Biology subjects

Davies, A. M.

Publications and source records attributed to Davies, A. M..

6 recordsLinked to original sources

bioRxiv2025

The Effects of Living at Altitude on the Prevalence of Dementia

A lower incidence of dementia has been observed in populations residing at high altitudes compared to those at low altitudes. A possible cause is the inverse relationship between altitude and the partial pressure of inspired oxygen. This paper investigates the long term impact that living at altitude has on mitochondrial function. We use simulation methods to model the dynamics of a population of mtDNA and the proliferation of deletion mutants. Clonal expansion of these deletion mutants over many years impairs mitochondrial function resulting in cell death, notably in post-mitotic cells such as neurons. Neuron loss leads to cognitive impairment, progressing to dementia over time. Our results show that there is a moderate reduction in neuron loss rates and associated cognitive decline with respect to dementia in the elderly. These results are consistent with published data on the regional prevalence of dementia when plotted against altitude.

evolutionary biology↗

bioRxiv2024

Impact of mitochondrial fission and fusion onneuronal health and incidence of dementia

Mitochondria are highly dynamic structures that undergo constant remodeling by the process of fission and fusion. Using simulation methods we study the effects of neuron loss in humans due to the proliferation of deletion mutations. We implement two models of an organelle, namely, closed cristae (CC) and open mitochondrion (OM). With CC, mtDNA are confined to a cristae unless mixed by the process of fission and fusion. Conversely, mtDNA can diffuse freely throughout the organelle in the OM model. We also implement selective mitophagy in the CC model. Higher rates of mixing mtDNA increase the rate of neuron loss which, in turn, increases the prevalence of dementia. Selective mitophagy mitigates against the effect of high rate mixing. However, this mitigation is all or nothing. Even at nominal rates compared to mixing, neuron loss is almost completely eliminated resulting in minimal cognitive decline. These results do not fit the observations of normal aging and dementia prevalence in the elderly human population. This study brings into question the role that fission and fusion is believed play in the removal of defective mtDNA.

cell biology↗

bioRxiv2023

The long term effects of uncoupling interventions as a therapy for dementia in humans

In this paper we use simulation methods to study a hypothetical uncoupling agent as a therapy for dementia. We simulate the proliferation of mitochondrial deletion mutants amongst a population of wild-type in human neurons. Mitochondria play a key role in ATP generation. Clonal expansion can lead to the wild-type being overwhelmed by deletions such that a diminished population can no longer fulfill a cells energy requirement, eventually leading its demise. The intention of uncoupling is to reduce the formation of deletion mutants by reducing mutation rate. However, a consequence of uncoupling is that the energy production efficacy is also reduced which in turn increases wild-type copy number in order to compensate for the energy deficit. The results of this paper showed that uncoupling reduced the severity of dementia, however, there was some increase in cognitive dysfunction pre-onset of dementia. The effectiveness of uncoupling was dependent upon the timing of intervention relative to the onset of dementia and would necessitate predicting its onset many years in advance.

systems biology↗

bioRxiv2023

The prevalence of dementia in humans could be the result of a functional adaptation

In this paper we propose that high copy number of the mitochondrial genome in neurons is a functional adaptation. We simulated the proliferation of deletion mutants of the human mitochondrial genome in a virtual mitochondrion and recorded the cell loss rates due to deletions overwhelming the wild-type. Our results showed that cell loss increased with mtDNA copy number. Given that neuron loss equates to cognitive dysfunction, it would seem counter-intuitive that there would be a selective pressure for high copy number over low. However, for a low copy number, the onset of cognitive decline, while mild, started early in life. Whereas, for high copy number, it did not start until middle age but progressed rapidly. There could have been an advantage to high copy number in the brain if it delayed the onset of cognitive decline until after reproductive age. The prevalence of dementia in our aged population is a consequence of this functional adaptation.

evolutionary biology↗

bioRxiv2022

A comparison of mtDNA deletion mutant proliferation mechanisms

In this paper we use simulation methods to investigate the proliferation of deletion mutations of mitochondrial DNA in neurons. We simulate three mtDNA proliferation mechanisms, namely, random drift, replicative advantage and vicious cycle. For each mechanism, we investigated the effect mutation rates have on neuron loss within a human host. We also compare heteroplasmy of each mechanism at mutation rates that yield the levels neuron loss that would be associated with dementia. Both random drift and vicious cycle predicted high levels of heteroplasmy, while replicative advantage showed a small number of dominant clones with a low background of heteroplasmy.

systems biology↗

bioRxiv2020

The significance of mitochondrial DNA half-life to the lifespan of post-mitotic cells

The proliferation of mitochondrial DNA (mtDNA) with deletion mutations has been linked to aging, and age related neurodegenerative conditions. In this study we model effect of mtDNA half-life on mtDNA competition and selection. Individual cells effectively form a closed ecosystem containing a large population of independently replicating mtDNA. We would expect competition and selection to occur between wild type mtDNA and various mutant variants. There is a symbiotic relationship between the cell and the mitochondria, and unrestricted mtDNA replication would be detrimental to the host cell. Deletion mutations of mtDNA are relatively common and give a replication advantage to the shorter sequence, as this could be lethal to the host cell, we would expect to see differences in mtDNA replication in short and long lived cells. In this paper, we use a computer simulation of mtDNA replication, where mtDNA sequences may undergo deletion errors and give rise to mutant species that can compete with the wild type. This study focuses on longer lived cells where the wild type mtDNA is expected to be more susceptible to displacement by mutants. Our simulations confirm that deletion mutations have a replication advantage over the wild type due to decreased replication time. Wild type survival times diminished with increased mutation probabilities. The relationship between survival time and mutation rate was non-linear; a ten-fold increase in mutation probability resulted in a halving in wild type survival time. In contrast a modest increase in the mtDNA half-life had a profound affect on the wild type survival time in the presence of deletion mutants, thereby, mitigating the replicative advantage of shorter sequence mutations. Given the relevance of mitochondrial dysfunction to various neurodegenerative conditions, we propose that therapies to increase mtDNA half-life could be a therapeutic strategy.

cell biology↗