Grant: $208,589 - National Institutes of Health - Sep. 30, 2009
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Award Description: The main objective of the parent and proposed research is to investigate the biogenesis of mitochondrial cytochrome c oxidase (COX) in wild type cells and in cells with mutations in evolutionary conserved COX assembly factors. COX deficiency is the most frequent cause of mitochondrial encephalomyopathies in humans. A better understanding of COX biogenesis is essential for elucidating the molecular basis underlying this group of diseases. Following the project proposed in the parent grant, we are using the yeast Saccharomyces cerevisiae as a research model to study COX biogenesis. We have obtained evidence of a translational regulatory system by which the synthesis of the mitochondrially encoded COX subunit 1 is regulated by the availability of its assembly partners thereby pacing Cox1p synthesis to its utilization during assembly. Several proteins have been identified to be involved in this regulatory system, including the translational activator Mss51p and the COX assembly factors Cox14p and Shy1p. Ms51p interacts with both the COX1 mRNA to promote translation and with the newly synthesized Cox1p, possibly to facilitate its maturation, forming a complex that is stabilizazed by Cox14p. The complex is disrupted when Cox1p proceeds downstream the assembly process by a step catalyzed by Shy1p and Mss51p is recycled to new rounds of translation as proposed in the parent grant. Interestingly, overexpression of Mss51p restores COX assembly and respiratory competence to mutants of shy1. COX assembly is signficantly conserved from yeast to human. SURF1, the human homologue of Shy1p is well characterized and has been found mutated in patients suffering from mitochondrial encephalomyopathies associated with COX deficiency. Instead, the human counterpart of the translational activator Mss51p has not been yet identified. By BLAST analyses we have now recognized the human gene ZMYND17, located in chromosome 10 as a distant Mss51p homologue. In this application we propose to use human cell cultures to characterize ZMYND17, its function and its ability to restoring COX biogenesis in SURF1-deficient human fibroblasts.
Project Description: The project has just started and no developments can be reported at this time.
Infrastructure Description: N/A
Jobs Summary: A PhD student will be retained and a postdoctoral position is in the process of been created. Since the award started on 9/30/2009 there has been no time to finalize the creation of the position yet. (Total jobs reported: 0)
Project Status: Less Than 50% Completed
This award's data was last updated on Sep. 30, 2009. Help expand these official descriptions using the wiki below.