Biology subjects

Calabrese, L.

Publications and source records attributed to Calabrese, L..

4 recordsLinked to original sources

bioRxiv2025

A Dual Homeostatic Regulation of Dry Mass and Volume Defines a Target Density in Proliferating Mammalian Cells

The concentration of macromolecules, especially proteins, is vital for cellular function and is influenced not only by synthesis and degradation but also by the total cell volume. While we understand various growth regulation mechanisms, the coupling of dry mass and volume in growing mammalian cells remains unclear. Here we show that two independent mechanisms acting in single cells --one regulating volume through biophysical modulation and the other controlling protein biosynthesis--work together to maintain macromolecular dry mass density and restore it following perturbations. These mechanisms ensure that proliferating cells remain within a specific range around a target density, providing density homeostasis at the population level. Although the target density appears consistent across different cell types, it is disrupted around cell division, upon perturbations of growth pathways and in senescent cells. It may represent an optimal value for cellular processes, ensuring the efficiency of essential intracellular functions.

cell biology↗

bioRxiv2023

Coupled ribosome allocation and nutrient sensing lead to incoherent feedback and oscillatory response in bacterial growth.

Current theories of bacterial growth physiology demonstrate impressive predictive power but are often phenomenological, lacking mechanistic detail. Incorporating such details would significantly enhance our ability to predict and control bacterial growth under varying environmental conditions. The "Flux Controlled Regulation" (FCR) model serves as a reference framework, linking ribosome allocation to translation efficiency through a steady-state assumption. However, it neglects ppGpp-mediated nutrient sensing and transcriptional regulation of ribosomal operons. Here, we propose a mechanistic model that extends the FCR framework by incorporating three key components: (i) the amino acid pool, (ii) ppGpp sensing of translation elongation rate, and (iii) transcriptional regulation of protein allocation by ppGpp-sensitive promoters. Our model aligns with observed steady-state growth laws and makes testable predictions for unobserved quantities. We show that during environmental changes, the incoherent feedback between sensing and regulation generates oscillatory relaxation dynamics, a behavior that we support by new and existing experimental data.

systems biology↗

bioRxiv2023

How total mRNA influences cell growth

Experimental observations tracing back to the 1960s imply that ribosome quantities play a prominent role in determining a cells growth. Nevertheless, in biologically relevant scenarios, growth can also be influenced by the levels of mRNA and RNA polymerase. Here, we construct a quantitative model of biosynthesis providing testable scenarios for these situations. The model explores a theoretically-motivated regime where RNA polymerases compete for genes and ribosomes for transcripts, and gives general expressions relating growth rate, mRNA concentrations, ribosome and RNA polymerase levels. On general grounds, the model predicts how the fraction of ribosomes in the proteome depends on total mRNA concentration, and inspects an underexplored regime in which the trade-off between transcript levels and ribosome abundances sets the cellular growth rate. In particular, we show that the model predicts and clarifies three important experimental observations, in budding yeast and E. coli bacteria: (i) that the growth-rate cost of unneeded protein expression can be affected by mRNA levels, (ii) that resource optimization leads to decreasing trends in mRNA levels at slow growth, and (iii) that ribosome allocation may increase, stay constant, or decrease, in response to transcription-inhibiting antibiotics. Since the data indicate that a regime of joint limitation may apply in physiological conditions and not only to perturbations, we speculate that this regime is likely self-imposed.

systems biology↗

bioRxiv2021

Role of protein degradation in growth laws

Growing cells adopt common basic strategies to achieve optimal resource allocation under limited resource availability. Our current understanding of such "growth laws" neglects degradation, assuming that it occurs slowly compared to the cell cycle duration. Here we argue that this assumption cannot hold at slow growth, leading to important consequences. We propose a simple framework showing that at slow growth protein degradation is balanced by a fraction of "maintenance" ribosomes. Consequently, active ribosomes do not drop to zero at vanishing growth, but as growth rate diminishes, an increasing fraction of active ribosomes performs maintenance. Through a detailed analysis of compiled data, we show that the predictions of this model agree with data from E. coli and S. cerevisiae. Intriguingly, we also find that protein degradation increases at slow growth, which we interpret as a consequence of active waste management and/or recycling. Our results highlight protein turnover as an underrated factor for our understanding of growth laws across kingdoms. Author summaryThe idea that simple quantitative relationships relate cell physiology to cellular composition dates back to the 1950s, but the recent years saw a leap in our understanding of such "growth laws", with relevant implications regarding the interdependence between growth, metabolism and biochemical networks. However, recent works on nutrient-limited growth mainly focused on laboratory conditions that are favourable to growth. Thus, our current mathematical understanding of the growth laws neglects protein degradation, under the argument that it occurs slowly compared to the timescale of the cell cycle. Instead, at slow growth the timescales of mass loss from protein degradation and dilution become comparable. In this work, we propose that protein degradation shapes the quantitative relationships between ribosome allocation and growth rate, and determines a fraction of ribosomes that do not contribute to growth and need to remain active to balance degradation.

systems biology↗