Cell and Organelle Size Control

Each cell in an organism has to control its size by balancing cell growth, division, and cell death. In particular, proliferating cells coordinate cell division with cell size and growth. In yeast as well as in humans, this coordination occurs in part at the G1/S transition: Cells that are smaller at their birth grow more before they divide compared to cells that are born bigger. Not surprisingly then, cancer cells – which lost the regulation of growth and division – often have altered and more variable sizes compared to healthy cells. Using live-cell time-lapse imaging combined with yeast genetics and molecular biology, we aim to understand the molecular processes through which cells can sense their own size, and adapt their size upon environmental changes such as changing nutrient conditions.

Relevant publications:

• Schmoller et al., Nature, 2015
• Chandler-Brown et al., Curr. Biol., 2017
• Schmoller, Curr. Opin. Cell Biol., 2017
• Swaffer et al., Mol. Cell, 2021
• Schmoller et al., MBoC, 2022
• Chadha et al., Physiol. Rev. 2024

Team members involved in this project: Yagya, Benedikt

For most proteins, the synthesis rate increases in direct proportion to the cell volume because also the limiting machinery for transcription and translation, including RNA polymerase and ribosomes, increases in abundance as cells get bigger. This means that more proteins are produced when the cell grows bigger and thereby, stable protein concentrations can be maintained. However, histone proteins, which bind to the DNA to pack it into the nucleus, this machinery-limited regulation is not appropriate, because rather than constant concentrations, the cell needs histone amounts that are proportional to the DNA content.

If too many histone proteins are produced but the DNA amount stays the same, the DNA gets more compacted, and highly condensed DNA forms an obstacle for many cellular processes. In contrast, too few histones would lead to loosely packed DNA that can be processed without any control. Both scenarios would harm the integrity and survival of the cell.

Thus, to maintain the right number of histones, cells couple histone production temporally to DNA duplication so that they are only produced when they are needed. But how do they ensure that the right amount of histones is produced, even though protein production rate during S-phase depends on cell size and growth rate, and S-phase duration varies in different environmental conditions? We aim to understand how cells can produce the right number of histones independently of their size and how this regulation is affected by different environmental conditions. By understanding the cell-size-dependent regulation of histones, we expect to reveal regulatory processes that are broadly used by cells to adjust their protein content according to the requirements that go along with changes in cell size.

Relevant publications:

• Swaffer et al., Mol. Cell., 2021
• Claude et al., Nat. Comm., 2021
• Chatzitheodoridou et al., BioRxiv, 2023

Team members involved in this project: Daniela, Dimitra, Arohi

Mitochondria are the powerhouses of cells. Mitochondrial DNA (mtDNA) is essential to mitochondria functions since it encodes for subunits of the respiratory chain. Defects in mtDNA maintenance and altered mtDNA copy number are linked to metabolic and neurodegenerative diseases, as well as many types of cancer. mtDNA replication mechanisms play a crucial role in maintaining the right mtDNA copy number and homeostasis.

When growing cells double in size, they need to ensure that also the amount of their DNA doubles. To achieve this, replication of nuclear DNA is coupled to cell cycle progression, ensuring that DNA is doubled exactly once per cell cycle. By contrast, mtDNA replication is not strictly coupled to the cell cycle and can occur throughout the cell cycle and even continue during long cell cycle arrests. How do cells ensure then that they produce the right amount of mtDNA? We found that mtDNA copy number increases with cell volume, which ensures constant concentrations. To understand mtDNA homeostasis during cell growth, we therefore now aim to reveal the molecular mechanisms that coordinate mtDNA amount with cell size.

Relevant publications:

• Seel et al., Nat. Struct. Mol. Biol. 2023
• Roussou et al., EMBO J. 2024

Team members involved in this project: Anika, Francesco, Alissa

Single-cell microscopy is a powerful tool that we use across all our biological questions. Ranging from microfluidics-based live-cell microscopy to follow cell growth and division over multiple cell cycles, quantification of mitochondrial network and DNA in live cells to single molecule FISH, microscopy can provide direct quantitative insights. Despite recent progress in AI-based approaches, image analysis can be very time-consuming and is often still the rate-limiting step. To address this, we use state-of-the-art deep-learning to improve automated image analysis and work on making these approaches easily accessible for a broad community. We envision that standardized tools and approaches will enable reproducibility and data sharing.

Relevant publications:

• Cuny et al., Biophys. Rev., 2022
• Padovani et al., BMC Biology, 2022
• Vitacolonna et al., Front. Bioeng. Biotechnol. 2024 

Team members involved in this project: Francesco, Benedikt.