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

TitleIncreased longevity and refractoriness to Ca(2+)-dependent neurodegeneration in Surf1 knockout mice.
Publication TypeJournal Article
Year of Publication2007
AuthorsDell'agnello, C, Leo, S, Agostino, A, Szabadkai, G, Tiveron, C, Zulian, A, Prelle, A, Roubertoux, P, Rizzuto, R, Zeviani, M
JournalHum Mol Genet
Date Published2007 Feb 15
KeywordsAnimals, Animals, Newborn, Calcium, Calcium Signaling, Cells, Cultured, Female, Glutamic Acid, Kainic Acid, Longevity, Male, Membrane Potential, Mitochondrial, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, Mitochondrial Proteins, Neurodegenerative Diseases, Phenotype

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.

Alternate JournalHum. Mol. Genet.
Citation Key10.1093/hmg/ddl477
PubMed ID17210671
Grant ListGGP05284 / / Telethon / Italy