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Mitochondrial DNA density homeostasis accounts for a threshold effect in a cybrid model of a human mitochondrial disease

Mitochondrial dysfunction is involved in a wide array of devastating diseases, but the heterogeneity and complexity of the symptoms of these diseases challenges theoretical understanding of their causation. With the explosion of omics data, we have the unprecedented opportunity to gain deep understa...

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Detalles Bibliográficos
Autores principales: Aryaman, Juvid, Johnston, Iain G., Jones, Nick S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705840/
https://www.ncbi.nlm.nih.gov/pubmed/29079678
http://dx.doi.org/10.1042/BCJ20170651
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author Aryaman, Juvid
Johnston, Iain G.
Jones, Nick S.
author_facet Aryaman, Juvid
Johnston, Iain G.
Jones, Nick S.
author_sort Aryaman, Juvid
collection PubMed
description Mitochondrial dysfunction is involved in a wide array of devastating diseases, but the heterogeneity and complexity of the symptoms of these diseases challenges theoretical understanding of their causation. With the explosion of omics data, we have the unprecedented opportunity to gain deep understanding of the biochemical mechanisms of mitochondrial dysfunction. This goal raises the outstanding need to make these complex datasets interpretable. Quantitative modelling allows us to translate such datasets into intuition and suggest rational biomedical treatments. Taking an interdisciplinary approach, we use a recently published large-scale dataset and develop a descriptive and predictive mathematical model of progressive increase in mutant load of the MELAS 3243A>G mtDNA mutation. The experimentally observed behaviour is surprisingly rich, but we find that our simple, biophysically motivated model intuitively accounts for this heterogeneity and yields a wealth of biological predictions. Our findings suggest that cells attempt to maintain wild-type mtDNA density through cell volume reduction, and thus power demand reduction, until a minimum cell volume is reached. Thereafter, cells toggle from demand reduction to supply increase, up-regulating energy production pathways. Our analysis provides further evidence for the physiological significance of mtDNA density and emphasizes the need for performing single-cell volume measurements jointly with mtDNA quantification. We propose novel experiments to verify the hypotheses made here to further develop our understanding of the threshold effect and connect with rational choices for mtDNA disease therapies.
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spelling pubmed-57058402017-12-12 Mitochondrial DNA density homeostasis accounts for a threshold effect in a cybrid model of a human mitochondrial disease Aryaman, Juvid Johnston, Iain G. Jones, Nick S. Biochem J Research Articles Mitochondrial dysfunction is involved in a wide array of devastating diseases, but the heterogeneity and complexity of the symptoms of these diseases challenges theoretical understanding of their causation. With the explosion of omics data, we have the unprecedented opportunity to gain deep understanding of the biochemical mechanisms of mitochondrial dysfunction. This goal raises the outstanding need to make these complex datasets interpretable. Quantitative modelling allows us to translate such datasets into intuition and suggest rational biomedical treatments. Taking an interdisciplinary approach, we use a recently published large-scale dataset and develop a descriptive and predictive mathematical model of progressive increase in mutant load of the MELAS 3243A>G mtDNA mutation. The experimentally observed behaviour is surprisingly rich, but we find that our simple, biophysically motivated model intuitively accounts for this heterogeneity and yields a wealth of biological predictions. Our findings suggest that cells attempt to maintain wild-type mtDNA density through cell volume reduction, and thus power demand reduction, until a minimum cell volume is reached. Thereafter, cells toggle from demand reduction to supply increase, up-regulating energy production pathways. Our analysis provides further evidence for the physiological significance of mtDNA density and emphasizes the need for performing single-cell volume measurements jointly with mtDNA quantification. We propose novel experiments to verify the hypotheses made here to further develop our understanding of the threshold effect and connect with rational choices for mtDNA disease therapies. Portland Press Ltd. 2017-12-01 2017-11-24 /pmc/articles/PMC5705840/ /pubmed/29079678 http://dx.doi.org/10.1042/BCJ20170651 Text en © 2017 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0) .
spellingShingle Research Articles
Aryaman, Juvid
Johnston, Iain G.
Jones, Nick S.
Mitochondrial DNA density homeostasis accounts for a threshold effect in a cybrid model of a human mitochondrial disease
title Mitochondrial DNA density homeostasis accounts for a threshold effect in a cybrid model of a human mitochondrial disease
title_full Mitochondrial DNA density homeostasis accounts for a threshold effect in a cybrid model of a human mitochondrial disease
title_fullStr Mitochondrial DNA density homeostasis accounts for a threshold effect in a cybrid model of a human mitochondrial disease
title_full_unstemmed Mitochondrial DNA density homeostasis accounts for a threshold effect in a cybrid model of a human mitochondrial disease
title_short Mitochondrial DNA density homeostasis accounts for a threshold effect in a cybrid model of a human mitochondrial disease
title_sort mitochondrial dna density homeostasis accounts for a threshold effect in a cybrid model of a human mitochondrial disease
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705840/
https://www.ncbi.nlm.nih.gov/pubmed/29079678
http://dx.doi.org/10.1042/BCJ20170651
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