Energetic costs of cellular and therapeutic control of stochastic mitochondrial DNA populations

Beard, D. A., Hoitzing, H., Gammage, P. A. , Haute, L. V., Minczuk, M., Johnston, I. G. and Jones, N. S. (2019) Energetic costs of cellular and therapeutic control of stochastic mitochondrial DNA populations. PLoS Computational Biology, 15(6), e1007023. (doi: 10.1371/journal.pcbi.1007023) (PMID:31242175) (PMCID:PMC6615642)

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Abstract

The dynamics of the cellular proportion of mutant mtDNA molecules is crucial for mitochondrial diseases. Cellular populations of mitochondria are under homeostatic control, but the details of the control mechanisms involved remain elusive. Here, we use stochastic modelling to derive general results for the impact of cellular control on mtDNA populations, the cost to the cell of different mtDNA states, and the optimisation of therapeutic control of mtDNA populations. This formalism yields a wealth of biological results, including that an increasing mtDNA variance can increase the energetic cost of maintaining a tissue, that intermediate levels of heteroplasmy can be more detrimental than homoplasmy even for a dysfunctional mutant, that heteroplasmy distribution (not mean alone) is crucial for the success of gene therapies, and that long-term rather than short intense gene therapies are more likely to beneficially impact mtDNA populations.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Gammage, Dr Payam
Authors: Beard, D. A., Hoitzing, H., Gammage, P. A., Haute, L. V., Minczuk, M., Johnston, I. G., and Jones, N. S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:PLoS Computational Biology
Publisher:Public Library of Science
ISSN:1553-734X
ISSN (Online):1553-7358
Copyright Holders:Copyright © 2019 Hoitzing et al.
First Published:First published in PLoS Computational Biology 15(6):e1007023
Publisher Policy:Reproduced under a Creative Commons License

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