Deciphering the molecular mechanisms linking abnormal mitochondrial respiratory chain activity to myeloid cell activation in systemic lupus erythematosus through multi-scale transcriptomics

Abnormal mitochondrial respiratory chain (MRC) activity is a pivotal driver in the pathogenesis of systemic lupus erythematosus (SLE). However, the molecular mechanisms linking it to immune phenotypes and disease progression remain unclear. This study aims to systematically determine core biomarkers of MRC dysfunction in SLE and explore their potential pathogenic mechanisms through multi-scale transcriptomic analysis. Five bulk transcriptomic series from the Gene Expression Omnibus (GEO) were integrated to screen for differentially expressed genes linked to MRC abnormalities. Three machine learning algorithms and SHAP analysis were applied to identify core signature genes. Leveraging these markers, a diagnostic model was developed, along with constructing molecular interaction and regulatory networks. We elucidated the biological functions through functional enrichment, immune infiltration analyzes, and correlation analysis with key therapeutic targets. Furthermore, we integrated three single-cell datasets and applied Seurat clustering, pseudotime analysis, and CellChat to characterize the expression patterns, differentiation trajectories, and interaction networks of core genes within specific cell subpopulations. Our results identified 18 biomarkers, with SCO2 emerging as the primary core gene. The diagnostic model achieved high discriminatory accuracy. Multi-dimensional functional analyzes uncovered a potential role for SCO2 bridging mitochondrial metabolic dysfunction with antiviral innate immune activation. Single-cell analysis localized SCO2 overexpression primarily to monocytes and dendritic cells, showing a downregulation trajectory during myeloid differentiation. We found that SCO2+ myeloid cells exhibit altered interaction networks within the immune microenvironment, characterized by enriched MHC-I/II and MIF signaling. In conclusion, SCO2 is a critical biomarker of MRC activity in SLE, reflecting the mitochondrial metabolic reprogramming that drives immune dysregulation.