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Hum Mol Genet. 2007 Feb 15;16(4):431-44. Epub 2007 Jan 8.

Increased longevity and refractoriness to Ca(2+)-dependent neurodegeneration in Surf1 knockout mice.

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  • 1Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Children's Mitochondrial Disorders, National Neurological Institute 'C. Besta', Milano, Italy.

Abstract

Leigh syndrome associated with cytochrome c oxidase (COX) deficiency is a mitochondrial disorder usually caused by mutations of SURF1, a gene encoding a putative COX assembly factor. We present here a Surf1-/- recombinant mouse obtained by inserting a loxP sequence in the open reading frame of the gene. The frequency of -/-, +/+ and +/- genotypes in newborn mice followed a mendelian distribution, indicating that the ablation of Surf1 is compatible with postnatal survival. The biochemical and assembly COX defect was present in Surf1(loxP)-/- mice, but milder than in humans. Surprisingly, not only these animals failed to show spontaneous neurodegeneration at any age, but they also displayed markedly prolonged lifespan, and complete protection from Ca(2+)-dependent neurotoxicity induced by kainic acid. Experiments on primary neuronal cultures showed markedly reduced rise of cytosolic and mitochondrial Ca(2+) in Surf1(loxP)-/- neurons, and reduced mortality, compared to controls. The mitochondrial membrane potential was unchanged in KO versus wild-type neurons, suggesting that the effects of the ablation of Surf1 on Ca(2+) homeostasis, and possibly on longevity, may be independent, at least in part, from those on COX assembly and mitochondrial bioenergetics.

PMID:
17210671
[PubMed - indexed for MEDLINE]
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