Purchase this article with an account.
M.C. Debrinsky, V. Kaltimbacher, C. Bonnet, T. Leveillard, D. Thiersé, J.A. Sahel; Role of mRNA Localization to the Mitochondrial Surface in the Physiopathology of Retina . Invest. Ophthalmol. Vis. Sci. 2005;46(13):5147.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Purpose: Known mitochondrial disorders, which involve retina degeneration, arise from mutations in both nuclear and mitochondrial genes encoding mitochondrial proteins such as Leber Hereditary Optic Neuropathy (LHON) and dominant optic atrophy (DOA). We predict that a growing number of genes involved in mitochondrial assembly will be discovered as causative of retina dysfunction. In yeast, mitochondrial assembly requires the delivery to the organelle surface of mRNAs, encoding mitochondrial proteins. We use this phenomenon as a tool for : (i) identifying new mitochondrial proteins. (ii) providing molecular mechanisms for retina disorders. (iii) developing a therapy to restore mitochondrial function in cells from LHON’s patients. Methods: (i) large scale proteomic survey of mitochondria purified from mouse retina and brain, as well as, from human cells are performed. (ii) the complete inventory of mRNAs localized to the mitochondrial surface will be obtained from mouse and human cells. (iii) DOA’s patients will be screneed to determine whether the disease could be the consequence of OPA1 mRNA abnormal localization. (iv) cytoplasmic versions of Atp6, Nd1 and Nd4 mitochondrial proteins will be examined for their ability of restoring mitochondrial function in cells with mutations of these genes. Results: (i) 2D gels were performed with mitochondrial proteins purified from mouse brain and retina. Several hundreds of spots are, currently, under identification. (ii) DNA microarrays hybridized with RNAs purified from mitochondrion–bound polysomes and free–cytoplasmic polysomes confirm the asymmetrical distribution of hundreds of mRNAs in mouse brain. (iii) Mitochondrial import ability of the cytoplasmic Atp6 protein is under investigation in HeLa cells. Conclusions: Human mitochondrion is probably composed of 1500 polypeptides, up today, only 750 are clearly known. Our project, which combine proteomic survey and investigation on the subcellular distribution of mRNAs, will lead to assess a more complete mammalian mitochondrial proteome. The research of mRNA sorting perturbations as causative of retinal diseases, will provide a new pathophysiological mechanism for these disorders. Finally, if we improve the cytoplasmic expression of proteins encoded by mitochondrial DNA using mRNA sorting to the mitochondrial surface, we will develop a innovative therapy to LHON that can ultimately be applied in gene therapy.
This PDF is available to Subscribers Only