与心房动相关的PITX2功能增益突变改变了人类iPSC心房样心肌细胞中的线粒体活性
Patrizia Benzoni1, Lorenzo Da Dalt2, Noemi Elia1,3
1The Cell Physiology MiLab, Department Biosciences, Università degli Studi di Milano, Milano, Italy.
Frontiers in physiology
|November 29, 2023
概括
在PITX2中发生的基因突变,这是一个关键的心房发育基因,在患者衍生的心脏细胞中引起线粒体功能障碍,导致心房动 (AF) 的发生. 这揭示了早期的细胞变化驱动这种常见的心律失常.
科学领域:
- 心血管研究研究心血管研究
- 分子心脏病学分子心脏病学
- 失律症的遗传学 失律症的遗传学
背景情况:
- 心房动 (AF) 是一种普遍存在的心律失常症,其发病机制尚不清楚.
- 遗传因素,特别是涉及PITX2基因,越来越多地被认为对AF发展至关重要.
- 诱导多能干细胞 (iPSC) 衍生心肌细胞提供了一个研究患者特异性,突变驱动的AF细胞变化的模型.
研究的目的:
- 为了研究由iPSC衍生的心房心肌细胞 (aCMs) 中的线粒体活性,来自患有PITX2功能获取突变导致 Paroxysmal AF的患者.
- 为了比较患者衍生的aCMs中的线粒体功能与突变纠正同位素控制 (CTRL).
- 阐明PITX2在细胞自主性线粒体变异中的作用,这是AF病原体的基础.
主要方法:
- 从患有PITX2功能增益突变 (rs138163892) 和同位素对照的患者中生成iPSC衍生的心房心肌细胞 (aCMs).
- 评估线粒体含量,基底活性和超氧化物产生.
- 使用FCCP和β-上腺刺激评估线粒体对工作量增加的反应.
主要成果:
- 与CTRL aCM相比,PITX2 aCM显示出更高的线粒体含量,基底线粒体活性增加和超氧化物产生增加.
- 在工作量增加的条件下 (FCCP或β-上腺刺激),PITX2 aCMs显示线粒体功能受损.
- 这种无法满足更高的能源需求导致PITX2 aCMs中的ATP缺乏.
结论:
- 在PITX2中获得功能突变导致心房心肌细胞在基线时内在线粒体过活和超氧化物产生.
- 这些PITX2突变导致线粒体缺陷,在细胞能量需求增加时导致ATP缺乏.
- 这些发现突出了特定的线粒体功能障碍作为PITX2相关心房的早期细胞自主机制.
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