在低压缺氧诱导的肾损伤模型中，铁下垂和焦下垂后的新表观遗传生物标志物。

IF 3 3区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Archives of biochemistry and biophysics Pub Date : 2025-10-09 DOI:10.1016/j.abb.2025.110637

Hongxuan Liu, Huishu Lin, Yuhong He, Shuhao Shi, Jiayan Ni, Lei Zhao, Yuxuan Ma, Weixia Li, Yuanyuan Yu, Chen Li, Qisijing Liu, Shike Hou, Xiaoxue Li, Liqiong Guo

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引用次数: 0

摘要

背景：快速低压缺氧暴露会损害氧敏感器官，如肾脏。在这种情况下，依赖氧的细胞死亡机制铁亡和焦亡，以及线粒体DNA （mtDNA）甲基化的作用仍未得到充分研究。方法：建立大鼠低氧缺氧（6000m/7000m, 6h/72h）模型。分析肾铁下垂（普鲁士蓝染色，LPO/MDA/GSH检测，ACSL4/GPX4表达）和焦下垂（Caspase1/GSDMD激活）。通过焦磷酸测序评估肾线粒体DNA、细胞质DNA和血清无细胞DNA （cf mtDNA）的mt-cox1/2/3甲基化。PCA鉴定生物标志物。结果：低压缺氧引起肾铁积累、脂质过氧化和肾小管损伤。铁下垂通过ACSL4上调和GPX4抑制介导，而焦下垂激活Caspase1/GSDMD。透射电镜观察线粒体损伤和mtDNA渗漏。血清无细胞mtDNA mt-cox3 pos2高甲基化通过PCA明显区分缺氧暴露大鼠。结论：铁下垂和焦下垂共同驱动低压缺氧所致肾损伤。无细胞mtDNA中mt-cox3 pos2甲基化成为肾脏发病的一种新的生物标志物。

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Novel epigenetic biomarkers following ferroptosis and pyroptosis in a hypobaric hypoxia-induced renal injury model.

Background: Rapid hypobaric hypoxia exposure damages oxygen-sensitive organs like the kidneys. Ferroptosis and pyroptosis, oxygen-dependent cell death mechanisms, remain understudied in this context, as does the role of mitochondrial DNA (mtDNA) methylation.

Methods: We established a rat model of hypobaric hypoxia (6000 m/7000 m, 6 h/72 h). Kidney ferroptosis (Prussian blue staining, LPO/MDA/GSH assays, ACSL4/GPX4 expression) and pyroptosis (Caspase1/GSDMD activation) were analyzed. mt-cox1/2/3 methylation was assessed in renal mitochondrial DNA, cytoplasmic DNA, and serum cell-free DNA (cf mtDNA) via pyrosequencing. PCA identified biomarkers.

Results: Hypobaric hypoxia induced renal iron accumulation, lipid peroxidation, and tubular injury. Ferroptosis was mediated by ACSL4 upregulation and GPX4 suppression, while pyroptosis activated Caspase1/GSDMD. Mitochondrial damage and mtDNA leakage were observed via TEM. mt-cox3 pos2 hypermethylation in serum cell-free mtDNA distinctly distinguished hypoxia-exposed rats via PCA.

Conclusion: Ferroptosis and pyroptosis synergize to drive hypobaric hypoxia-induced renal injury. mt-cox3 pos2 methylation in cell-free mtDNA emerges as a novel biomarker for renal pathogenesis.

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来源期刊

Archives of biochemistry and biophysics 生物-生化与分子生物学

CiteScore

7.40

自引率

0.00%

发文量

245

审稿时长

26 days

期刊介绍： Archives of Biochemistry and Biophysics publishes quality original articles and reviews in the developing areas of biochemistry and biophysics. Research Areas Include: • Enzyme and protein structure, function, regulation. Folding, turnover, and post-translational processing • Biological oxidations, free radical reactions, redox signaling, oxygenases, P450 reactions • Signal transduction, receptors, membrane transport, intracellular signals. Cellular and integrated metabolism.