Dysfunction in mitochondrial electron transport chain drives the pathogenesis of pulmonary arterial hypertension: insights from a multi-omics investigation

作者：Xin Zhang, Jieling Li, Minyi Fu, Xijie Geng, Junjie Hu, Kejing Tang, Pan Chen, Jianyong Zou, Xiaoman Liu, Bo Zeng · 发表于：Respiratory Research · 年份：2025 · DOI：10.1186/s12931-025-03099-8 · 被引用次数：15 · 研究领域：Pulmonary Hypertension Research and Treatments、Mitochondrial Function and Pathology、Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

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. Mitochondrial dysfunction is implicated in the development of PAH, but the key mitochondrial functional alterations in the pathogenesis have yet to be elucidated. 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 mitochondria-related 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 signaling pathways were significantly enriched in PAH samples, in particular the electron transport chain (ETC) in mitochondrial oxidative phosphorylation system. Notably, the electron transport from cytochrome c to oxygen in ETC was identified as the most crucial mitochondria-related pathway, which was down-regulated in PAH samples. Transcriptomic profiling of the clinical lung tissue analysis identified 14 differentially expressed genes (DEGs) related to mitochondrial function. Metabolomi...