Oleuropein Modulates Mitophagy and Metabolism in Cardiomyocyte Via the PINK1/Parkin Signaling Pathway

IF 4.2 4区医学 Q2 CHEMISTRY, MEDICINAL

Drug Development Research Pub Date : 2025-09-26 DOI:10.1002/ddr.70171

Hao Ling, Chunli Song

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Abstract

‌Oleuropein (OLEU), a natural polyphenol, exhibits cardioprotective potential through mitochondrial modulation, yet its precise mechanisms remain elusive. This study elucidates OLEU's role in alleviating oxidative stress and regulating mitochondrial quality control via the PINK1/Parkin pathway. In vitro, H9C2 cardiomyocytes exposed to H₂O₂-induced oxidative stress were treated with OLEU (0–200 μM), and analyses included cell viability, ROS, SOD, MDA, ΔΨm, ATP, PINK1/Parkin expression and detection of Mitophagic Flux. In vivo, myocardial infarction (MI) was induced in SD rats via coronary ligation, followed by OLEU administration, with assessments of cardiac function, histopathology, and mitophagy using echocardiography, electron microscopy, immunohistochemistry and immunofluorescence. Results showed that OLEU (≤200 μM) dose-dependently restored cell viability, reduced ROS, and normalized SOD/MDA (p < 0.05), while mitigating ΔΨm collapse and ATP depletion, indicating enhanced mitochondrial bioenergetics. OLEU upregulated PINK1/Parkin, promoting mitophagic clearance of damaged mitochondria, and metabolomic analysis revealed modulation of arginine/proline and lipid pathways. In MI rats, OLEU attenuated ROS, preserved myocardial structure, and improved cardiac function, supported by elevated mitophagy in electron microscopy. These findings demonstrate that OLEU protects cardiomyocytes by suppressing oxidative stress, stabilizing mitochondrial integrity, and activating PINK1/Parkin-mediated mitophagy, highlighting its therapeutic potential for myocardial injury and mitochondrial dysfunction.

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橄榄苦苷通过PINK1/Parkin信号通路调节心肌细胞的线粒体自噬和代谢

橄榄苦苷（OLEU）是一种天然多酚，通过线粒体调节显示出保护心脏的潜力，但其确切机制尚不清楚。本研究阐明了OLEU通过PINK1/Parkin通路在缓解氧化应激和调节线粒体质量控制中的作用。在体外，用OLEU （0 ~ 200 μM）处理H₂O₂诱导氧化应激的H9C2心肌细胞，分析细胞活力、ROS、SOD、MDA、ΔΨm、ATP、PINK1/Parkin表达和线粒体自噬通量的检测。在体内，通过冠状动脉结扎诱导SD大鼠心肌梗死（MI），随后给予OLEU，并使用超声心动图、电镜、免疫组织化学和免疫荧光评估心功能、组织病理学和线粒体自噬。结果显示，OLEU（≤200 μM）剂量依赖性地恢复了细胞活力，降低了ROS，并使SOD/MDA正常化（p < 0.05），同时减轻了ΔΨm崩溃和ATP消耗，表明线粒体生物能量增强。OLEU上调PINK1/Parkin，促进受损线粒体的自噬清除，代谢组学分析显示精氨酸/脯氨酸和脂质途径的调节。在心肌梗死大鼠中，OLEU可减弱ROS，保留心肌结构，改善心功能，电镜显示线粒体自噬升高。这些发现表明OLEU通过抑制氧化应激、稳定线粒体完整性和激活PINK1/帕金森介导的线粒体自噬来保护心肌细胞，突出了其对心肌损伤和线粒体功能障碍的治疗潜力。

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来源期刊

Drug Development Research 医学-药学

CiteScore

6.40

自引率

2.60%

发文量

104

审稿时长

6-12 weeks

期刊介绍： Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.