Mfn2 downregulation in excitotoxicity causes mitochondrial dysfunction and delayed neuronal death.

Détails

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Etat: Serval
Version: de l'auteur
ID Serval
serval:BIB_833104A8E676
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Mfn2 downregulation in excitotoxicity causes mitochondrial dysfunction and delayed neuronal death.
Périodique
Embo Journal
Auteur(s)
Martorell-Riera A., Segarra-Mondejar M., Muñoz J.P., Ginet V., Olloquequi J., Pérez-Clausell J., Palacín M., Reina M., Puyal J., Zorzano A., Soriano F.X.
ISSN
1460-2075 (Electronic)
ISSN-L
0261-4189
Statut éditorial
Publié
Date de publication
10/2014
Peer-reviewed
Oui
Volume
33
Numéro
20
Pages
2388-2407
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Résumé
Mitochondrial fusion and fission is a dynamic process critical for the maintenance of mitochondrial function and cell viability. During excitotoxicity neuronal mitochondria are fragmented, but the mechanism underlying this process is poorly understood. Here, we show that Mfn2 is the only member of the mitochondrial fusion/fission machinery whose expression is reduced in in vitro and in vivo models of excitotoxicity. Whereas in cortical primary cultures, Drp1 recruitment to mitochondria plays a primordial role in mitochondrial fragmentation in an early phase that can be reversed once the insult has ceased, Mfn2 downregulation intervenes in a delayed mitochondrial fragmentation phase that progresses even when the insult has ceased. Downregulation of Mfn2 causes mitochondrial dysfunction, altered calcium homeostasis, and enhanced Bax translocation to mitochondria, resulting in delayed neuronal death. We found that transcription factor MEF2 regulates basal Mfn2 expression in neurons and that excitotoxicity-dependent degradation of MEF2 causes Mfn2 downregulation. Thus, Mfn2 reduction is a late event in excitotoxicity and its targeting may help to reduce excitotoxic damage and increase the currently short therapeutic window in stroke.
Mots-clé
Animals, Calcium/metabolism, Cell Death, Cell Line, Cells, Cultured, Down-Regulation, Dynamins/genetics, Dynamins/metabolism, Gene Expression Regulation, Homeostasis, Humans, MEF2 Transcription Factors/genetics, MEF2 Transcription Factors/metabolism, Male, Membrane Proteins/genetics, Membrane Proteins/metabolism, Mitochondria/physiology, Mitochondrial Dynamics/physiology, Mitochondrial Proteins/genetics, Mitochondrial Proteins/metabolism, Models, Animal, Mutation, Neurons/physiology, Rats, Rats, Sprague-Dawley, bcl-2-Associated X Protein/genetics, bcl-2-Associated X Protein/metabolism
Pubmed
Web of science
Création de la notice
17/11/2014 11:58
Dernière modification de la notice
03/03/2018 18:52
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