Zhang Xin, Li Jieling, Fu Minyi, Geng Xijie, Hu Junjie, Tang Ke-Jing, Chen Pan, Zou Jianyong, Liu Xiaoman, Zeng Bo
Department of Thoracic Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Department of Pharmacy, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
Respir Res. 2025 Jan 20;26(1):29. doi: 10.1186/s12931-025-03099-8.
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.
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.
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. Metabolomic analysis revealed three differential metabolites in PAH samples: increased 3-phenyllactic acid and ADP, and decreased citric acid. Mitochondria-related genes highly correlated with these metabolites included KIT, OTC, CAMK2A, and CHRNA1.
Down-regulation of electron transport from cytochrome c to oxygen in mitochondrial ETC and disruption of the citric acid cycle homeostasis may contribute 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.
肺动脉高压（PAH）是一种进行性疾病，可导致右心室衰竭及严重后果。尽管付出了巨大努力，但在预防PAH进展方面取得的进展有限。线粒体功能障碍与PAH的发生发展有关，但其发病机制中关键的线粒体功能改变尚未阐明。
我们整合了来自基因表达综合数据库（GEO）的三个微阵列数据集，包括222个肺样本（164个PAH样本，58个对照样本），进行差异表达和功能富集分析。机器学习确定了关键的线粒体相关信号通路。收集PAH和对照肺组织样本，并进行转录组和代谢组分析。京都基因与基因组百科全书（KEGG）分析研究了共享通路，典型相关分析评估了基因-代谢物关系。
在GEO数据集中，线粒体相关信号通路在PAH样本中显著富集，尤其是线粒体氧化磷酸化系统中的电子传递链（ETC）。值得注意的是，ETC中从细胞色素c到氧的电子传递被确定为最关键的线粒体相关通路，在PAH样本中下调。临床肺组织分析的转录组分析确定了14个与线粒体功能相关的差异表达基因（DEG）。代谢组分析揭示了PAH样本中的三种差异代谢物：3-苯乳酸和ADP增加，柠檬酸减少。与这些代谢物高度相关的线粒体相关基因包括KIT、OTC、CAMK2A和CHRNA1。
线粒体ETC中从细胞色素c到氧的电子传递下调以及柠檬酸循环稳态的破坏可能有助于PAH的发病机制。3-苯乳酸成为PAH潜在的新型诊断生物标志物。这些发现为开发新型PAH治疗方法和诊断方法提供了思路。
