RGD Reference Report - Mfn2 downregulation in excitotoxicity causes mitochondrial dysfunction and delayed neuronal death. - Rat Genome Database

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

Authors: Martorell-Riera, Alejandro  Segarra-Mondejar, Marc  Muñoz, Juan P  Ginet, Vanessa  Olloquequi, Jordi  Pérez-Clausell, Jeús  Palacín, Manuel  Reina, Manuel  Puyal, Julien  Zorzano, Antonio  Soriano, Francesc X 
Citation: Martorell-Riera A, etal., EMBO J. 2014 Oct 16;33(20):2388-407. doi: 10.15252/embj.201488327. Epub 2014 Aug 21.
RGD ID: 13204807
Pubmed: (View Article at PubMed) PMID:25147362
DOI: Full-text: DOI:10.15252/embj.201488327

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.

Annotation

Disease Annotations    

Gene Ontology Annotations    

Biological Process

Objects Annotated

Genes (Rattus norvegicus)
Mfn2  (mitofusin 2)

Genes (Mus musculus)
Mfn2  (mitofusin 2)

Genes (Homo sapiens)
MFN2  (mitofusin 2)


Additional Information