Increased longevity and refractoriness to Ca(2+)-dependent neurodegeneration in Surf1 knockout mice.
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.
Dell'agnello
Carlotta
C
Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Children's Mitochondrial Disorders, National Neurological Institute 'C. Besta', Milano, Italy.
Leo
Sara
S
Agostino
Alessandro
A
Szabadkai
György
G
Tiveron
Cecilia
C
Zulian
Alessandra
A
Prelle
Alessandro
A
Roubertoux
Pierre
P
Rizzuto
Rosario
R
Zeviani
Massimo
M
D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D007608:Kainic Acid; D008136:Longevity / Q000235:genetics*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000235:genetics; D010641:Phenotype
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C092928:Surf-1 protein; D018698:Glutamic Acid; D007608:Kainic Acid; D002118:Calcium