Abstract
Mitochondrial cytopathies present a tissue specificity characterized by the fact that even if a mitochondrial DNA mutation is present in all tissues, only some will be affected and induce a pathology. Several mechanisms have been proposed to explain this phenomenon such as the appearance of a sporadic mutation in a given stem cell during embryogenesis or mitotic segregation, giving different degrees of heteroplasmy in tissues. However, these mechanisms cannot be the only ones involved in tissue specificity. In this paper, we propose an additional mechanism contributing to tissue specificity. It is based on the metabolic expression of the defect in oxidative phosphorylation (OXPHOS) complexes that can present a biochemical threshold. The value of this threshold for a given OXPHOS complex can vary according to the tissue; thus different tissues will display different sensitivities to a defect in an OXPHOS complex. To verify this hypothesis and to illustrate the pathological consequences of the variation in biochemical thresholds, we studied their values for seven OXPHOS complexes in mitochondria isolated from five different rat tissues. Two types of behavior in the threshold curves can be distinguished corresponding to two modes of OXPHOS response to a deficiency. We propose a classification of tissues according to their type of OXPHOS response to a complex deficiency and therefore to their threshold values.
Highlights
Mitochondrial cytopathies present a tissue specificity characterized by the fact that even if a mitochondrial DNA mutation is present in all tissues, only some will be affected and induce a pathology
To verify this hypothesis and to illustrate the pathological consequences of the variation in the biochemical thresholds, we studied their values for seven oxidative phosphorylation (OXPHOS) complexes in mitochondria isolated from five different tissues
Titration Curves and Threshold Curves—In this paper, we use identical experimental conditions to study the variation in biochemical threshold for seven steps of the oxidative phosphorylations in mitochondria isolated from five different tissues
Summary
We propose an additional mechanism contributing to tissue specificity It is based on the metabolic expression of the defect in oxidative phosphorylation (OXPHOS) complexes that can present a biochemical threshold. In patients where the mitochondrial mutation is homoplasmic [25, 28] and in the case of nuclear mutations giving a uniform deficiency in all tissues, this mechanism can no longer explain the tissue specificity For this reason, we propose another mechanism based on the threshold effect in the expression of a defect. Its extent for each OXPHOS complex can vary according to the tissues, changing their sensitivity to a defect in this complex To verify this hypothesis and to illustrate the pathological consequences of the variation in the biochemical thresholds, we studied their values for seven OXPHOS complexes in mitochondria isolated from five different tissues. Two types of behavior in the threshold curves can be distinguished, corresponding to two modes of OXPHOS response to a deficiency evidencing either an “excess of enzyme activity” or a “buffering effect by the metabolic network.” We propose a classification of the tissues according to the threshold values and the type of OXPHOS response to a given complex deficiency
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