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Robustness of the Krebs Cycle under Physiological Conditions and in Cancer: New Clues for Evaluating Metabolism-Modifying Drug Therapies

The Krebs cycle in cells that contain mitochondria is necessary for both energy production and anabolic processes. In given cell/condition, the Krebs cycle is dynamic but remains at a steady state. In this article, we first aimed at comparing the properties of a closed cycle versus the same metaboli...

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Autores principales: Franco, Rafael, Serrano-Marín, Joan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9138339/
https://www.ncbi.nlm.nih.gov/pubmed/35625935
http://dx.doi.org/10.3390/biomedicines10051199
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author Franco, Rafael
Serrano-Marín, Joan
author_facet Franco, Rafael
Serrano-Marín, Joan
author_sort Franco, Rafael
collection PubMed
description The Krebs cycle in cells that contain mitochondria is necessary for both energy production and anabolic processes. In given cell/condition, the Krebs cycle is dynamic but remains at a steady state. In this article, we first aimed at comparing the properties of a closed cycle versus the same metabolism in a linear array. The main finding is that, unlike a linear metabolism, the closed cycle can reach a steady state (SS) regardless of the nature and magnitude of the disturbance. When the cycle is modeled with input and output reactions, the “open” cycle is robust and reaches a steady state but with exceptions that lead to sustained accumulation of intermediate metabolites, i.e., conditions at which no SS can be achieved. The modeling of the cycle in cancer, trying to obtain marked reductions in flux, shows that these reductions are limited and therefore the Warburg effect is moderate at most. In general, our results of modeling the cycle in different conditions and looking for the achievement, or not, of SS, suggest that the cycle may have a regulation, not yet discovered, to go from an open cycle to a closed one. Said regulation could allow for reaching the steady state, thus avoiding the unwanted effects derived from the aberrant accumulation of metabolites in the mitochondria. The information in this paper might be useful to evaluate metabolism-modifying medicines.
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spelling pubmed-91383392022-05-28 Robustness of the Krebs Cycle under Physiological Conditions and in Cancer: New Clues for Evaluating Metabolism-Modifying Drug Therapies Franco, Rafael Serrano-Marín, Joan Biomedicines Article The Krebs cycle in cells that contain mitochondria is necessary for both energy production and anabolic processes. In given cell/condition, the Krebs cycle is dynamic but remains at a steady state. In this article, we first aimed at comparing the properties of a closed cycle versus the same metabolism in a linear array. The main finding is that, unlike a linear metabolism, the closed cycle can reach a steady state (SS) regardless of the nature and magnitude of the disturbance. When the cycle is modeled with input and output reactions, the “open” cycle is robust and reaches a steady state but with exceptions that lead to sustained accumulation of intermediate metabolites, i.e., conditions at which no SS can be achieved. The modeling of the cycle in cancer, trying to obtain marked reductions in flux, shows that these reductions are limited and therefore the Warburg effect is moderate at most. In general, our results of modeling the cycle in different conditions and looking for the achievement, or not, of SS, suggest that the cycle may have a regulation, not yet discovered, to go from an open cycle to a closed one. Said regulation could allow for reaching the steady state, thus avoiding the unwanted effects derived from the aberrant accumulation of metabolites in the mitochondria. The information in this paper might be useful to evaluate metabolism-modifying medicines. MDPI 2022-05-22 /pmc/articles/PMC9138339/ /pubmed/35625935 http://dx.doi.org/10.3390/biomedicines10051199 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Franco, Rafael
Serrano-Marín, Joan
Robustness of the Krebs Cycle under Physiological Conditions and in Cancer: New Clues for Evaluating Metabolism-Modifying Drug Therapies
title Robustness of the Krebs Cycle under Physiological Conditions and in Cancer: New Clues for Evaluating Metabolism-Modifying Drug Therapies
title_full Robustness of the Krebs Cycle under Physiological Conditions and in Cancer: New Clues for Evaluating Metabolism-Modifying Drug Therapies
title_fullStr Robustness of the Krebs Cycle under Physiological Conditions and in Cancer: New Clues for Evaluating Metabolism-Modifying Drug Therapies
title_full_unstemmed Robustness of the Krebs Cycle under Physiological Conditions and in Cancer: New Clues for Evaluating Metabolism-Modifying Drug Therapies
title_short Robustness of the Krebs Cycle under Physiological Conditions and in Cancer: New Clues for Evaluating Metabolism-Modifying Drug Therapies
title_sort robustness of the krebs cycle under physiological conditions and in cancer: new clues for evaluating metabolism-modifying drug therapies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9138339/
https://www.ncbi.nlm.nih.gov/pubmed/35625935
http://dx.doi.org/10.3390/biomedicines10051199
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