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通过扰乱线粒体动态和加剧心肌细胞亡,PGAM5加剧了多克索鲁比诱导的心脏毒性
Weibin He1, Jieying Wang2, Wenlong He1
1Department of Cardiology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University, 510080, Guangzhou, China; Department of Cardiology, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Guangdong Cardiovascular Institute, 510080, Guangzhou, China.
Free radical biology & medicine
|April 25, 2025
概括
线粒体酸酶PGAM5通过破坏线粒体动力学和增加心脏细胞中氧化应激和亡来恶化多克索鲁比诱导的心脏毒性.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 心脏病学 心脏病学
背景情况:
- 多克索鲁比 (DOX) 是一种重要的化疗药物,但会引起心脏毒性.
- 线粒体动力学对心脏细胞健康至关重要,其破坏有助于DOX诱导的心脏毒性 (DIC).
- 底层DIC和线粒体功能障碍的精确分子机制仍然不完全理解.
研究的目的:
- 研究线粒体酸酶PGAM5在DOX诱导心脏毒性的作用.
- 在DOX治疗的背景下,阐明PGAM5影响线粒体动态和细胞死亡途径的分子机制.
主要方法:
- 研究了对DOX暴露的PGAM5裂变和活性.
- 利用过度表达系统研究PGAM5对线粒体形态学 (裂变/融合动态) 的影响.
- 评估了氧化应激,细胞亡和其他受调细胞死亡 (RCD) 途径的标志物.
主要成果:
- 德克索鲁比治疗诱导PGAM5由OMA1和YME1L1蛋白酶分裂.
- 过度表达PGAM5会破坏线粒体动力学,促进碎片化和抑制延长.
- PGAM5加剧了DOX诱导的氧化应激和心肌细胞亡,独立于其裂变,但依赖于其酸酶活性. 它不会促进铁或热.
结论:
- PGAM5通过损害线粒体动力学和增加氧化应激和亡,显著促进DOX诱导的心脏毒性.
- PGAM5的酸酶活性是其对线粒体延长的有害影响的关键.
- PGAM5代表了预防或减少多克索鲁比诱导心肌病的潜在治疗标.
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