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Mfn2 downregulation in excitotoxicity causes mitochondrial dysfunction and delayed neuronal death
Author(s) -
MartorellRiera Alejandro,
SegarraMondejar Marc,
Muñoz Juan P,
Ginet Vanessa,
Olloquequi Jordi,
PérezClausell Jeús,
Palacín Manuel,
Reina Manuel,
Puyal Julien,
Zorzano Antonio,
Soriano Francesc X
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201488327
Subject(s) - excitotoxicity , biology , mfn2 , downregulation and upregulation , mitochondrion , neuroscience , programmed cell death , microbiology and biotechnology , mitochondrial fusion , apoptosis , mitochondrial dna , genetics , gene
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 M fn2 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, D rp1 recruitment to mitochondria plays a primordial role in mitochondrial fragmentation in an early phase that can be reversed once the insult has ceased, M fn2 downregulation intervenes in a delayed mitochondrial fragmentation phase that progresses even when the insult has ceased. Downregulation of M fn2 causes mitochondrial dysfunction, altered calcium homeostasis, and enhanced Bax translocation to mitochondria, resulting in delayed neuronal death. We found that transcription factor MEF 2 regulates basal Mfn2 expression in neurons and that excitotoxicity‐dependent degradation of MEF 2 causes M fn2 downregulation. Thus, M fn2 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.