Increased longevity and refractoriness to Ca2+-dependent neurodegeneration in Surf1 knockout mice

Carlotta Dell'Agnello, Sara Leo, Alessandro Agostino, György Szabadkai, C. Cecilia Tiveron, A. Alessandra Zulian, Alessandro Prelle, Pierre Roubertoux, Rosario Rizzuto, Massimo Zeviani

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)431-444
Number of pages14
JournalHuman Molecular Genetics
Issue number4
Publication statusPublished - Feb 15 2007

ASJC Scopus subject areas

  • Genetics


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