Our cells are filled with populations of mitochondrial DNA (mtDNA) molecules, which encode vital cellular machinery that supports our energy requirements. The cell invests energy in maintaining its mtDNA population, like us using electricity-powered tools to help maintain our power stations. Our cellular power stations can vary in quality (for example, mutations can damage mtDNA), and are subject to random influences. How should the cell best invest energy in controlling and maintaining its power stations? And can we use this answer to design better therapies to address damaged mtDNA?
In a new paper "Energetic costs of cellular and therapeutic control of stochastic mitochondrial DNA populations" free here in PLoS Computational Biology, we attempt to answer this question using mathematical modelling, linking with genetic experiments done by our excellent collaborators at Cambridge (Payam Gammage, Lindsey Van Haute and Michal Minczuk). We first expand a mathematical model for how diverse mtDNA populations within cells change over time – building new power stations and decommissioning old ones, under the “governance” of the cell. We then produce an “energy budget” for the cellular “society” – describing the costs of building, decommissioning, and maintaining different power stations, and the corresponding profits of energy generation.
We find some surprising results. First, it can get harder to maintain a good energy budget in a tissue (a collection of individual cellular “societies”) over time, even if demands stay the same and average mtDNA quality doesn’t change. This is because the cell-to-cell variability in mtDNA quality does increase, carrying with it an added energetic challenge. This increased challenge could be a contributing factor to the collection of problems involved in ageing.
An overview of our approach. A mathematical model for the processes and "budget" involved in controlling mtDNA populations makes a general set of biological predictions and explains gene-therapy observations
Next, we found that cells with only low-quality mtDNA can perform worse than cells with a mix of low- and high-quality mtDNA. This is because low-quality mtDNA may consume less cellular resource, although global efficiency is decreased. Linked to this, removal of low-quality mtDNA (decommissioning bad power stations) alone is not always the best strategy to improve performance. Instead, jointly elevating low- and high-quality mtDNA levels, avoiding this detrimental mixed regime, is the best strategy for some situations. These insights may help explain some of the negative effects recently observed in cells with mixed mtDNA populations.
Our theory suggests that mixed mtDNA populations may do worse than pure ones, even if the pure population is a low-functionality mutant. Image from Hanne's post here
We identified how best to control cellular mtDNA populations across the full range of possible populations, and used this insight to link with exciting gene therapies where low-quality mtDNA is preferentially removed through an experimental intervention (using so-called “endonucleases” to cut particular mtDNA molecules). We found that strong, single treatments will be outperformed by weaker, longer-term treatments, and identified how the mtDNA variability we know is present can practically effect the outcome of these therapies. We hope that the principles found in this work both add to our basic understanding of ageing and mixed (“heteroplasmic”) mitochondrial populations, and may inform more efficient therapeutic approaches in the future. Iain, Hanne, Nick
(Hanne's also written a post about this paper, you can read it here)