Many biological processes are subject to rhythmic changes. Well-known examples of this are the so-called circadian cycle, an "internal clock" with an approximately 24-hour period, or the shorter ultradian cycle. Cell division is often coupled with this rhythm. Biologists from Saarbrücken and Kaiserslautern have now discovered that this cycle and its coupling with cell division are controlled by a class of proteins called peroxiredoxin and hydrogen peroxide. The study was published in the renowned journal Nature Chemical Biology.
The processes in living organisms follow a finely orchestrated choreography down to the molecular level. Of great importance for these processes in the body are strictly prescribed rhythms, which follow certain cycles. For example, the 24-hour circadian cycle, a kind of "internal clock", plays an important role in metabolic and cell division mechanisms in the cells.
Scientists from the Technische Universität Kaiserslautern (TUK) and Saarland University have now taken a closer look at a similar cycle, the shorter ultradian cycle of baker's yeast, which is about five hours long.
“There are still open questions about the molecular mechanisms controlling circadian rhythms,” Dr. Prince Saforo Amponsah, a biochemist in the TUK Molecular Genetics Lab and the first paper author. “Our research is a piece to solving that puzzle.”
Under the leadership of Bruce Morgan, Professor of Biochemistry at Saarland University, the scientists investigated what happens in the model organism baker's yeast when cell metabolism is specifically altered. Metabolic processes and cell division cycles in healthy cells are known to often run in sync. Until now, it was not known whether rhythmic changes in metabolism are the cause or consequence of cell division.
Using novel peroxiredoxin-based fluorescent sensors, the team was able to observe rhythmic changes in hydrogen peroxide levels. Hydrogen peroxide is a normal by-product of metabolism, but is also well known for stressing and damaging cells. Peroxiredoxins are enzymes involved in cellular “reduction-oxidization” chemical reactions, and help regulate hydrogen peroxide levels.
To look at the importance of peroxiredoxins and hydrogen peroxide for the ultradian cycle of baker’s yeast, “we studied the protein peroxiredoxin and the consequence of its inactivation or loss for metabolism and the cell division cycle," explains Morgan. This is because the protein peroxiredoxin is very sensitive to hydrogen peroxide, thus, its activity serves as a proxy for hydrogen peroxide levels and lends itself particularly well to further understanding the role of hydrogen peroxide in regulating the cells' "internal clock."
Before, it was unclear if peroxiredoxins only report metabolic-related activity, or if they play an active role in cellular rhythms. The researchers discovered that peroxiredoxins are the critical player linking the timing of the metabolic cycle to the cell division cycle.
"We were able to determine that the coupling between metabolism and cell division is interrupted when we inactivate the peroxiredoxin in baker's yeast," explains biochemist Morgan, who was a junior professor at TUK before moving to Saarland recently. Cell division then proceeds decoupled from the metabolism of the cells. In addition, the authors were able to control when cells enter and exit the cell division cycle by precisely controlling metabolic cycling.
“We show for the first time that peroxiredoxins play a decisive role in cellular timekeeping, using hydrogen peroxide as a fuel source to perform their function,” says Amponsah, who conducted the research for his Ph.D. from TUK. “This is a culmination of about four years of hard work and a year of peer-review. I really enjoyed working on this project because it involved a lot of innovation and first-times.”
These fundamental findings could be important to better understand uncontrolled cell division in tumor cells. It is known that cell division in cancer cells is often uncoupled from the circadian clock. In the future, it will be important to investigate whether disturbed hydrogen peroxide regulation is involved.
The collaboration also included Prof. Zuzana Storchová, who heads TUK’s Molecular Genetics Lab, and Dr. Galal Yahya Metwally, a visiting scientist and Humboldt Fellow in her lab.
“This collaboration shows how combination of different approaches brings novel insights to old questions,” Storchová says. “We hope that using our model system will bring in future further understanding about how the cell cycle is synchronized with the ticking of the metabolic clock.”
The work was published in the journal Nature Chemical Biology:
Amponsah, P.S., Yahya, G., Zimmermann, J., Mai, M., Mergel, S., Mühlhaus, T., Storchova, Z. and Morgan, B. Peroxiredoxins couple metabolism and cell division in an ultradian cycle.
Nat Chem Biol (2021). https://doi.org/10.1038/s41589-020-00728-9
Contacts for further information:
Dr. Prince Saforo Amponsah
Prof. Dr. Bruce Morgan
Phone: +49 681 3023005