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Analyse bio-informatique du protéome mitochondrial et du spectre des mutations de la protéine Opa1

Abstract : Mitochondria are involved in several essential cellular processes including nutrient catabolism, oxidative phosphorylation, apoptosis and regulation of the calcium flux. The dynamic structure of mitochondria is constantly adapted to cellular needs by regulatory networks that determine the mass, structure and function of the organelles. The mitochondrial proteome is composed of a wide variety of proteins inherited in part from the prokaryotic ancestors of mitochondria and mainly encoded by the nuclear genome, as well as a smaller number of proteins encoded by the mitochondrial genome. So far, about 700 mitochondrial proteins have been characterized in humans by means of proteomics, genomics and bioinformatics. However, the actual number of mitochondrial proteins may be much higher. The characterization of these proteins is essential to the understanding of many common genetic diseases associated with mitochondrial dysfunction. We first compared in silico sequences of human mitochondrial proteins with those of prokaryotes and showed that most of the proteins involved in such diseases are homologous to prokaryotic proteins. We then developed a bioinformatics research strategy to identify new mitochondrial proteins on the basis of their prokaryotic origin and the presence of a characteristic N-terminal extension. All known prokaryotic proteomes were compared to the human genome and various filtering tools were developed to identify new proteins. In parallel to this overall strategy of screening, we focused on the study of the Opa1 protein, one of the proteins associated with autosomal dominant optic atrophy, which is involved in mitochondrial fusion. Opa1, a dynamin GTPase, is involved in the remodeling of the mitochondrial inner membrane, apoptosis, maintenance of mitochondrial DNA, and energy metabolism. We finally developed an international database listing the variations of Opa1 so as to characterize its mutational spectrum. This tool was used as a complement to a multicentric clinical study involving nearly a thousand patients with optic neuropathy. Our work has led to the development of novel bioinformatics tools that should contribute to a better understanding of mitochondrial pathophysiology.
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Submitted on : Wednesday, February 17, 2010 - 2:33:34 PM
Last modification on : Monday, October 19, 2020 - 10:56:21 AM


  • HAL Id : tel-00457327, version 1


Marc Ferré. Analyse bio-informatique du protéome mitochondrial et du spectre des mutations de la protéine Opa1. Biologie cellulaire. Université d'Angers, 2009. Français. ⟨tel-00457327⟩



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