https://ror.org/05kb8h459 Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
Life Sci Alliance. 2023 Sep 11;6(12). doi: 10.26508/lsa.202302091. Print 2023 Dec.
Mitochondria are central to numerous metabolic pathways whereby mitochondrial dysfunction has a profound impact and can manifest in disease. The consequences of mitochondrial dysfunction can be ameliorated by adaptive responses that rely on crosstalk from the mitochondria to the rest of the cell. Such mito-cellular signalling slows cell cycle progression in mitochondrial DNA-deficient (ρ) cells, but the initial trigger of the response has not been thoroughly studied. Here, we show that decreased mitochondrial membrane potential (ΔΨm) acts as the initial signal of mitochondrial stress that delays G1-to-S phase transition in both ρ and control cells containing mtDNA. Accordingly, experimentally increasing ΔΨm was sufficient to restore timely cell cycle progression in ρ cells. In contrast, cellular levels of oxidative stress did not correlate with the G1-to-S delay. Restored G1-to-S transition in ρ cells with a recovered ΔΨm is likely attributable to larger cell size, whereas the timing of G1/S transcription remained delayed. The identification of ΔΨm as a regulator of cell cycle progression may have implications for disease states involving mitochondrial dysfunction.
线粒体是许多代谢途径的核心，线粒体功能障碍对这些代谢途径有着深远的影响，并可能在疾病中表现出来。线粒体功能障碍的后果可以通过适应性反应来缓解，这种反应依赖于线粒体与细胞其他部分的相互作用。这种线粒体-细胞信号传导会减缓线粒体 DNA 缺失（ρ）细胞的细胞周期进程，但反应的初始触发因素尚未得到彻底研究。在这里，我们表明，线粒体膜电位（ΔΨm）的降低是线粒体应激的初始信号，它会延迟含有 mtDNA 的 ρ 和对照细胞从 G1 期到 S 期的转变。因此，实验上增加 ΔΨm 足以恢复 ρ 细胞的适时细胞周期进程。相比之下，细胞内氧化应激水平与 G1 到 S 期的延迟没有相关性。在 ΔΨm 恢复的 ρ 细胞中，G1 到 S 期的转变得以恢复，这可能归因于细胞体积增大，而 G1/S 转录的时间仍然延迟。ΔΨm 作为细胞周期进程调节剂的鉴定可能对涉及线粒体功能障碍的疾病状态具有重要意义。
