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- Title
Increased longevity and refractoriness to Ca(2+)-dependent neurodegeneration in Surf1 knockout mice.
- Authors
Dell'agnello, Carlotta; Leo, Sara; Agostino, Alessandro; Szabadkai, György; Tiveron, Cecilia; Zulian, Alessandra; Prelle, Alessandro; Roubertoux, Pierre; Rizzuto, Rosario; Zeviani, Massimo
- 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.
- Publication
Human molecular genetics, 2007, Vol 16, Issue 4, p431
- ISSN
0964-6906
- Publication type
Journal Article
- DOI
10.1093/hmg/ddl477