Institute of Functional Epigenetics, Molecular Targets and Therapeutics Center, Helmholtz Zentrum München, Neuherberg, Germany.
Institute of Cell Biology, University of Bayreuth, Bayreuth, Germany.
Nat Struct Mol Biol. 2023 Oct;30(10):1549-1560. doi: 10.1038/s41594-023-01091-8. Epub 2023 Sep 7.
To maintain stable DNA concentrations, proliferating cells need to coordinate DNA replication with cell growth. For nuclear DNA, eukaryotic cells achieve this by coupling DNA replication to cell-cycle progression, ensuring that DNA is doubled exactly once per cell cycle. By contrast, mitochondrial DNA replication is typically not strictly coupled to the cell cycle, leaving the open question of how cells maintain the correct amount of mitochondrial DNA during cell growth. Here, we show that in budding yeast, mitochondrial DNA copy number increases with cell volume, both in asynchronously cycling populations and during G1 arrest. Our findings suggest that cell-volume-dependent mitochondrial DNA maintenance is achieved through nuclear-encoded limiting factors, including the mitochondrial DNA polymerase Mip1 and the packaging factor Abf2, whose amount increases in proportion to cell volume. By directly linking mitochondrial DNA maintenance to nuclear protein synthesis and thus cell growth, constant mitochondrial DNA concentrations can be robustly maintained without a need for cell-cycle-dependent regulation.
为了维持稳定的 DNA 浓度，增殖细胞需要将 DNA 复制与细胞生长协调起来。对于核 DNA，真核细胞通过将 DNA 复制与细胞周期进程偶联来实现这一点，从而确保 DNA 在每个细胞周期中准确地复制两次。相比之下，线粒体 DNA 的复制通常与细胞周期没有严格偶联，这就留下了一个悬而未决的问题，即细胞在细胞生长过程中如何维持正确的线粒体 DNA 量。在这里，我们表明在芽殖酵母中，线粒体 DNA 拷贝数随着细胞体积的增加而增加，无论是在异步循环群体中还是在 G1 期停滞期间。我们的研究结果表明，细胞体积依赖性线粒体 DNA 维持是通过核编码的限制因素实现的，包括线粒体 DNA 聚合酶 Mip1 和包装因子 Abf2，它们的含量与细胞体积成比例增加。通过将线粒体 DNA 维持直接与核蛋白合成以及细胞生长联系起来，无需细胞周期依赖性调节即可稳健地维持恒定的线粒体 DNA 浓度。
