title: Mfn2 downregulation in excitotoxicity causes mitochondrial dysfunction and delayed neuronal death.
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.
authors.affiliation: Department of Cell Biology, University of Barcelona, Barcelona, Spain CELLTEC-UB, University of Barcelona, Barcelona, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martorell-Riera
authors.affiliation: Department of Cell Biology, University of Barcelona, Barcelona, Spain CELLTEC-UB, University of Barcelona, Barcelona, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Segarra-Mondejar
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Muñoz
authors.affiliation: Department of Fundamental Neurosciences, Faculty of Biology and Medicine University of Lausanne, Lausanne, Switzerland Clinic of Neonatology, Department of Pediatrics and Pediatric Surgery University Hospital Center and University of Lausanne, Lausanne, Switzerland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Ginet
authors.affiliation: Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Talca, Chile.
authors.forename: Jordi
authors.initials: J
authors.lastname: Olloquequi
authors.affiliation: Department of Cell Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Jeús
authors.initials: J
authors.lastname: Pérez-Clausell
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Palacín
authors.affiliation: Department of Cell Biology, University of Barcelona, Barcelona, Spain CELLTEC-UB, University of Barcelona, Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Reina
authors.affiliation: Department of Fundamental Neurosciences, Faculty of Biology and Medicine University of Lausanne, Lausanne, Switzerland Clinic of Neonatology, Department of Pediatrics and Pediatric Surgery University Hospital Center and University of Lausanne, Lausanne, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Puyal
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
authors.affiliation: Department of Cell Biology, University of Barcelona, Barcelona, Spain CELLTEC-UB, University of Barcelona, Barcelona, Spain f.x.soriano@ub.edu.
authors.forename: Francesc X
authors.initials: FX
authors.lastname: Soriano
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D020558:GTP Phosphohydrolases; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D064326:MEF2 Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D063154:Mitochondrial Dynamics / Q000502:physiology; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D023421:Models, Animal; D009154:Mutation; D009474:Neurons / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C494828:Bax protein, rat; D064326:MEF2 Transcription Factors; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D051028:bcl-2-Associated X Protein; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat; C519851:Dnm1l protein, rat; D034281:Dynamins; D002118:Calcium
keywords: excitotoxicity; mitochondrial dynamics; neuron; transcriptional regulation