Human Molecular Genetics Advance Access originally published online on January 8, 2007
Human Molecular Genetics 2007 16(4):431-444; doi:10.1093/hmg/ddl477
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Increased longevity and refractoriness to Ca2+-dependent neurodegeneration in Surf1 knockout mice
1 Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Children's Mitochondrial Disorders, National Neurological Institute ‘C. Besta’, Milano, Italy, 2 Department of Experimental and Diagnostic Medicine, Section of General Pathology, Interdisciplinary Center for the Study of Inflammation (ICSI) and ER-GenTech, University of Ferrara, Ferrara, Italy, 3 Foundation EBRI Rita Levi-Montalcini Disease Modelling Facility, Rome, Italy, 4 Centro Dino Ferrari, UO Neurologia, Fondazione Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, IRCCS, Milano and 5 Université Marseille-2, CNRS-Université de la Méditerranée, Marseille, France
* Correspondence should be addressed to: Via L. Temolo 4, 20126 Milano, Italy. Tel: +33 390223942630; Fax: +33 390223942619; Email: zeviani{at}fastwebnet.it
Received November 3, 2006; Revised December 19, 2006; Accepted December 28, 2006
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 Surf1loxP–/– 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 Ca2+-dependent neurotoxicity induced by kainic acid. Experiments on primary neuronal cultures showed markedly reduced rise of cytosolic and mitochondrial Ca2+ in Surf1loxP–/– 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 Ca2+ homeostasis, and possibly on longevity, may be independent, at least in part, from those on COX assembly and mitochondrial bioenergetics.
These authors contributed equally to the work.
Present address: INSERM U807, University Paris 5, Faculty of Medicine Necker-Enfants Malades, Paris, France.
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