Protons in small spaces: Discrete simulations of vesicle acidification.

Autor: Singh A; College of Letters and Science, University of California Berkeley, Berkeley, California, United States of America.; Cardiovascular Research Institute, Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America., Marcoline FV; Cardiovascular Research Institute, Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America., Veshaguri S; Bionanotecnology and Nanomedicine Laboratory, University of Copenhagen, Copenhagen, Denmark.; Department of Chemistry, University of Copenhagen, Copenhagen, Denmark.; Nano-Science Center, University of Copenhagen, Copenhagen, Denmark.; Lundbeck Foundation Center Biomembranes in Nanomedicine, University of Copenhagen, Copenhagen, Denmark., Kao AW; Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, California, United States of America., Bruchez M; Department of Chemistry, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.; Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America.; Molecular Biosensor and Imaging Center, Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America., Mindell JA; Membrane Transport Biophysics Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America., Stamou D; Bionanotecnology and Nanomedicine Laboratory, University of Copenhagen, Copenhagen, Denmark.; Department of Chemistry, University of Copenhagen, Copenhagen, Denmark.; Nano-Science Center, University of Copenhagen, Copenhagen, Denmark.; Lundbeck Foundation Center Biomembranes in Nanomedicine, University of Copenhagen, Copenhagen, Denmark., Grabe M; Cardiovascular Research Institute, Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, United States of America.
Jazyk: angličtina
Zdroj: PLoS computational biology [PLoS Comput Biol] 2019 Dec 23; Vol. 15 (12), pp. e1007539. Date of Electronic Publication: 2019 Dec 23 (Print Publication: 2019).
DOI: 10.1371/journal.pcbi.1007539
Abstrakt: The lumenal pH of an organelle is one of its defining characteristics and central to its biological function. Experiments have elucidated many of the key pH regulatory elements and how they vary from compartment-to-compartment, and continuum mathematical models have played an important role in understanding how these elements (proton pumps, counter-ion fluxes, membrane potential, buffering capacity, etc.) work together to achieve specific pH setpoints. While continuum models have proven successful in describing ion regulation at the cellular length scale, it is unknown if they are valid at the subcellular level where volumes are small, ion numbers may fluctuate wildly, and biochemical heterogeneity is large. Here, we create a discrete, stochastic (DS) model of vesicular acidification to answer this question. We used this simplified model to analyze pH measurements of isolated vesicles containing single proton pumps and compared these results to solutions from a continuum, ordinary differential equations (ODE)-based model. Both models predict similar parameter estimates for the mean proton pumping rate, membrane permeability, etc., but, as expected, the ODE model fails to report on the fluctuations in the system. The stochastic model predicts that pH fluctuations decrease during acidification, but noise analysis of single-vesicle data confirms our finding that the experimental noise is dominated by the fluorescent dye, and it reveals no insight into the true noise in the proton fluctuations. Finally, we again use the reduced DS model explore the acidification of large, lysosome-like vesicles to determine how stochastic elements, such as variations in proton-pump copy number and cycling between on and off states, impact the pH setpoint and fluctuations around this setpoint.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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