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线粒体 sORF 编码的MODICA 通过抑制 VDAC 寡合化来保护心脏免受多克索鲁比引起的心脏损伤

Jialing Wu^1,2, Kang Li^1,2, Youchen Yan^1,2

¹Department of Cardiology, Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. (J.W., K.L., Y.Y., X.X., T.X., H.X., H.Z., T.D., Y.L., C.L., X.L., Y.D., J.-S.O., Y.C., Z.-P.H.).

Circulation. Heart failure

|September 4, 2025

概括

通过预防线粒体功能障碍和亡,线粒体MODICA可以预防多克索鲁比 (DOX) 引起的心脏损伤. 缺少MODICA会加重DOX的心脏毒性,突出其治疗潜力.

科学领域:

心脏病学
分子生物学
生物化学

背景情况:

主要通过线粒体损伤引起心脏毒性,从而增加癌症患者的心血管风险.
精确的DOX诱导心脏毒性机制和线粒体短开放读取编码的作用尚未完全理解.

研究的目的:

研究线粒体短开读框架编码的潜力,特别是MODICA,减轻DOX诱导的心脏毒性.
阐明MODICA对DOX引起的心脏损伤的保护作用的分子机制.

主要方法:

在DOX诱导心脏毒性小鼠模型中查表达线粒体短开读的腺相关病毒.
使用心声学和分子/组织学分析评估MODICA过度表达或缺乏的雄性和雌性小鼠的心功能.
蛋白质组分析以确定MODICA的相互作用伙伴和分子标.

主要成果:

确定了线粒体的短开放读取编码的MODICA,并发现DOX对其进行了下调.
在两种性别中,MODICA对心脏的过度表达显著减轻了DOX引起的心脏损伤和纤维化.
缺少MODICA会加剧DOX引起的心脏毒性,蛋白质组分析显示MODICA抑制了电压依赖的离子通道寡合化,减少了线粒体的透性和亡.

结论:

线粒体短开放读取编码的MODICA有效地缓解了多克索鲁比引起的心脏功能障碍.
莫迪卡的保护机制涉及抑制与亡相关的外线粒体膜的电压依赖性离子通道蛋白.
对于预防或治疗多克索鲁比辛心脏毒性,MODICA 是一个有前途的治疗点.

关键词:

其他动物心脏疾病化物危险因素样本的大小

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