Int J Chron Obstruct Pulmon Dis. 2026 Jan 17;21:553092. doi: 10.2147/COPD.S553092. eCollection 2026.

ABSTRACT

BACKGROUND: As a relatively common respiratory disease, chronic obstructive pulmonary disease (COPD) has a high incidence and mortality rate. Mitochondrial dysfunction has been implicated in COPD pathogenesis, but the causal genes and underlying molecular mechanisms remain unclear.

METHODS: We performed a summary data-based Mendelian Randomization (SMR) study integrating summary data from genome-wide association studies (GWAS) with blood-based methylation (mQTL), expression (eQTL), and protein quantitative trait loci (pQTL) to identify mitochondrial-related genes causally associated with COPD. Significant findings were validated using two-sample MR, independent lung tissue transcriptomic data (GSE76925), and weighted gene co-expression network analysis (WGCNA) to assess transcriptional consistency and functional convergence.

RESULTS: Our integrative SMR and colocalization analyses identified 77 mitochondrial genes linked to COPD risk, including GPX1, TUFM, COQ5, BPHL, and NAGS. A methylation-to-expression regulatory cascade was observed, with hypermethylation at GPX1 cg24011261 associated with increased gene expression and higher COPD risk-despite its role as an antioxidant enzyme. Two-sample MR confirmed robust causal effects of GPX1, BPHL, TUFM and COQ5 expression on COPD. These findings were replicated in lung tissue: GPX1, COQ5, and TUFM were significantly upregulated in COPD patients (GSE76925). WGCNA revealed that these genes reside within a highly interconnected turquoise module strongly correlated with COPD status (r = 0.43, p < 0.001) and enriched in oxidative phosphorylation and mitochondrial energy metabolism pathways.

CONCLUSION: This study provides systematic genetic and transcriptomic evidence that mitochondrial-related genes, particularly GPX1 and TUFM, exert causal effects on COPD risk through regulatory cascades and coordinated network dysregulation. The convergence of genetic, epigenetic, and co-expression evidence underscores mitochondrial dysfunction as a central mechanism in COPD pathogenesis and highlights potential targets for future therapeutic development.

PMID:41868721 | PMC:PMC13003660 | DOI:10.2147/COPD.S553092