octubre14Referencia

EMBO J. 2014 Aug 21. Pii: e201488327.

Autores

Martorell-Riera A, Segarra-Mondejar M, Muñoz JP, Ginet V, Olloquequi J, Pérez-Clausell J, Palacín M, Reina M, Puyal J, Zorzano A, Soriano FX.

Resumen

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.

Descripción

Según la Organización Mundial de la Salud, el ictus o infarto cerebrovascular es la segunda causa de muerte y no existen terapias efectivas para combatirlo. Tanto en el ictus como en la mayoría de enfermedades neurodegenerativas, aparece el efecto excitotóxico que se produce por una entrada masiva de iones calcio al interior de la neurona a través de los receptores NMDA. Este calcio activa varias vías de señalización que actúan sobre la dinámica mitocondrial. En el presente trabajo hemos estudiado la relevancia de Mfn2 no solamente en el mantenimiento de la morfología y el buen funcionamiento de las mitocondrias en excitotoxicidad, sino también en la viabilidad de las neuronas.

grupo

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo dirigido por el Dr. Francesc X. Soriano se centra en la regulación del metabolismo y la dinámica mitocondrial en neuronas corticales de rata. Su investigación va dirigida por un lado en determinar el papel de Mfn2 y su relevancia en el control de la morfología mitocondrial y la viabilidad neuronal bajo condiciones de excitotoxicidad. Por otro lado, en una segunda línea de investigación estudia la regulación de distintas vías metabólicas por la actividad sináptica y sus implicaciones en la neuroprotección y el crecimiento neurítico.

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