Molecular analysis of Shy1/Surf1 function in early steps of cytochrome c oxidase assembly

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The cytochrome oxidase of the inner mitochondrial membrane assembles from mitochondria- and nuclear-encoded subunits. Defects in the assembly process lead to severe neuromuscular disorders in human. Shy1/SURF1 is an assembly factor with a yet undefined role for incorporation of haem a3 into Cox1. Defects of Shy1/SURF1 function cause cytochrome oxidase deficiency and Leigh Syndrome in human. The goal of our analyses is to understand the molecular function of Shy1/SURF1 in the assembly process and how a loss of its function causes cytochrome oxidase deficiency. Our analyses have demonstrated that Shy1/SURF1 mediates progression of the assembly process on the one hand while on the other hand it plays a direct or indirect role for translational regulation of Cox1. In this project we will assess how the translational regulator Mss51 is activated and inactivated in its regulatory cycle in order to understand how this process is affected by Shy1/SURF1. Moreover, we will address how Shy1/SURF1 cooperates with the haem synthesis machinery of mitochondria. We will analyze if complexes are formed between Shy1 and Cox15 and how defects in haem synthesis affect interaction of Shy1 with assembly intermediates. The identification of a SURF1 interacting protein in human cells, which is conserved in metazoa, allows us to address if SURF1 affects mitochondrial translation in human mitochondria through assembly intermediates. For these analyses we will make use of a SURF1 knockout mouse model. These analyses will provide important insight into the mechanism of cytochrome oxidase biogenesis and allow us to better understand the patho-biochemistry underlying Leigh Syndrom.