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

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State: Serval
Version: author
Serval ID
serval:BIB_833104A8E676
Type
Article: article from journal or magazin.
Collection
Publications
Title
Mfn2 downregulation in excitotoxicity causes mitochondrial dysfunction and delayed neuronal death.
Journal
Embo Journal
Author(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
Publication state
Published
Issued date
10/2014
Peer-reviewed
Oui
Volume
33
Number
20
Pages
2388-2407
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Abstract
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.
Keywords
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
Create date
17/11/2014 11:58
Last modification date
03/03/2018 18:52
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