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Mfn2 downregulation in excitotoxicity causes mitochondrial dysfunction and delayed neuronal death

dc.contributor.authorMartorell-Riera A.
dc.contributor.authorSegarra-Mondejar M.
dc.contributor.authorMuñoz J.P.
dc.contributor.authorGinet V.
dc.contributor.authorOlloquequi J.
dc.contributor.authorPérez-Clausell J.
dc.contributor.authorPalacín M.
dc.contributor.authorReina M.
dc.contributor.authorPuyal J.
dc.contributor.authorZorzano A.
dc.contributor.authorSoriano F.X.
dc.date.accessioned2020-09-02T22:22:23Z
dc.date.available2020-09-02T22:22:23Z
dc.date.issued2014
dc.identifier10.15252/embj.201488327
dc.identifier.citation33, 20, 2388-2407
dc.identifier.issn02614189
dc.identifier.urihttps://hdl.handle.net/20.500.12728/5218
dc.descriptionMitochondrial 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. Synopsis Excitotoxicity leads to mitochondrial fragmentation, altered calcium homeostasis and neuronal death in two phases: a reversible Drp1-dependent one, followed by the irreversible degradation of MEF2, causing reduced Mfn2 transcription and Bax translocation to mitochondria. MEF2 regulates Mfn2 basal transcription in neurons. MEF2 degradation in excitotoxicity causes Mfn2 downregulation. Reduced Mfn2 expression causes mitochondrial dysfunction and altered calcium homeostasis. Mfn2 downregulation in excitotoxicity participates in delayed cell death by facilitating Bax recruitment to mitochondria. Excitotoxicity leads to mitochondrial fragmentation, altered calcium homeostasis and neuronal death in two phases: a reversible Drp1-dependent one, followed by the irreversible degradation of MEF2, causing reduced Mfn2 transcription and Bax translocation to mitochondria. © 2014 The Authors.
dc.language.isoen
dc.publisherWiley-VCH Verlag
dc.subjectexcitotoxicity
dc.subjectmitochondrial dynamics
dc.subjectneuron
dc.subjecttranscriptional regulation
dc.subjectcalcium ion
dc.subjectmitofusin 2
dc.subjectmyocyte enhancer factor 2
dc.subjectprotein Bax
dc.subjectBax protein, rat
dc.subjectcalcium
dc.subjectDrp1 protein, rat
dc.subjectdynamin
dc.subjectmembrane protein
dc.subjectmitochondrial protein
dc.subjectmitofusin 2 protein, rat
dc.subjectmyocyte enhancer factor 2
dc.subjectprotein Bax
dc.subjectanimal cell
dc.subjectanimal experiment
dc.subjectanimal model
dc.subjectanimal tissue
dc.subjectArticle
dc.subjectbrain cell culture
dc.subjectbrain ischemia
dc.subjectbrain mitochondrion
dc.subjectbrain nerve cell
dc.subjectcalcium homeostasis
dc.subjectcontrolled study
dc.subjectdisorders of mitochondrial functions
dc.subjectdown regulation
dc.subjectexcitotoxicity
dc.subjectfemale
dc.subjectgene expression regulation
dc.subjectgene translocation
dc.subjectin vitro study
dc.subjectin vivo study
dc.subjectmale
dc.subjectmitochondrion
dc.subjectnerve cell necrosis
dc.subjectnonhuman
dc.subjectprimary cell culture
dc.subjectprotein degradation
dc.subjectprotein expression
dc.subjectrat
dc.subjecttranscription regulation
dc.subjectanimal
dc.subjectcell culture
dc.subjectcell death
dc.subjectcell line
dc.subjectdown regulation
dc.subjectgene expression regulation
dc.subjectgenetics
dc.subjecthomeostasis
dc.subjecthuman
dc.subjectmetabolism
dc.subjectmitochondrial dynamics
dc.subjectmutation
dc.subjectnerve cell
dc.subjectphysiology
dc.subjectSprague Dawley rat
dc.subjectAnimals
dc.subjectbcl-2-Associated X Protein
dc.subjectCalcium
dc.subjectCell Death
dc.subjectCell Line
dc.subjectCells, Cultured
dc.subjectDown-Regulation
dc.subjectDynamins
dc.subjectGene Expression Regulation
dc.subjectHomeostasis
dc.subjectHumans
dc.subjectMale
dc.subjectMEF2 Transcription Factors
dc.subjectMembrane Proteins
dc.subjectMitochondria
dc.subjectMitochondrial Dynamics
dc.subjectMitochondrial Proteins
dc.subjectModels, Animal
dc.subjectMutation
dc.subjectNeurons
dc.subjectRats
dc.subjectRats, Sprague-Dawley
dc.titleMfn2 downregulation in excitotoxicity causes mitochondrial dysfunction and delayed neuronal death
dc.typeArticle


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