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

Alessandro Agostino, Federica Invernizzi, Cecilia Tiveron, Gigliola Fagiolari, Alessandro Prelle, Eleonora Lamantea, Alessio Giavazzi, Giorgio Battaglia, Laura Tatangelo, Valeria Tiranti, Massimo Zeviani

Research output: Contribution to journalArticle

Abstract

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 Surfl-1- 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.

Original languageEnglish
Pages (from-to)399-413
Number of pages15
JournalHuman Molecular Genetics
Volume12
Issue number4
DOIs
Publication statusPublished - Feb 15 2003

ASJC Scopus subject areas

  • Genetics

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    Agostino, A., Invernizzi, F., Tiveron, C., Fagiolari, G., Prelle, A., Lamantea, E., Giavazzi, A., Battaglia, G., Tatangelo, L., Tiranti, V., & Zeviani, M. (2003). Constitutive knockout of Surf1 is associated with high embryonic lethality, mitochondrial disease and cytochrome c oxidase deficiency in mice. Human Molecular Genetics, 12(4), 399-413. https://doi.org/10.1093/hmg/ddg038