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

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

The EMBO journal (2014-08-26)
Alejandro Martorell-Riera, Marc Segarra-Mondejar, Juan P Muñoz, Vanessa Ginet, Jordi Olloquequi, Jeús Pérez-Clausell, Manuel Palacín, Manuel Reina, Julien Puyal, Antonio Zorzano, Francesc X Soriano
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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