Cited by 308Mitochondrial Function and PathologyMetabolism and Genetic DisordersCoenzyme Q10 studies and effects

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

Dell'Agnello, Carlotta, Leo, Sara, Agostino, Alessandro, Szabadkai, György, Tiveron, Cecilia, Zulian, Alessandra, Prelle, Alessandro, Roubertoux, Pierre +2 more·2007·Human Molecular Genetics

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.

Integrity signals

Registry

Crossref · 10.1093/hmg/ddl477

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44 of 44 references verified0 citation errors · 0 not checkable

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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
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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