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MDMA impairs mitochondrial neuronal trafficking in a Tau- and Mitofusin2/Drp1-dependent manner

2014; Springer Science+Business Media; Volume: 88; Issue: 8 Linguagem: Inglês

10.1007/s00204-014-1209-7

1432-0738

Daniel José Barbosa, Román Serrat, Serena Mirra, Martí Quevedo, Elena Gómez de Barreda, Jesús Ávila, Eduarda Fernandes, Maria de Lourdes Bastos, João Paulo Capela, Félix Carvalho, Eduardo Soriano,

Metabolomics and Mass Spectrometry Studies

Identification of the mechanisms by which drugs of abuse cause neuronal dysfunction is essential for understanding the biological bases of their acute and long-lasting effects in the brain. Here, we performed real-time functional experiments of axonal transport of mitochondria to explore the role of in situ mitochondrial dysfunction in 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy")-related brain actions. We showed that MDMA dramatically reduced mitochondrial trafficking in hippocampal neurons in a Tau-dependent manner, in which glycogen synthase kinase 3β activity was implicated. Furthermore, we found that these trafficking abnormalities were rescued by over-expression of Mitofusin2 and dynamin-related protein 1, but not of Miro1. Given the relevance of mitochondrial targeting for neuronal function and neurotransmission, our data underscore a novel mechanism of action of MDMA that may contribute to our understanding of how this drug of abuse alters neuronal functioning.