Abstract

Mitochondria are highly dynamic structures that undergo constant remodelling 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 crista 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, a prerequisite for cognitive decline and dementia. Selective mitophagy mitigates the effect of high rate mixing. However, this mitigation is all or nothing. Even at nominal rates of mitophagy compared to higher mixing rates, neuron loss is almost completely eliminated. The results of our model suggest that the role of fission and fusion, in removing defective mtDNA, may be inconsistent with observed patterns of ageing and dementia. The model serves as a hypothesis-generating tool to stimulate experimental re-evaluation of the role of fission and fusion.

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