Life is based on energy conversion. In particular, in the nervous system, significant amounts of energy are needed to maintain synaptic transmission and homeostasis. To a large extent, neurons depend on oxidative phosphorylation in mitochondria to meet their high energy demand. For a comprehensive understanding of the metabolic demands in neuronal signaling, accurate models of ATP production in mitochondria are required. Here, we present a thermodynamically consistent model of ATP production in mitochondria based on previous work. The significant improvement of the model is that the reaction rate constants are set such that detailed balance is satisfied. Moreover, using thermodynamic considerations, the dependence of the reaction rate constants on membrane potential, pH, and substrate concentrations are explicitly provided. These constraints assure that the model is physically plausible. Furthermore, we explore different parameter regimes to understand in which conditions ATP production or its export are the limiting steps in making ATP available in the cytosol. The outcomes reveal that, under the conditions used in our simulations, ATP production is the limiting step and not its export. Finally, we performed spatial simulations with nine 3-D realistic mitochondrial reconstructions and linked the ATP production rate in the cytosol with morphological features of the organelles.
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4 September 2023
Article|
August 24 2023
Mitochondrial morphology governs ATP production rate
Guadalupe C. Garcia
,
Guadalupe C. Garcia
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Computational Neurobiology Laboratory,
Salk Institute for Biological Studies
, La Jolla, CA, USA
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Kavya Gupta
,
Kavya Gupta
(Software, Validation, Visualization)
2Department of Mechanical and Aerospace Engineering,
University of California, San Diego
, La Jolla, CA, USA
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Thomas M. Bartol
,
Thomas M. Bartol
(Software, Supervision, Validation, Writing - review & editing)
1Computational Neurobiology Laboratory,
Salk Institute for Biological Studies
, La Jolla, CA, USA
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Terrence J. Sejnowski
,
Terrence J. Sejnowski
(Conceptualization, Funding acquisition, Supervision, Writing - review & editing)
1Computational Neurobiology Laboratory,
Salk Institute for Biological Studies
, La Jolla, CA, USA
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Padmini Rangamani
(Conceptualization, Formal analysis, Funding acquisition, Writing - original draft, Writing - review & editing)
2Department of Mechanical and Aerospace Engineering,
University of California, San Diego
, La Jolla, CA, USA
Correspondence to Padmini Rangamani: prangamani@ucsd.edu
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Guadalupe C. Garcia
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1Computational Neurobiology Laboratory,
Salk Institute for Biological Studies
, La Jolla, CA, USA
Kavya Gupta
Software, Validation, Visualization
2Department of Mechanical and Aerospace Engineering,
University of California, San Diego
, La Jolla, CA, USA
Thomas M. Bartol
Software, Supervision, Validation, Writing - review & editing
1Computational Neurobiology Laboratory,
Salk Institute for Biological Studies
, La Jolla, CA, USA
Terrence J. Sejnowski
Conceptualization, Funding acquisition, Supervision, Writing - review & editing
1Computational Neurobiology Laboratory,
Salk Institute for Biological Studies
, La Jolla, CA, USA
Correspondence to Padmini Rangamani: prangamani@ucsd.edu
1
These calculations were reported to be in a Ph.D. thesis we could not access (Magnus, 1995). Recently, we found part of these calculations were included in another Ph.D. thesis (Balbir, 2007).
Received:
September 13 2022
Revision Received:
March 21 2023
Revision Received:
June 01 2023
Accepted:
July 07 2023
Online ISSN: 1540-7748
Print ISSN: 0022-1295
Funding
Funder(s):
Air Force Office of Scientific Research
Funder(s):
Multidisciplinary University Research Initiative
- Award Id(s): FA9550-18-1-0051
Funder(s):
Office of Naval Research
- Award Id(s): N00014-20-1-2469
© 2023 Garcia et al.
2023
Garcia et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Gen Physiol (2023) 155 (9): e202213263.
Article history
Received:
September 13 2022
Revision Received:
March 21 2023
Revision Received:
June 01 2023
Accepted:
July 07 2023
Citation
Guadalupe C. Garcia, Kavya Gupta, Thomas M. Bartol, Terrence J. Sejnowski, Padmini Rangamani; Mitochondrial morphology governs ATP production rate. J Gen Physiol 4 September 2023; 155 (9): e202213263. doi: https://doi.org/10.1085/jgp.202213263
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