Cytochrome c oxidase (COX) deficiency is the most frequent cause of mitochondrial neuromyopathiesin humans. Patients afflicted with these diseases present heterogeneous clinical phenotypes, including Leigh syndrome, muscle weakness and encephalomyopathy.A complete understanding of COX biogenesis is essential for elucidating the molecular basis underlying this group of diseases. The main objective of the proposed research is to use the yeast Saccharomycescerevisiae as a model to investigate COXassembly in wild type cells and in cells with mutations in evolutionary conservedassembly factors. Several specific aims will be pursued. 1) We have recently reported that Shylp, the yeast homologue of humanSurMp, responsible for most cases of Leigh's syndrome,catalyzes the formation of a COX assembly intermediate involving Coxlp, a mitochondrially encoded catalytic subunit of COX. The role of Shylp in expression of Coxlp will be studied. 2) More recent evidence indicates that this intermediate regulates Cox1 pexpression in a process involving other COX metabolism factors, such as Mss51p and Cox14p.The mechanisms by which these proteins regulate COX expression will be studied. Appropriately tagged Mss51p and Cox14p will be purified from over-expressing yeast cells. The availability of purified proteins will permit hypotheses concerning their activities to be tested directly. 3) The proteins involved in regulation of Coxlp synthesis by COX assembly are likely to interact transiently or permanently amongthem to perform their functions. The nature of these interactions will be characterized. In summary,the yeast system will be explored as a means of deciphering the general principles operating in the assembly of a complex membrane enzyme composed of subunit polypeptides derived from two spatially separated genetic sources. The yeast paradigm will be exploited by biochemical and genetic meansto gain a complete understanding of the function of Shylp and therefore of Surflp as well, and to clarifythe molecular basis of human COX deficiencies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM071775-05
Application #
7756627
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Anderson, Vernon
Project Start
2006-02-01
Project End
2011-12-31
Budget Start
2010-02-01
Budget End
2011-12-31
Support Year
5
Fiscal Year
2010
Total Cost
$220,617
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
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Bourens, Myriam; Barrientos, Antoni (2017) A CMC1-knockout reveals translation-independent control of human mitochondrial complex IV biogenesis. EMBO Rep 18:477-494
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Soto, Iliana C; Barrientos, Antoni (2016) Mitochondrial Cytochrome c Oxidase Biogenesis Is Regulated by the Redox State of a Heme-Binding Translational Activator. Antioxid Redox Signal 24:281-98
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Tu, Ya-Ting; Barrientos, Antoni (2015) The Human Mitochondrial DEAD-Box Protein DDX28 Resides in RNA Granules and Functions in Mitoribosome Assembly. Cell Rep :
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Abrams, Alexander J; Hufnagel, Robert B; Rebelo, Adriana et al. (2015) Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder. Nat Genet 47:926-32

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