Mitochondrial-related hub genes in dermatomyositis: muscle and skin datasets-based identification and in vivo validation

Abstract

<b>Background:</b> Mitochondrial dysfunction has been implicated in the pathogenesis of dermatomyositis (DM), a rare autoimmune disease affecting the skin and muscles. However, the genetic basis underlying dysfunctional mitochondria and the development of DM remains incomplete. <b>Methods:</b> The datasets of DM muscle and skin tissues were retrieved from the Gene Expression Omnibus database. The mitochondrial related genes (MRGs) were retrieved from MitoCarta. DM-related modules in muscle and skin tissues were identified with the analysis of weighted gene co-expression network (WGCNA), and then compared with the MRGs to obtain the overlapping mitochondrial related module genes (mito-MGs). Subsequently, differential expression genes (DEGs) obtained from muscle and skin datasets were overlapped with MRGs to identify mitochondrial related DEGs (mito-DEGs). Next, functional enrichment analysis was applied to analyze possible relevant biological pathways. We used the Jvenn online tool to intersect mito-MGs with mito-DEGs to identify hub genes and validate them using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry staining. In addition, we evaluated immune infiltration in muscle and skin tissues of DM patients using the one-sample gene set enrichment analysis (ssGSEA) algorithm and predicted potential transcription factor (TF) -gene network by NetworkAnalyst. <b>Results:</b> The WGCNA analysis revealed 105 mito-MGs, while the DEG analysis identified 3 mito-DEGs. These genes showed functional enrichment for amino acid metabolism, energy metabolism and oxidative phosphorylation. Through the intersection analysis of the mito-MGs from the WGCNA analysis and the mito-DEGs from the DEG set, three DM mito-hub genes (<i>IFI27</i>, <i>CMPK2</i>, and <i>LAP3</i>) were identified and validated by RT-qPCR and immunohistochemistry analysis. Additionally, positive correlations were observed between hub genes and immune cell abundance. The TF-hub gene regulatory network revealed significant interactions involving ERG, VDR, and ZFX with <i>CMPK2</i> and <i>LAP3</i>, as well as SOX2 with <i>LAP3</i> and <i>IFI27</i>, and AR with <i>IFI27</i> and <i>CMPK2</i>. <b>Conclusion:</b> The mito-hub genes (<i>IFI27</i>, <i>CMPK2</i>, and <i>LAP3</i>) are identified in both muscles and skin tissues from DM patients. These genes may be associated with immune infiltration in DM, providing a new entry point for the pathogenesis of DM.