Capturing intracellular pH dynamics by coupling its molecular mechanisms within a fully tractable mathematical model

PLoS One. 2014 Jan 17;9(1):e85449. doi: 10.1371/journal.pone.0085449. eCollection 2014.

Abstract

We describe the construction of a fully tractable mathematical model for intracellular pH. This work is based on coupling the kinetic equations depicting the molecular mechanisms for pumps, transporters and chemical reactions, which determine this parameter in eukaryotic cells. Thus, our system also calculates the membrane potential and the cytosolic ionic composition. Such a model required the development of a novel algebraic method that couples differential equations for slow relaxation processes to steady-state equations for fast chemical reactions. Compared to classical heuristic approaches based on fitted curves and ad hoc constants, this yields significant improvements. This model is mathematically self-consistent and allows for the first time to establish analytical solutions for steady-state pH and a reduced differential equation for pH regulation. Because of its modular structure, it can integrate any additional mechanism that will directly or indirectly affect pH. In addition, it provides mathematical clarifications for widely observed biological phenomena such as overshooting in regulatory loops. Finally, instead of including a limited set of experimental results to fit our model, we show examples of numerical calculations that are extremely consistent with the wide body of intracellular pH experimental measurements gathered by different groups in many different cellular systems.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acidosis / metabolism
  • Animals
  • Carbon Dioxide / metabolism
  • Computer Simulation
  • Hydrogen-Ion Concentration
  • Intracellular Space / metabolism*
  • Ischemia / metabolism
  • Kinetics
  • Models, Biological*

Substances

  • Carbon Dioxide

Grants and funding

This work was supported by the University of Nice-Sophia Antipolis, the CNRS Bio Maths Info PEPS 2012 and the INSERM “Physique-Cancer” Program (H+ Cancer). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.