Abstract
One of the main salient features recognized in mitochondrial diseases is the existence of a threshold in the degree of a mitochondrial deficit for the expression of the disease. When expressed as a function of the degree of heteroplasmy, the value of the threshold can be very high, around 90% (mutated DNA/total DNA). This means that 10% of normal DNA is enough to sustain a quasi normal mitochondrial oxidative phosphorylating flux. We have shown that most of the compensation is done at the metabolic level: for instance a 70% deficit of cytochrome oxidase decreases the oxidative flux by just 10%. Similar patterns are observed for the other complexes. Using Metabolic Control Anlaysis (MCA), we have shown that this kind of result is inescapable: the threshold value can be correlated to the control coefficient of the deficient step. The value of the threshold is reinforced by slight increases at the transcriptional and translational level as we show in a simple mathematical model.
Finally we associate the threshold in the expression of a deficit, to the threshold in the energy demand of different tissues, in order to describe various patterns of onset of mitochondrial diseases (double threshold hypothesis).
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Letellier, T., Malgat, M., Rossignol, R. et al. Metabolic control, analysis and mitochondrial pathologies. Mol Cell Biochem 184, 409–417 (1998). https://doi.org/10.1023/A:1006826927220
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DOI: https://doi.org/10.1023/A:1006826927220