributing to plaque severity. These shared and location-specific MitoDEGs offer novel mechanistic insights and represent potential therapeutic targets for intervening in plaque development and achieving personalized management of atherosclerotic disease.