Increased longevity and refractoriness to Ca2+-dependent neurodegeneration in Surf1 knockout mice
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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Reduced mitochondrial function can, in some circumstances, increase lifespan.
“Unexpectedly, reduced mitochondrial function can, in some circumstances, increase lifespan.”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [41]
This mouse also exhibits protection against neuronal excitotoxicity in the brain.
“Intriguingly, this mouse also exhibits protection against neuronal excitotoxicity in the brain.”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [41]
A mouse model with reduced activity of the cytochrome c oxidase complex shows increased lifespan.
“Furthermore, a mouse model with reduced activity of the cytochrome c oxidase complex, a component of the electron transport chain, shows increased lifespan (41).”
From Neural mechanisms of ageing and cognitive decline (2010) · cites this paper as [41]
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- Authors
- Dell'Agnello, C., Leo, S., Agostino, A., Szabadkai, G., Tiveron, C., Zulian, A., Prelle, A., Roubertoux, P., Rizzuto, R., & Zeviani, M.
- Affiliations
- University of Ferrara (IT)
- Fondazione Pierfranco e Luisa Mariani (IT)
- European Brain Research Institute (IT)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Zeviani, Massimo
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-01-08
- Volume
- 16
- Issue
- 4
- Pages
- 431-444
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2122267356
- Cited by
- 308
- References
- 44
- Citations by year
- 2026: 13 · 2025: 16 · 2024: 12 · 2023: 8 · 2022: 14 · 2021: 19 · 2020: 22 · 2019: 5 · 2018: 22 · 2017: 8 · 2016: 23 · 2015: 16 · 2014: 27 · 2013: 16 · 2012: 19
- FWCI
- 6.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- European Commission
- Fondazione Telethon
- Fondazione Pierfranco e Luisa Mariani
- Associazione Italiana per la Ricerca sul Cancro
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
- Keywords
- SURF1, Leigh syndrome, cytochrome c oxidase deficiency, longevity, lifespan extension, kainic acid neurotoxicity, mitochondrial calcium homeostasis, intracellular calcium, mitochondrial calcium, neuronal survival, mitochondrial disease
- MeSH terms
- Animals, Animals, Newborn, Calcium, Cells, Cultured, Female, Kainic Acid, Longevity, Male, Membrane Proteins, Mice, Inbred C57BL, Mice, Inbred DBA, Phenotype, Mice, Knockout, Glutamic Acid, Neurodegenerative Diseases, Calcium Signaling, Mitochondrial Proteins, Mice, Membrane Potential, Mitochondrial
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