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We report here the creation of a constitutive knockout mouse for SURF1, a gene encoding one of the assembly proteins involved in the formation of cytochrome  c  oxidase (COX). Loss-of-function mutations of SURF1 cause Leigh syndrome associated with an isolated and generalized COX deficiency in humans. The murine phenotype is characterized by the following hallmarks: ( 1 ) high post-implantation embryonic lethality, affecting ∼90% of the  Surf1  −/−  individuals; ( 2 ) early-onset mortality of post-natal individuals; ( 3 ) highly significant deficit in muscle strength and motor performance; ( 4 ) profound and isolated defect of COX activity in skeletal muscle and liver, and, to a lesser extent, heart and brain; ( 5 ) morphological abnormalities of skeletal muscle, characterized by reduced histochemical reaction to COX and mitochondrial proliferation; ( 6 ) no obvious abnormalities in brain morphology, reflecting the virtual absence of overt neurological symptoms. These results indicate a function for murine Surf1 protein (Surf1p) specifically related to COX and recapitulate, at least in part, the human phenotype. This is the first mammalian model for a nuclear disease gene of a human mitochondrial disorder. Our model constitutes a useful tool to investigate the function of Surf1p, help understand the pathogenesis of Surf1p deficiency  in vivo , and evaluate the efficacy of treatment.

Constitutive knockout of Surf1 is associated with high embryonic lethality, mitochondrial disease and cytochrome c oxidase deficiency in mice