Journal Article

Mimicking a <i>SURF1</i> allele reveals uncoupling of cytochrome <i>c</i> oxidase assembly from translational regulation in yeast

Robert Reinhold, Bettina Bareth, Martina Balleininger, Mirjam Wissel, Peter Rehling and David U. Mick

in Human Molecular Genetics

Volume 20, issue 12, pages 2379-2393
Published in print June 2011 | ISSN: 0964-6906
Published online April 2011 | e-ISSN: 1460-2083 | DOI:
Mimicking a SURF1 allele reveals uncoupling of cytochrome c oxidase assembly from translational regulation in yeast

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Defects in mitochondrial energy metabolism lead to severe human disorders, mainly affecting tissues especially dependent on oxidative phosphorylation, such as muscle and brain. Leigh Syndrome describes a severe encephalomyopathy in infancy, frequently caused by mutations in SURF1. SURF1, termed Shy1 in Saccharomyces cerevisiae, is a conserved assembly factor for the terminal enzyme of the respiratory chain, cytochrome c oxidase. Although the molecular function of SURF1/Shy1 is still enigmatic, loss of function leads to cytochrome c oxidase deficiency and reduced expression of the central subunit Cox1 in yeast. Here, we provide insights into the molecular mechanisms leading to disease through missense mutations in codons of the most conserved amino acids in SURF1. Mutations affecting G124 do not compromise import of the SURF1 precursor protein but lead to fast turnover of the mature protein within the mitochondria. Interestingly, an Y274D exchange neither affects stability nor localization of the protein. Instead, SURF1Y274D accumulates in a 200 kDa cytochrome c oxidase assembly intermediate. Using yeast as a model, we demonstrate that the corresponding Shy1Y344D is able to overcome the stage where cytochrome c oxidase assembly links to the feedback regulation of mitochondrial Cox1 expression. However, Shy1Y344D impairs the assembly at later steps, most apparent at low temperature and exhibits a dominant-negative phenotype upon overexpression. Thus, exchanging the conserved tyrosine (Y344) with aspartate in yeast uncouples translational regulation of Cox1 from cytochrome c oxidase assembly and provides evidence for the dual functionality of Shy1.

Journal Article.  9248 words.  Illustrated.

Subjects: Genetics and Genomics

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