Disruption of mitochondrial metabolism in systemic lupus erythematosus: multi-omics insights from a patient-derived cohort

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by dysregulated immune responses and metabolic disturbances. Growing evidence implicates mitochondrial dysfunction in the pathogenesis of SLE; however, a comprehensive multi-omics analysis of mitochondrial pathways has been lacking. Here, we originally performed integrative transcriptomic, proteomic, and phosphoproteomic profiling of peripheral blood mononuclear cells (PBMCs) from SLE patients and systematically assessed mitochondrial functional pathways using the MitoCarta3.0 database. Our study revealed widespread dysregulation of mitochondrial processes in SLE. Proteomic analysis revealed significant upregulation of proteins involved in OXPHOS and metabolic pathways, as well as differential expression of proteins associated with mitochondrial transport and ATP synthase complexes. Phosphoproteomic profiling identified marked alterations in PDHA1 phosphorylation (S232/S293/S300), linking disruption of the glycolysis-TCA cycle to SLE pathogenesis. Longitudinal analysis indicated that SDHB expression progressively increased from inactive to active SLE, serving as a marker of disease progression, while NDUFB9 emerged as a key factor sustaining pathological mitochondrial dysfunction. Transcriptomics uncovered key regulatory transcription factors (TFs; e.g., STAT1, RELA, HDAC2) and kinases (e.g., TBK1, IKBKB) associated with SLE pathogenesis, suggesting potential therapeutic targets. Finally, by integrating the molecular alterations in proteins and phosphorylation modifications identified in this study, along with upstream regulatory features of TFs and kinases, we constructed a multi‑level regulatory network depicting mitochondrial dysfunction in SLE. This network provides a systematic framework for understanding the metabolic‑immune interplay in SLE and providing candidate targets that warrant further experimental investigation.