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Utilisation du modèle levure pour la recherche de voies thérapeutiques contre le syndrome de Barth

Abstract : The phospholipid cardiolipin (CL) has many roles in mitochondrial structure and function, ranging from assembly/stability and functioning of the oxidative phosphorylation (OXPHOS) system, fusion and fission of mitochondrial membranes, mitochondrial protein import, iron-sulfur (Fe-S) biogenesis, apoptosis, and protection of mitochondria against oxidative damage. The maintenance of a proper unsaturated acyl chain composition of CL involves the acyltransferase tafazzin in which mutations cause Barth syndrome (BTHS), resulting in cardiac and skeletal myopathy, cyclic neutropenia and respiratory chain defects. Despite considerable progress in the understanding of the underlying pathogenic mechanisms, there are still no effective therapies to treat this disease. We are using the yeast Saccharomyces cerevisiae, in which the tafazzin-based cardiolipin remodeling pathway is conserved, as a model system for the exploration of potential therapeutic pathways against BTHS, by way of genetic suppressors and chemical screening. We first constructed a yeast strain lacking the orthologous taffazin gene (Δtaz1). Consistent with previous studies, our Δtaz1 yeast failed to grow on non-fermentable carbon sources at elevated temperatures (36°C) and exhibited defects in several components of the mitochondrial respiratory system. Interestingly, we found that oxidative phosphorylation was fully restored in Δtaz1 yeast by overexpressing Odc1p [1]-a mitochondrial carrier that transports Krebs cycle intermediates- and by a number of chemical compounds. Some of the rescuing drugs, especially cycloheximide, act by partially inhibiting cytosolic protein synthesis leading to a full recovery of oxidative phosphorylations. Our findings identify potential cellular components and pathways for the pharmacological treatment of BTHS patients.
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Contributor : Abes Star :  Contact
Submitted on : Tuesday, April 3, 2018 - 10:53:39 AM
Last modification on : Thursday, September 3, 2020 - 5:01:02 AM


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  • HAL Id : tel-01756397, version 2



Maxence de Taffin de Tilques. Utilisation du modèle levure pour la recherche de voies thérapeutiques contre le syndrome de Barth. Médecine humaine et pathologie. Université de Bordeaux, 2017. Français. ⟨NNT : 2017BORD0876⟩. ⟨tel-01756397v2⟩



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