Dissecting the role of redox signaling in coupling oscillatory metabolism to cell division

在特定的恒化器生长条件下，酵母细胞群体自发地同步经历持续的代谢振荡，这似乎与细胞的生长和分裂紧密相连。这种振荡行为统称为酵母代谢周期(YMC)。有趣的是，我们的实验室和其他实验室最近表明，新陈代谢振荡在没有细胞分裂的情况下持续存在，甚至似乎对控制细胞周期的进出很重要。此外，在YMC(Morgan Lab)的背景下，我们证明了氧化还原信号与稳定的集体代谢振荡行为的出现以及振荡代谢状态与细胞分裂的耦合有关。最近的研究，包括来自Charvin实验室的大量初步实验，揭示了在单细胞水平上存在代谢、氧化还原信号和蛋白激酶A活性振荡。与YMC一致，这些振荡可以与细胞分裂相结合，似乎对调节细胞周期的进出很重要，但也可以独立于细胞分裂而持续。然而，在单细胞水平上观察到的代谢周期是否与在YMC同步群体中观察到的代谢周期相对应尚不清楚。这两个系统中代谢循环的机制基础完全未知，代谢周期和细胞分裂之间的确切因果关系、串扰和相互作用仍然难以捉摸。现在，摩根和查尔文实验室将结合他们的专业知识，开发一种新的方法，将人口规模的动态测量与基于微流体的单细胞跟踪相结合。结合我们在酵母遗传学、新型基因编码的氧化还原传感器、定量活细胞成像、微流体和恒化器培养方面的专业知识，我们将以迄今无法获得的空间和时间分辨率阐明种群的新陈代谢周期和细胞分裂的异质性。此外，我们将讨论氧化还原信号和蛋白激酶A活性在细胞分裂和振荡代谢中的作用。通过将我们的方法与计算分析相结合，我们将采取重要步骤来破译支配代谢振荡出现的基本原理，阐明它们在波动环境下的潜在适应性优势，并了解它们与细胞分裂的相关性。

Under specific chemostat growth conditions, yeast cell populations spontaneously synchronize to undergo sustained metabolic oscillations, which appear to be tightly coupled to cell growth and division. Collectively this oscillatory behavior is referred to as the yeast metabolic cycle (YMC). Intriguingly, our lab and others have recently shown that metabolic oscillations persist in the absence of cell division and even seem to be important for gating cell cycle entry and exit. Furthermore, we demonstrated that redox signaling is implicated in the emergence of a stable collective metabolic oscillatory behavior and in the coupling of oscillatory metabolic state to cell division in the context of the YMC (Morgan lab). Recent studies, including extensive preliminary experiments from the Charvin lab, reveal the existence of metabolic, redox signaling, and protein kinase A activity oscillations at the single cell level. Consistent with the YMC, these oscillations can be coupled to cell division and seem to be important for regulating cell cycle entry and exit but can also persist independently of cell division. However, whether metabolic cycles observed at the single cell level correspond to those observed in YMC-synchronized populations is unclear. The mechanistic basis of metabolic cycling in both systems is completely unknown and the exact causal relationships, crosstalk and interplay between metabolic cycles and cell division remain elusive. Now, the Morgan and Charvin labs will combine their expertise to develop a novel methodology that merges population-scale dynamic measurements with microfluidics-based single-cell tracking. Combining our expertise in yeast genetics, novel genetically encoded redox sensors, quantitative live-cell imaging, microfluidics, and chemostat cultures we will elucidate population heterogeneity in terms of metabolic cycling and cell division with thus far unobtainable spatial and temporal resolution. Furthermore, we will address the role of redox signaling and protein kinase A activity in coupling cell division with oscillatory metabolism. By combining our approaches with computational analyses, we will take important steps towards deciphering the fundamental principles that govern the emergence of metabolic oscillations, elucidate their potential fitness advantages under fluctuating environments and understand their relevance for cell division.