Abstract
Atherosclerosis (AS) is a leading cause of cardiovascular disease and stroke. Although mitochondria's role in AS is recognized, effective molecular targets are lacking. This study investigated mitochondria-associated signature biomarkers in AS, providing insights for mechanistic research and targeted therapy. AS-related transcripts were retrieved from public databases. Bioinformatics analyses (differential expression, machine learning, and expression verification) were integrated to screen biomarkers, and a nomogram was constructed. The functions, immune features, and single-cell expression (cellular landscape) of the identified biomarkers were analyzed. The L-lactate dehydrogenase B and SLC25A4 genes emerged as mitochondrial signature biomarkers in both tissues and blood samples from patients with AS. The nomogram exhibited robust performance in predicting the prevalence of AS. Notably, these biomarkers were significantly involved in pathways associated with the pathogenesis of AS, such as the Toll-like receptor pathway. Compared with the findings in control samples, 27 types of immune cells exhibited increased infiltration in AS samples, and the biomarkers generally displayed a strong negative correlation with these infiltrating immune cells. Nine cell types were annotated at the single-cell level, among which vascular smooth muscle cells (VSMCs) represented the key cell population, being characterized by high pyruvate metabolism activity. Furthermore, VSMCs were primarily engaged in cell-cell communication with macrophages. Additionally, the expression profiles of the biomarkers exhibited an inverted U-shaped dynamic pattern corresponding to the expression changes in VSMCs. This study identified two mitochondrial signature biomarkers, preliminarily revealed their potential roles in AS, provided new insights for targeted therapy research, and laid a foundation for unraveling mitochondria-related pathological mechanisms in AS.