Article

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

Unit of Molecular Neurogenetics, Pierfranco and Luisa Mariani Center for the Study of Children's Mitochondrial Disorders, National Neurological Institute 'C. Besta', Milano, Italy.
Human Molecular Genetics (impact factor: 7.64). 03/2007; 16(4):431-44. DOI:10.1093/hmg/ddl477 pp.431-44
Source: PubMed

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.

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Keywords

+/- genotypes
 
Ca(2+)-dependent neurotoxicity induced
 
complete protection
 
cytochrome c oxidase
 
cytosolic
 
kainic acid
 
KO
 
Leigh syndrome
 
loxP sequence
 
mitochondrial membrane potential
 
newborn mice
 
open reading frame
 
postnatal survival
 
primary neuronal cultures
 
putative COX assembly factor
 
SURF1
 
Surf1(loxP)-/- mice
 
Surf1(loxP)-/- neurons
 
Surf1-/- recombinant mouse