Résumé :
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Communication n° 4. Mitochondrial diseases are caused by mutations in mitochondrial or nuclear DNA. They generally lead to the impairement of mitochondrial oxidative phosphorylation that is responsible for cellular energy deprivation and redox imbalance in numerous tissues. However, the clinical study of mitochondrial diseases has revealed a dramatic variability in the phenotypic presentation of the same mitochondrial genetic or biochemical defect in different individuals. To study this variability, different authors have analysed the impairement of mitochondrial energy metabolism and its consequence for the cell in transmitochondrial cell lines carrying different proportions of pathogenic mutations in mitochondrial DNA. The same kinds of experiments was also performed on isolated mitochondria, or on tissue biopsies taken from patients with mitochondrial diseases. The results have shown that, in most cases, the cellular manifestation of the genetic defect occured only when a threshold level was exceeded, and this phenomenon has been named the "phenotypic threshold effect". Subsequently, we showed that it was possible to inhibit considerably the activity of a respiratory chain complex, up to a critical value, without affecting the rate of mitochondrial respiration or ATP synthesis. This phenomenon was called the "biochemical threshold effect". More recently, quantitative analysis of the effects of various mutations in mitochondrial DNA on the rate of mitochondrial protein synthesis has revealed the existence of a "translational threshold effect". Recently, we brought together several evidences for the existence of these different mitochondrial threshold effects and discussed their molecular bases, as well as the roles that they play in the presentation of mitochondrial diseases (see Rossignol et al. Biochem J review (2003)370,751-62). We present here the different fundamental approaches ongoing in our laboratory to study (i) the molecular bases of this biochemical threshold effect and (ii) the compensatory mechanisms occuring at the cellular level in response to a mitochondrial defect.
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