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

• Published in: Archives of toxicology Vol. 88; no. 8; pp. 1561 - 1572
• Main Authors: Barbosa, Daniel José, Serrat, Román, Mirra, Serena, Quevedo, Martí, Gómez de Barreda, Elena, Ávila, Jesús, Fernandes, Eduarda, Bastos, Maria de Lourdes, Capela, João Paulo, Carvalho, Félix, Soriano, Eduardo
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.08.2014; Springer Nature B.V
• Subjects: Animals; Axonal Transport - drug effects; Biomedical and Life Sciences; Biomedicine; Calcium - metabolism; Cells, Cultured; Cellular biology; Dynamins - metabolism; Ecstasy; Environmental Health; GTP Phosphohydrolases - metabolism; Hippocampus - cytology; Hippocampus - drug effects; Hippocampus - embryology; Mice, Inbred C57BL; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Dynamics - drug effects; Molecular Toxicology; N-Methyl-3,4-methylenedioxyamphetamine - toxicity; Neurons; Neurons - drug effects; Neurons - metabolism; Neurotoxicity; Occupational Medicine/Industrial Medicine; Pharmacology/Toxicology; Phosphorylation; tau Proteins - metabolism; Neurotoxicity; Mitochondrial dysfunction; Drugs of abuse; 3,4-Methylenedioxymethamphetamine (MDMA; “ecstasy”); Mitochondrial trafficking
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-014-1209-7

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.