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

  • Molecular Toxicology
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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.

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Acknowledgments

We thank Luca Scorrano (University of Geneva) and Miquel Vila (VHIR, Barcelona) for providing the Mitofusin and Drp1 constructs, and Isidre Ferrer (University of Barcelona) for providing the P-Tau Thr181 antibody. This study was supported by grant BFU2008-3980 (“Ministerio de Ciencia e Innovacion” (MICINN), Spain) and a grant from the “Plan Nacional de Drogas” to ES, and by the “Fundação para a Ciência e Tecnologia (FCT),” Portugal (Project PTDC/SAU-FCF/102958/2008), under the framework of the “Programa Operacional Temático Factores de Competitividade (COMPTE) do Quadro Comunitário de Apoio III” and “Fundo Comunitário Europeu (FEDER)” (FCOMP-01-0124-FEDER-011079). DJB’s stay at IRB Barcelona was partially supported by FCT, Portugal. DJB was supported by fellowship (SFRH/BD/64939/2009) from FCT, Portugal.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. 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

    Daniel José Barbosa, Maria de Lourdes Bastos, João Paulo Capela & Félix Carvalho

  2. Developmental Neurobiology and Regeneration Lab, Institute for Research in Biomedicine, Barcelona Science Park, C/Baldiri I Reixac 10-12, 08028 Barcelona, Spain

    Daniel José Barbosa, Román Serrat, Serena Mirra, Martí Quevedo & Eduardo Soriano

  3. Department of Cell Biology, University of Barcelona, Barcelona, Spain

    Daniel José Barbosa, Román Serrat, Serena Mirra, Martí Quevedo & Eduardo Soriano

  4. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain

    Daniel José Barbosa, Román Serrat, Serena Mirra, Martí Quevedo, Elena Gómez de Barreda, Jesús Ávila & Eduardo Soriano

  5. Center of Molecular Biology Severo Ochoa (CSIC-UAM), Campus de la Universidad Autónoma de Madrid, C/Nicolás Cabrera 1, 28049, Madrid, Spain

    Elena Gómez de Barreda & Jesús Ávila

  6. REQUIMTE, Laboratory of Applied Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo Ferreira 228, 4050-313, Porto, Portugal

    Eduarda Fernandes

  7. Faculty of Health Sciences, University Fernando Pessoa , Praça 9 de Abril 349, 4249-004, Porto, Portugal

    João Paulo Capela

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  1. Daniel José Barbosa
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  2. Román Serrat
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Corresponding authors

Correspondence to Félix Carvalho or Eduardo Soriano.

Additional information

Daniel José Barbosa and Romàn Serrat have contributed equally to this work.

Félix Carvalho and Eduardo Soriano are co-senior authors.

Electronic supplementary material

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204_2014_1209_MOESM1_ESM.avi

Supplementary Movie 1 Axonal transport of mitochondria in a hippocampal neuron, at 6DIV, under control conditions. (AVI 596 kb)

204_2014_1209_MOESM2_ESM.avi

Supplementary Movie 2 Axonal transport of mitochondria in a hippocampal neuron, after exposure to MDMA (1.6 mM), for 90 min. (AVI 572 kb)

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Barbosa, D.J., Serrat, R., Mirra, S. et al. MDMA impairs mitochondrial neuronal trafficking in a Tau- and Mitofusin2/Drp1-dependent manner. Arch Toxicol 88, 1561–1572 (2014). https://doi.org/10.1007/s00204-014-1209-7

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  • DOI: https://doi.org/10.1007/s00204-014-1209-7

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