Mitochondrial dysfunction drives the pathogenesis of pulmonary arterial hypertension: insights from a multi-omics investigation

Abstract

Abstract Background Pulmonary arterial hypertension (PAH) is a progressive disorder that can lead to right ventricular failure and severe consequences. Despite extensive efforts, limited progress has been made in preventing the progression of PAH. Understanding its pathogenesis is crucial for developing better treatments. Methods We integrated three microarray datasets from the Gene Expression Omnibus (GEO), including 222 lung samples (164 PAH, 58 controls), for differential expression and functional enrichment analyses. Machine learning identified key signaling pathways. PAH and control lung tissue samples were collected, and transcriptomic and metabolomic profiling were performed. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis investigated shared pathways, and canonical correlation analysis assessed gene-metabolite relationships. Results In the GEO datasets, mitochondria-related pathways were significantly enriched in PAH samples, in particular the electron transport chain in mitochondrial oxidative phosphorylation, notably the electron transport from cytochrome c to oxygen. Transcriptomic profiling of the clinical lung tissue analysis identified 14 differentially expressed genes (DEGs) related to mitochondrial function. Metabolomic analysis revealed three differential metabolites: increased 3-phenyllactic acid and ADP, and decreased citric acid in PAH samples. Mitochondria-related genes highly correlated with these metabolites included KIT, OTC, CAMK2A, and CHRNA1. Conclusions Disruption of the mitochondrial electron transport chain and citric acid cycle homeostasis likely contributes to PAH pathogenesis. 3-phenyllactic acid emerges as a potential novel diagnostic biomarker for PAH. These findings offer insights for developing novel PAH therapies and diagnostics.