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

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...

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Bibliographic Details
Published in:Archives of toxicology 2014-08, Vol.88 (8), p.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: Article
Language:English
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
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Summary: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.
ISSN:0340-5761
1432-0738
DOI:10.1007/s00204-014-1209-7