Mitochondrial DNA Density Homeostasis Accounts for a Threshold Effect in a Cybrid Model of a Human Mitochondrial Disease

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Title: Mitochondrial DNA Density Homeostasis Accounts for a Threshold Effect in a Cybrid Model of a Human Mitochondrial Disease
Author(s): Aryaman, J
Johnston, IG
Jones, NS
Item Type: Journal Article
Abstract: 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.
Publication Date: 24-Nov-2017
Date of Acceptance: 27-Oct-2017
URI: http://hdl.handle.net/10044/1/52595
DOI: https://dx.doi.org/10.1042/BCJ20170651
ISSN: 1470-8728
Publisher: Portland Press
Start Page: 4019
End Page: 4034
Journal / Book Title: Biochemical Journal
Volume: 474
Issue: 23
Sponsor/Funder: Medical Research Council (MRC)
Engineering & Physical Science Research Council (EPSRC)
BBSRC DTP
Funder's Grant Number: MR/J013617/1
EP/N014529/1
BB/J014575/1
Copyright Statement: © 2017 The Author(s). 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).
Keywords: MELAS
mitochondria
mitochondrial dysfunction
mtDNA
threshold effect
06 Biological Sciences
11 Medical And Health Sciences
03 Chemical Sciences
Biochemistry & Molecular Biology
Publication Status: Published
Appears in Collections:Mathematics
Applied Mathematics and Mathematical Physics
Faculty of Natural Sciences



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