| 引用本文: | 张泊宁,冯雪儿,刘缨,卢涛.吡咯喹啉醌通过调控pmk-1/p38 MAPK[]通路缓解秀丽线虫缺氧损伤[J].生物信息学,2026,24(3):208-228. |
| Zhang Boning,Feng Xueer,Liu Ying,Lu Tao.Pyrroloquinoline quinone alleviates hypoxia injury in Caenorhabditis elegans via regulating the pmk 1/p38 mapk pathway[J].Chinese Journal of Bioinformatics,2026,24(3):208-228. |
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| 吡咯喹啉醌通过调控pmk-1/p38 MAPK[]通路缓解秀丽线虫缺氧损伤 |
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张泊宁,冯雪儿,刘 缨,卢涛
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(北京中医药大学 生命科学学院,北京 102488)
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| 摘要: |
| 高原低氧会引发剧烈的氧化应激反应,这也是急性高原病、高原肺水肿及细胞功能损伤发生的核心诱因,目前临床上仍缺乏有效的干预手段。吡咯喹啉醌(PQQ)是一种天然存在的邻醌类氧化还原辅因子,具备极强的自由基清除能力与金属螯合作用,能够提升机体的低氧耐受能力。但其具体分子作用机制,尤其是对保守应激信号通路的调控作用,尚未被全面阐明。本研究以秀丽隐杆线虫为模型,探究 PQQ 对低氧所致氧化损伤的细胞保护效应及作用靶点。实验采用野生型线虫(N2 Bristol 品系)与多种突变株线虫(pmk-1(km25)、sek-1(km4)、daf-16(mu86)),利用浓度为 2.0 g/L 的亚硫酸钠构建稳定低氧模型,体系内溶解氧含量低于 0.1 mg/L。实验检测了线虫存活率、形态特征、运动能力等表型指标,同时测定活性氧、脂褐素水平；结合转录组测序(RNA-seq)与基因验证实验,筛选关键信号通路。结果发现PQQ 的保护作用呈浓度依赖性,其中 1 mmol/L 为最佳作用浓度。低氧对照组线虫存活率仅为19.9±2.4%,经该浓度 PQQ 处理后,存活率提升至73.2±4.2%(p<0.001)。PQQ 可改善低氧造成的形态异常,将线虫运动能力恢复至常氧状态的 80%~90%；同时使体内活性氧含量下降 54.96%,脂褐素含量下降 31.29%,两项指标差异均具有极显著统计学意义(p<0.001)。转录组测序结果表明,低氧环境可造成 849 个基因表达发生改变,其中 740 个基因上调、109 个基因下调,差异基因主要富集于氧化磷酸化、脂肪酸代谢及钙信号通路。而 PQQ 可逆转上述基因表达变化,对钙稳态相关基因与丝裂原活化蛋白激酶(MAPK)通路基因的下调作用尤为突出。进一步通过基因功能验证实验发现,在 daf-16(mu86)突变株中,PQQ 的保护效果出现部分减弱；而在 pmk-1(km25)与 sek-1(km4)突变株中,PQQ 的保护效应完全消失。综上所述,PQQ 可通过维持钙稳态、抑制促凋亡的 pmk-1/p38 MAPK 通路,并部分依托胰岛素/胰岛素样生长因子信号通路,缓解秀丽隐杆线虫因低氧诱导产生的氧化应激。本研究揭示了 PQQ 抗氧化、提升机体适应能力的分子机制,为将其应用于高原低氧相关疾病的防治提供了理论依据。 |
| 关键词: 吡咯喹啉醌(PQQ) 低氧 氧化应激 秀丽隐杆线虫 钙信号 p38 MAPK 通路 |
| DOI：10.12113/202605013 |
| 分类号:Q78；R363.2 |
| 文献标识码:A |
| 基金项目:国家自然科学基金项目(No. U23A20522)；LUTAO: “Investigation on the Mechanism of Action and Clinical Efficacy Observation of PQQ and Its Compound Formulations in Alzheimers Disease, Age Reversal, and Anti-Aging Related Diseases” (No. 90020371720023). |
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| Pyrroloquinoline quinone alleviates hypoxia injury in Caenorhabditis elegans via regulating the pmk 1/p38 mapk pathway |
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Zhang Boning, Feng Xueer, Liu Ying,Lu Tao
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(School of Life Sciences, Beijing University of Chinese Medicine, Beijing 102488, China)
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| Abstract: |
| High-altitude hypoxia induces severe oxidative stress, a key driver of acute mountain sickness (AMS), high-altitude pulmonary edema (HAPE), and cellular dysfunction with limited effective interventions. Pyrroloquinoline quinone (PQQ), a naturally occurring redox-active ortho-quinone cofactor with robust free radical scavenging and metal-chelating properties, enhances hypoxia tolerance, but its molecular mechanisms—especially modulation of conserved stress-signaling cascades—remain incompletely defined. We investigated PQQs cytoprotective effects and mechanistic targets against hypoxia-induced oxidative injury using Caenorhabditis elegans(C.elegans). Wild-type (N2 Bristol) and mutant (pmk-1(km25),sek-1(km4), daf-16(mu86) worms were exposed to 2.0 g/L sodium sulfite (Na2SO3) to induce stable hypoxia (<0.1 mg/L dissolved oxygen). Phenotypic analyses included survival, morphometry, locomotor activity, and measurements of reactive oxygen species (ROS) and lipofuscin, with transcriptomic profiling (RNA-seq) and genetic validation to identify key signaling pathways. PQQ exerted concentration-dependent protection, with 1 mmol/L as the optimal concentration, increasing survival from 19.9±2.4% (hypoxia control) to 73.2±4.2% (p<0.001).It reversed hypoxia-induced morphological abnormalities, restored locomotor function to 80-90% of normoxic levels, and reduced ROS by 54.96% and lipofuscin by 31.29% (both p< 0.001). RNA-seq revealed hypoxia altered 849 genes (740 upregulated, 109 downregulated), enriched in oxidative phosphorylation, fatty acid metabolism, and calcium signaling—effects reversed by PQQ, particularly downregulation of calcium homeostasis and mitogen-activated protein kinase (MAPK) pathway genes. Genetic validation showed PQQs protection was partially attenuated in daf-16(mu86) mutants but completely abrogated in pmk-1(km25) and sek-1(km4) mutants. These findings demonstrate PQQ mitigates hypoxia-induced oxidative stress in C.elegans via maintaining calcium homeostasis, suppressing the pro-apoptotic pmk-1/p38 MAPK pathway, and partially engaging the insulin/insulin-like growth factor signaling (IIS) pathway, providing novel mechanistic insights into PQQs antioxidant and adaptogenic properties to support its potential therapeutic utility for high-altitude hypoxic pathologies. |
| Key words: Pyrroloquinoline quinone (PQQ) Hypoxia Oxidative stress Caenorhabditis elegans Calcium signaling p38 MAPK pathway |
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