Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8258436 | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | 2018 | 45 Pages |
Abstract
Leigh syndrome (LS) associated with cytochrome c oxidase (COX) deficiency is an early onset, fatal mitochondrial encephalopathy, leading to multiple neurological failure and eventually death, usually in the first decade of life. Mutations in SURF1, a nuclear gene encoding a mitochondrial protein involved in COX assembly, are among the most common causes of LS. LSSURF1 patients display severe, isolated COX deficiency in all tissues, including cultured fibroblasts and skeletal muscle. Recombinant, constitutive SURF1â/â mice show diffuse COX deficiency, but fail to recapitulate the severity of the human clinical phenotype. Pigs are an attractive alternative model for human diseases, because of their size, as well as metabolic, physiological and genetic similarity to humans. Here, we determined the complete sequence of the swine SURF1 gene, disrupted it in pig primary fibroblast cell lines using both TALENs and CRISPR/Cas9 genome editing systems, before finally generating SURF1â/â and SURF1â/+ pigs by Somatic Cell Nuclear Transfer (SCNT). SURF1â/â pigs were characterized by failure to thrive, muscle weakness and highly reduced life span with elevated perinatal mortality, compared to heterozygous SURF1â/+ and wild type littermates. Surprisingly, no obvious COX deficiency was detected in SURF1â/â tissues, although histochemical analysis revealed the presence of COX deficiency in jejunum villi and total mRNA sequencing (RNAseq) showed that several COX subunit-encoding genes were significantly down-regulated in SURF1â/â skeletal muscles. In addition, neuropathological findings, indicated a delay in central nervous system development of newborn SURF1â/â piglets. Our results suggest a broader role of sSURF1 in mitochondrial bioenergetics.
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Authors
C. Quadalti, D. Brunetti, I. Lagutina, R. Duchi, A. Perota, G. Lazzari, R. Cerutti, I. Di Meo, M. Johnson, E. Bottani, P. Crociara, C. Corona, S. Grifoni, V. Tiranti, E. Fernandez-Vizarra, A.J. Robinson, C. Viscomi, C. Casalone, C. Galli,