Impact of Mitochondrial Fission and Fusion on Neuronal Health and Incidence of Dementia

Abstract 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.