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Neuroprotection by mitochondrial NAD against glutamate-induced excitotoxicity

2025-04-12Research article Open access
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datacite.subject.sdg03:Saúde de Qualidade
dc.contributor.authorPaiva, Bruna S.
dc.contributor.authorNeves, Diogo
dc.contributor.authorTomé, Diogo
dc.contributor.authorCosta, Filipa J.
dc.contributor.authorBruno, Inês C.
dc.contributor.authorTrigo, Diogo
dc.contributor.authorSilva, Raquel M.
dc.contributor.authorAlmeida, Ramiro D.
dc.date.accessioned2025-08-13T14:47:15Z
dc.date.available2025-08-13T14:47:15Z
dc.date.issued2025-04-12
dc.description.abstractExcitotoxicity is a pathological process that occurs in many neurological diseases, such as stroke or epilepsy, and is characterized by the extracellular accumulation of high concentrations of glutamate or other excitatory amino acids (EAAs). Nicotinamide adenine dinucleotide (NAD) depletion is an early event following excitotoxicity in many in vitro and in vivo excitotoxic-related models and contributes to the deregulation of energy homeostasis. However, the interplay between glutamate excitotoxicity and the NAD biosynthetic pathway is not fully understood. To address this question, we used a primary culture of rat cortical neurons and found that an excitotoxic glutamate insult alters the expression of the NAD biosynthetic enzymes. Additionally, using a fluorescent NAD mitochondrial sensor, we observed that glutamate induces a significant decrease in the mitochondrial NAD pool, which was reversed when exogenous NAD was added. We also show that exogenous NAD protects against the glutamate-induced decrease in mitochondrial membrane potential (MMP). Glutamate excitotoxicity changed mitochondrial retrograde transport in neurites, which seems to be reversed by NAD addition. Finally, we show that NAD and NAD precursors protect against glutamate-induced cell death. Together, our results demonstrate that glutamate-induced excitotoxicity acts by compromising the NAD biosynthetic pathway, particularly in the mitochondria. These results also uncover a potential role for mitochondrial NAD as a tool for central nervous system (CNS) regenerative therapies.eng
dc.identifier.citationPaiva, B. S., Neves, D., Tomé, D., & Costa, F. J. et al. (2025). Neuroprotection by mitochondrial NAD against glutamate-induced excitotoxicity. Cells, 14(8), Article 582. https://doi.org/10.3390/cells14080582
dc.identifier.doi10.3390/cells14080582
dc.identifier.eid105003484994
dc.identifier.issn2073-4409
dc.identifier.othera2f2c389-79e2-4d7c-838a-caf9eac3d43d
dc.identifier.pmcPMC12025592
dc.identifier.pmid40277908
dc.identifier.urihttp://hdl.handle.net/10400.14/54551
dc.identifier.wos001474373000001
dc.language.isoeng
dc.peerreviewedyes
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectExcitotoxicity
dc.subjectGlutamate
dc.subjectMitochondria
dc.subjectNAD metabolism
dc.titleNeuroprotection by mitochondrial NAD against glutamate-induced excitotoxicityeng
dc.typeresearch article
dspace.entity.typePublication
oaire.citation.issue8
oaire.citation.titleCells
oaire.citation.volume14
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85

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