Mitochondrial Dysfunction across Synovial and Peripheral Compartments in Rheumatoid Arthritis: A Multi-tissue Transcriptomic Integration of PBMC, Synovial Biopsy and Whole Blood

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease with synovial inflammation and systemic immune alterations. Mitochondrial dysfunction has been implicated in RA pathogenesis, but its tissue-specific and shared molecular signatures remain poorly characterized. We performed an integrative transcriptomic analysis of three public datasets: GSE17755 (PBMC), GSE89408 (synovial biopsy), and GSE93272 (whole blood). Differentially expressed genes (DEGs) were identified (P<0.05, |log2FC| ≥ 1) and intersected with MitoCarta 3.0 to obtain mitochondria-related DEGs (mito-DEGs). Protein-protein interaction networks, hub genes (identified using the MCC algorithm), functional enrichment (GO/KEGG), and regulatory networks (miRNA-TF-mRNA) were constructed. PBMC, synovial biopsy, and whole blood yielded 37, 220, and 119 mito-DEGs, respectively. Only one gene (AKAP1) was common across all three tissues. Hub genes predominantly encoded subunits of mitochondrial respiratory chain complexes (NDUF family and UQCR genes). Enriched pathways included oxidative phosphorylation, thermogenesis, and neurodegeneration-related pathways. Regulatory analysis identified FOXC1, GATA2, and hsa-miR-16-5p as key transcriptional and post-transcriptional regulators. Mitochondrial dysfunction in RA is tissue-specific, but converges on the dysregulation of oxidative phosphorylation. AKAP1 emerges as a potential systemic mitochondrial biomarker, pending validation in independent cohorts. These findings provide a multi-tissue resource for targeting mitochondrial pathways in RA.

Keywords

• Rheumatoid arthritis
• Mitochondrial dysfunction
• Transcriptomics
• Oxidative phosphorylation
• Biomarker

Ethical Statement

Ethics committee approval was not required because this study used only publicly available, de-identified transcriptomic datasets.

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