Lupus Sci Med. 2026 Sep 12. pii: e002041. [Epub ahead of print]13(2):
BACKGROUND: Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus. Mitochondrial dysfunction and inflammation are key contributors to its pathogenesis, yet the underlying mechanisms remain incompletely understood and reliable biomarkers are limited. This study investigates mitochondrial-related genes (MRGs) in LN and evaluates their potential as biomarkers.
METHODS: Differentially expressed genes (DEGs) were obtained from the Gene Expression Omnibus database and MRGs were derived from the MitoCarta3.0 dataset. Weighted gene co-expression network analysis identified key modules, followed by Gene Ontology and Kyoto Encyclopaedia of Genes and Genomes enrichment analyses of mitochondrial DEGs (MitoDEGs). Protein-protein interaction network analysis and random forest modelling were applied to identify hub MitoDEGs. Their diagnostic performance was evaluated using receiver operating characteristic curves. Immune cell infiltration was estimated using single-sample gene set enrichment analysis and correlations with hub MitoDEGs were analysed. Immunofluorescence staining and functional assays in HK-2 cells were performed to validate the expression and biological roles of the hub genes.
RESULTS: Among the 36 MitoDEGs, synthesis of cytochrome c oxidase 1 (SCO1) was identified. SCO1 exhibited strong discriminatory power in both the training and validation sets. After false discovery rate correction, SCO1 showed significant positive correlations with CD8+T cells, naive CD4+T cells and resting memory CD4+T cells. Immunofluorescence staining confirmed that SCO1 was predominantly expressed in renal tubules and was significantly upregulated in patients with LN compared with healthy controls. Functional validation demonstrated that SCO1 overexpression enhanced cell viability, whereas its knockdown reduced cell viability, increased mitochondrial reactive oxygen apecies and decreased mitochondrial membrane potential, without affecting ATP levels. SCO1 modulation altered P62 expression but did not significantly affect PARKIN, PINK1, or LC3B levels.
CONCLUSION: SCO1 showed elevated expression in renal tubules and strong discriminatory ability. It may help preserve tubular cell viability and mitochondrial homeostasis under inflammatory stress, highlighting its potential as a diagnostic biomarker and a candidate for further mechanistic investigation in LN.
Keywords: Autoimmune Diseases; Autoimmunity; Lupus Nephritis