title: MDMA impairs mitochondrial neuronal trafficking in a Tau- and Mitofusin2/Drp1-dependent manner.
abstract: 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.
authors: REQUIMTE (Rede de Química e Tecnologia), Toxicology Laboratory, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal.
authors: Daniel José
authors: DJ
authors: Barbosa
authors: Román
authors: R
authors: Serrat
authors: Serena
authors: S
authors: Mirra
authors: Martí
authors: M
authors: Quevedo
authors: Elena
authors: E
authors: Gómez de Barreda
authors: Jesús
authors: J
authors: Avila
authors: Eduarda
authors: E
authors: Fernandes
authors: Maria de Lourdes
authors: Mde L
authors: Bastos
authors: João Paulo
authors: JP
authors: Capela
authors: Félix
authors: F
authors: Carvalho
authors: Eduardo
authors: E
authors: Soriano
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D034281:Dynamins / Q000378:metabolism*; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C558298:Mapt protein, mouse; D016875:tau Proteins; D020558:GTP Phosphohydrolases; C488751:Mfn2 protein, mouse; C486391:Dnm1l protein, mouse; D034281:Dynamins; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D002118:Calcium