Mfn2 downregulation in excitotoxicity causes mitochondrial dysfunction and delayed neuronal death
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| Title: | Mfn2 downregulation in excitotoxicity causes mitochondrial dysfunction and delayed neuronal death |
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| Authors: | Manuel Reina, Alejandro Martorell-Riera, Juan Pablo Muñoz, Vanessa Ginet, Jordi Olloquequi, Marc Segarra-Mondejar, Jeús Pérez-Clausell, Julien Puyal, Manuel Palacín, Francesc X. Soriano, Antonio Zorzano |
| Contributors: | Universitat de Barcelona |
| Source: | Recercat. Dipósit de la Recerca de Catalunya instname Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia) Dipòsit Digital de la UB Universidad de Barcelona Embo Journal, vol. 33, no. 20, pp. 2388-2407 |
| Publisher Information: | Springer Science and Business Media LLC, 2014. |
| Publication Year: | 2014 |
| Subject Terms: | Dynamins, Male, 0301 basic medicine, Down-Regulation, Mitochondrial Dynamics, Mitocondris, Cell Line, GTP Phosphohydrolases, Mitochondrial Proteins, 03 medical and health sciences, Animals, Homeostasis, Humans, Cells, Cultured, Neurons, Cell Death, MEF2 Transcription Factors, Calcium/metabolism, Dynamins/genetics, Dynamins/metabolism, Gene Expression Regulation, MEF2 Transcription Factors/genetics, MEF2 Transcription Factors/metabolism, 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, Malalties neurodegeneratives, Membrane Proteins, Neurodegenerative Diseases, 6. Clean water, Mitochondria, Calcium |
| Description: | 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. |
| Document Type: | Article |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 1460-2075 0261-4189 |
| DOI: | 10.15252/embj.201488327 |
| Access URL: | https://europepmc.org/articles/pmc4253527?pdf=render https://pubmed.ncbi.nlm.nih.gov/25147362 http://hdl.handle.net/2445/127749 https://hdl.handle.net/2445/127749 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253527/figure/fig03/ https://zenodo.org/record/161776 http://diposit.ub.edu/dspace/bitstream/2445/127749/1/645393.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253527/ https://www.embopress.org/doi/full/10.15252/embj.201488327 https://emboj.embopress.org/content/33/20/2388 https://serval.unil.ch/notice/serval:BIB_833104A8E676 http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_833104A8E6764 https://serval.unil.ch/resource/serval:BIB_833104A8E676.P001/REF.pdf |
| Rights: | Wiley Online Library User Agreement |
| Accession Number: | edsair.doi.dedup.....f29168a9cdb8a9e8c66572d2fd05c261 |
| Database: | OpenAIRE |
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Nájsť tento článok vo Web of Science | 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. |
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| ISSN: | 14602075 02614189 |
| DOI: | 10.15252/embj.201488327 |