Metabolic implications for the mechanism of mitochondrial endosymbiosis and human hereditary disorders

The endosymbiosis of proto-mitochondrial prokaryotes (PMP) into proto-eukaryotic host-cells was a major advance in eukaryotic evolution. The nature of the initial relationship remains the subject of controversy. Various conceptual models have been proposed, but none has definitive support. We construct a model of inter-species interactions based upon well-established respiratory pathways, describing the respective energy gain of host-cell and PMP resulting from varying levels of cooperation. The model demonstrates conflicting evolutionary strategies (‘‘Prisoner’s Dilemmas’’) in the interspecies molecular transfers. Nevertheless, we show that coercion and iterated, multilevel selection on both species encourage endosymbiosis. Mutualism is favored if host-cells are significantly more effective than PMPs at gathering food. Otherwise, an unambiguous asymmetry between host-cell and PMP benefits implies that the initial relationship consisted of the host-cell deriving a reproductive advantage at the PMPs’ expense—a cellular version of farming. Other initial relationships such as oxygen-detoxification mutualism and parasitism are not strongly supported by the model. We compare the model behavior with experiments on mutant human mitochondria and find the model predicts proliferation rates consistent with that data. We derive from the evolutionary dynamics counter-intuitive therapeutic targets for two human hereditary mitochondrial disorders that reflect the ongoing effect of short-term selection at the mitochondrial level.