单细胞分析揭示了mtDNA的情境依赖,细胞层面的选择
Anna V Kotrys1,2, Timothy J Durham1,2, Xiaoyan A Guo1,2
1Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Nature
|April 24, 2024
概括
线粒体DNA (mtDNA) 异质体转移是由分裂细胞中的选择驱动的,而不是漂移. 环境条件决定mtDNA突变是否有益或有害于细胞适应性,影响异质体水平.
科学领域:
- 细胞生物学
- 遗传学
- 生物化学
背景情况:
- 异构体,细胞内野生型和突变型线粒体DNA (mtDNA) 的共存,在发育,疾病和衰老过程中发生动态变化.
- 驱动这些异质体转变的机制 - - 选择与漂移,以及细胞与细胞内部水平 - - 尚不清楚.
研究的目的:
- 研究分裂细胞中异质体的动态.
- 确定选择或漂移是否影响异质体水平.
- 了解选择是否在细胞或细胞内作用.
主要方法:
- 使用精确的mtDNA基编辑 (DdCBE) 针对向突变.
- 使用SCI-LITE (利用单细胞组合索引来查询目标表达) 进行超高吞吐量单细胞异质体追踪.
- 具有同义或非同义复合I mtDNA突变的工程细胞.
主要成果:
- 非同义mtDNA变异被清除,而同义变异被维持在标准细胞培养中,表明选择占主导地位.
- 单细胞异质体和祖先追踪显示,尽管有种群变化,但血统异质体仍然稳定,这表明选择对细胞适应性起作用.
- 细胞在特定环境中积累了高水平的截断复合I mtDNA异质体,其中复合I活动的丧失赋予了适应性益处.
结论:
- 在分裂的细胞中,选择,而不是简单的漂移,形成了种群异质体.
- 选择在细胞适应水平上起作用,受细胞环境的影响.
- 非同义的mtDNA异质体对细胞适应性的影响取决于环境条件,从有害到有益.
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