线粒体单碳通路支持癌细胞中的细胞酸完整性
Yuxiang Zheng1, Ting-Yu Lin1, Gina Lee2
1Department of Medicine, Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
Cell
|December 1, 2018
概括
线粒体叶酸代谢对于防止细胞质中的叶酸降解至关重要. 干扰这种途径或使用甲醇会导致严重的叶酸损失,影响细胞健康,并可能解释临床叶酸缺乏症.
科学领域:
- 生物化学
- 细胞生物学
- 代谢途径
背景情况:
- 哺乳动物的叶酸代谢涉及不同的细胞和线粒体通路,反应重叠.
- 部分化叶酸代谢的功能意义尚不完全理解.
- 氧化应激会损害重要的叶酸辅因子,如四叶酸 (THF).
研究的目的:
- 研究线粒体叶酸代谢的功能后果.
- 阐明特定酶在维持叶酸平衡中的作用.
- 研究抗叶酸药物对叶酸代谢的影响.
主要方法:
- 用基因组编辑来破坏哺乳动物细胞系中的线粒体叶酸通路.
- 生物化学测定用于量化叶酸水平和酶活性.
- 在各种实验条件下进行了叶酸降解的比较分析.
主要成果:
- 线粒体叶酸代谢的消去导致细胞质中叶酸的显著降解.
- 发现昆二降解酶 (QDPR) 能够修复THF的氧化损伤.
- 细胞质THF积累,因缺少线粒体形式而加剧,压倒了QDPR的修复能力,导致THF降解.
- 除了已知的DHFR抑制之外,甲基治疗还在多种癌细胞系中诱导了广泛的叶酸降解.
结论:
- 线粒体叶酸代谢在预防细胞酸叶酸降解方面起着至关重要的作用.
- 在四生物代谢和THF修复中QDPR的双重作用对叶酸平衡至关重要.
- 这些发现为在QDPR缺乏的人群中观察到的叶酸缺乏提供了生物化学基础.
- 在癌细胞中表现出一种非特征性的,强烈的叶酸降解作用.
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