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

TitleEnergetic costs of cellular and therapeutic control of stochastic mitochondrial DNA populations.
Publication TypeJournal Article
Year of Publication2019
AuthorsHoitzing, H, Gammage, PA, Van Haute, L, Minczuk, M, Johnston, IG, Jones, NS
JournalPLoS Comput Biol
Volume15
Issue6
Paginatione1007023
Date Published2019 Jun
ISSN1553-7358
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.

DOI10.1371/journal.pcbi.1007023
Alternate JournalPLoS Comput. Biol.
Citation Key10.1371/journal.pcbi.1007023
PubMed ID31242175