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MITOsym®: A Mechanistic, Mathematical Model of Hepatocellular Respiration and Bioenergetics

PURPOSE: MITOsym, a new mathematical model of hepatocellular respiration and bioenergetics, has been developed in partnership with the DILIsym® model with the purpose of translating in vitro compound screening data into predictions of drug induced liver injury (DILI) risk for patients. The combined...

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Autores principales: Yang, Y., Nadanaciva, S., Will, Y., Woodhead, J. L., Howell, B. A., Watkins, P. B., Siler, S. Q.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422870/
https://www.ncbi.nlm.nih.gov/pubmed/25504454
http://dx.doi.org/10.1007/s11095-014-1591-0
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author Yang, Y.
Nadanaciva, S.
Will, Y.
Woodhead, J. L.
Howell, B. A.
Watkins, P. B.
Siler, S. Q.
author_facet Yang, Y.
Nadanaciva, S.
Will, Y.
Woodhead, J. L.
Howell, B. A.
Watkins, P. B.
Siler, S. Q.
author_sort Yang, Y.
collection PubMed
description PURPOSE: MITOsym, a new mathematical model of hepatocellular respiration and bioenergetics, has been developed in partnership with the DILIsym® model with the purpose of translating in vitro compound screening data into predictions of drug induced liver injury (DILI) risk for patients. The combined efforts of these two models should increase the efficiency of evaluating compounds in drug development in addition to enhancing patient care. METHODS: MITOsym includes the basic, essential biochemical pathways associated with hepatocellular respiration and bioenergetics, including mitochondrial oxidative phosphorylation, electron transport chain activity, mitochondrial membrane potential, and glycolysis; also included are dynamic feedback signals based on perturbation of these pathways. The quantitative relationships included in MITOsym are based primarily on published data; additional new experiments were also performed in HepG2 cells to determine the effects on oxygen consumption rate as media glucose concentrations or oligomycin concentrations were varied. The effects of varying concentrations of FCCP on the mitochondrial proton gradient were also measured in HepG2 cells. RESULTS: MITOsym simulates and recapitulates the reported dynamic changes to hepatocellular oxygen consumption rates, extracellular acidification rates, the mitochondrial proton gradient, and ATP concentrations in the presence of classic mitochondrial toxins such as rotenone, FCCP, and oligomycin. CONCLUSIONS: MITOsym can be used to simulate hepatocellular respiration and bioenergetics and provide mechanistic hypotheses to facilitate the translation of in vitro data collection to predictions of in vivo human hepatotoxicity risk for novel compounds. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11095-014-1591-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-44228702015-05-13 MITOsym®: A Mechanistic, Mathematical Model of Hepatocellular Respiration and Bioenergetics Yang, Y. Nadanaciva, S. Will, Y. Woodhead, J. L. Howell, B. A. Watkins, P. B. Siler, S. Q. Pharm Res Research Paper PURPOSE: MITOsym, a new mathematical model of hepatocellular respiration and bioenergetics, has been developed in partnership with the DILIsym® model with the purpose of translating in vitro compound screening data into predictions of drug induced liver injury (DILI) risk for patients. The combined efforts of these two models should increase the efficiency of evaluating compounds in drug development in addition to enhancing patient care. METHODS: MITOsym includes the basic, essential biochemical pathways associated with hepatocellular respiration and bioenergetics, including mitochondrial oxidative phosphorylation, electron transport chain activity, mitochondrial membrane potential, and glycolysis; also included are dynamic feedback signals based on perturbation of these pathways. The quantitative relationships included in MITOsym are based primarily on published data; additional new experiments were also performed in HepG2 cells to determine the effects on oxygen consumption rate as media glucose concentrations or oligomycin concentrations were varied. The effects of varying concentrations of FCCP on the mitochondrial proton gradient were also measured in HepG2 cells. RESULTS: MITOsym simulates and recapitulates the reported dynamic changes to hepatocellular oxygen consumption rates, extracellular acidification rates, the mitochondrial proton gradient, and ATP concentrations in the presence of classic mitochondrial toxins such as rotenone, FCCP, and oligomycin. CONCLUSIONS: MITOsym can be used to simulate hepatocellular respiration and bioenergetics and provide mechanistic hypotheses to facilitate the translation of in vitro data collection to predictions of in vivo human hepatotoxicity risk for novel compounds. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11095-014-1591-0) contains supplementary material, which is available to authorized users. Springer US 2014-12-12 2015 /pmc/articles/PMC4422870/ /pubmed/25504454 http://dx.doi.org/10.1007/s11095-014-1591-0 Text en © The Author(s) 2014 https://creativecommons.org/licenses/by/4.0/ Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.
spellingShingle Research Paper
Yang, Y.
Nadanaciva, S.
Will, Y.
Woodhead, J. L.
Howell, B. A.
Watkins, P. B.
Siler, S. Q.
MITOsym®: A Mechanistic, Mathematical Model of Hepatocellular Respiration and Bioenergetics
title MITOsym®: A Mechanistic, Mathematical Model of Hepatocellular Respiration and Bioenergetics
title_full MITOsym®: A Mechanistic, Mathematical Model of Hepatocellular Respiration and Bioenergetics
title_fullStr MITOsym®: A Mechanistic, Mathematical Model of Hepatocellular Respiration and Bioenergetics
title_full_unstemmed MITOsym®: A Mechanistic, Mathematical Model of Hepatocellular Respiration and Bioenergetics
title_short MITOsym®: A Mechanistic, Mathematical Model of Hepatocellular Respiration and Bioenergetics
title_sort mitosym®: a mechanistic, mathematical model of hepatocellular respiration and bioenergetics
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4422870/
https://www.ncbi.nlm.nih.gov/pubmed/25504454
http://dx.doi.org/10.1007/s11095-014-1591-0
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