Mimicking a SURF1 allele reveals uncoupling of cytochrome c oxidase assembly from translational regulation in XXXX .

@entity1 @entity1522 @entity72797 @entity7319 @entity72795 @entity17903 @entity8433 @entity72796 @entity492 @entity375 @entity669 @entity45810
Defects in mitochondrial energy metabolism lead to severe @entity1 disorders, mainly affecting tissues especially dependent on oxidative phosphorylation, such as muscle and brain. @entity8433 describes a severe @entity17903 in infancy, frequently caused by mutations in SURF1. SURF1, termed @entity72795 in @entity375 , is a conserved assembly factor for the terminal enzyme of the respiratory chain, cytochrome c oxidase. Although the molecular function of SURF1/ @entity72795 is still enigmatic, loss of function leads to cytochrome @entity7319 and reduced expression of the central subunit @entity45810 in @entity375 . Here, we provide insights into the molecular mechanisms leading to disease through missense mutations in codons of the most conserved @entity1522 in SURF1. Mutations affecting G(124) do not compromise import of the SURF1 precursor protein but lead to fast turnover of the mature protein within the mitochondria. Interestingly, an Y(274)D exchange neither affects stability nor localization of the protein. Instead, SURF1( @entity72796 ) accumulates in a 200 kDa cytochrome c oxidase assembly intermediate. Using @entity375 as a model, we demonstrate that the corresponding @entity72795 ( @entity72797 ) is able to overcome the stage where cytochrome c oxidase assembly links to the feedback regulation of mitochondrial @entity45810 expression. However, @entity72795 ( @entity72797 ) impairs the assembly at later steps, most apparent at low temperature and exhibits a dominant-negative phenotype upon overexpression. Thus, exchanging the conserved @entity669 (Y(344)) with @entity492 in @entity375 uncouples translational regulation of @entity45810 from cytochrome c oxidase assembly and provides evidence for the dual functionality of @entity72795 .
