线粒体转移拯救了呼吸,以支持新型金胺生物合成和瘤进展
Maria Dubisova1, Klara Bohacova1, Zuzana Nahacka2
1Institute of Biotechnology of the Czech Academy of Sciences, Vestec, Czech Republic.
Cancer research
|November 17, 2025
概括
缺乏线粒体DNA (mtDNA) 的癌细胞可以从其他细胞中获得它,以恢复呼吸和胺合成. 抑制二基酸脱酶 (DHODH) 阻断瘤生长,表明一种治疗点.
科学领域:
- 细胞生物学 细胞生物学
- 癌症生物学 癌症生物学
- 代谢途径 代谢途径
背景情况:
- 具有线粒体DNA (mtDNA) 缺陷的癌细胞可以通过水平线粒体转移 (HMT) 恢复呼吸.
- 线粒体呼吸的燃料是二基酸脱酶 (DHODH),对新型胺合成至关重要.
研究的目的:
- 研究de novo胺合成在mtDNA缺陷 (ρ0) 癌细胞瘤生长中的作用.
- 确定DHODH抑制对瘤进展的影响.
主要方法:
- 在小鼠体内移植p0癌细胞,其中一些是用替代氧化酶 (AOX) 改造的.
- 分析瘤生长,线粒体呼吸和皮里米丁生产.
- 在瘤细胞中删除DHODH并评估瘤生长.
- 调查免疫细胞的招募和线粒体的转移从介质细胞 stromal 细胞 (MSCs).
主要成果:
- ρ0细胞在体内获得mtDNA,尽管AOX表达延迟了这一点.
- ρ0 AOX细胞维持了糖解,DHODH活性和胺素的产生.
- 删除DHODH显著抑制或阻止瘤生长.
- 移植的p0细胞招募了包括MSC在内的前瘤免疫细胞,促进了线粒体的转移.
结论:
- 有缺陷mtDNA的癌细胞利用HMT恢复DHODH依赖的呼吸和pyrimidine合成.
- 通过DHODH抑制向皮里米丁合成,为各种癌症提供了一个有前途的治疗策略.
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