基于机器学习算法识别和验证肺移植体外肺灌注过程中与线粒体相关的生物标记物。

IF 2.6 3区生物学 Q2 GENETICS & HEREDITY

Gene Pub Date : 2024-11-15 DOI:10.1016/j.gene.2024.149097

Zhi-Chang Yang , Wen-Yuan Lu , Zhen-Yang Geng , Yang Zhao , Xiao-Ming Chen , Tong Zheng , Ji-Ze Wu , Kai-Jun Huang , Hao-Xiang Yuan , Yang Yang

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引用次数: 0

摘要

背景：体外肺灌注（EVLP）是恢复边缘供体肺，从而提高肺移植（LTx）率的关键策略。肺移植过程中不可避免地会发生缺血再灌注（I/R）损伤。探索EVLP和I/R之间的共同机制可能会发现新的治疗靶点，从而提高LTx的治疗效果：我们从公共基因表达总库（GEO）中获取了 EVLP（GSE127055 和 GSE127057）和 I/R （GSE145989）过程的数据集。我们对差异基因表达（DEGs）和基因组富集分析（GSEA）进行了分析。线粒体基因来自 MitoCarta 3.0 数据库。利用蛋白质-蛋白质相互作用网络和机器学习方法，确定了线粒体相关的枢纽DEGs（MitoDEGs），并在EVLP的细胞和小鼠模型中进行了进一步验证：结果：对EVLP和I/R后的DEGs进行GSEA分析，发现线粒体功能通路受到显著抑制，包括线粒体中枢原理、mtRNA代谢、OXPHOS组装因子、金属和辅助因子以及血红素合成和处理过程。包括随机森林、LASSO 和 XGBoost 在内的机器学习算法确定了五个下调基因（MTERF1、ACACA、COX15、OSGEPL1 和 COQ9）作为 EVLP 和 I/R 过程的中枢 MitoDEG。我们证实，在 EVLP 期间，这些中枢 MitoDEGs 在内皮细胞中的表达量减少，并观察到内皮细胞中线粒体受损，其特征是形态肿胀和嵴消失：结论：线粒体平衡失调是 EVLP 和 I/R 诱导的肺损伤的共同病理过程。已确定的线粒体相关中枢基因（MTERF1、ACACA、COX15、OSGEPL1 和 COQ9）是治疗 LTx 肺损伤的有望靶点。这些基因的下调表明线粒体功能受到严重破坏。这项研究为I/R诱导的肺损伤和LTx EVLP过程中供肺修复提供了潜在的线粒体相关治疗靶点。

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Identification and validation of biomarkers related to mitochondria during ex vivo lung perfusion for lung transplants based on machine learning algorithm

Background

Ex vivo lung perfusion (EVLP) is a critical strategy to rehabilitate marginal donor lungs, thereby increasing lung transplantation (LTx) rates. Ischemia–reperfusion (I/R) injury inevitably occurs during LTx. Exploring the common mechanisms between EVLP and I/R may unveil new treatment targets to enhance LTx outcomes.

Methods

We obtained datasets from the public Gene Expression Omnibus (GEO) for EVLP (GSE127055 and GSE127057) and I/R (GSE145989) processes. We performed analysis of differentially expressed genes (DEGs) and Gene Set Enrichment Analysis (GSEA). Mitochondrial genes were sourced from the MitoCarta 3.0 database. Hub mitochondrial-related DEGs (MitoDEGs) were identified using a combination of protein–protein interaction networks and machine learning methods, which were further validated in cell and mice models of EVLP.

Results

GSEA analysis of DEGs following EVLP and I/R revealed significant inhibition of mitochondrial function pathways, encompassing mitochondrial central dogma, mtRNA metabolism, OXPHOS assembly factors, metals and cofactors, and heme synthesis and processing processes. Machine learning algorithms including Random Forest, LASSO, and XGBoost identified five downregulated genes (MTERF1, ACACA, COX15, OSGEPL1, and COQ9) as hub MitoDEGs for both EVLP and I/R processes. We confirmed the reduced expression of these hub MitoDEGs in endothelial cells during EVLP and observed mitochondrial damage in endothelial cells characterized by swollen morphology and cristae disappearance.

Conclusions

Imbalance in mitochondrial homeostasis is a shared pathological process during EVLP and I/R-induced lung injury. The identified hub mitochondrial-related genes (MTERF1, ACACA, COX15, OSGEPL1, and COQ9) suggest promising therapeutic targets for lung injury during LTx. The downregulation of these genes indicates a significant disruption in mitochondrial function. This study provides potential mitochondrial-related therapeutic targets for I/R-induced lung injury and for donor lung repair during EVLP procedure in LTx.

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来源期刊

Gene 生物-遗传学

CiteScore

6.10

自引率

2.90%

发文量

718

审稿时长

42 days

期刊介绍： Gene publishes papers that focus on the regulation, expression, function and evolution of genes in all biological contexts, including all prokaryotic and eukaryotic organisms, as well as viruses.