TY  - JOUR
PY  - 2014//
TI  - The mixture of "ecstasy" and its metabolites impairs mitochondrial fusion/fission equilibrium and trafficking in hippocampal neurons, at in vivo relevant concentrations
JO  - Toxicological sciences
A1  - Barbosa, Daniel José
A1  - Serrat, Romàn
A1  - Mirra, Serena
A1  - Quevedo, Martí
A1  - Goméz de Barreda, Elena
A1  - Avila, Jesús
A1  - Ferreira, Luísa Maria
A1  - Branco, Paula Sério
A1  - Fernandes, Eduarda
A1  - Bastos, Maria de Lourdes
A1  - Capela, João Paulo
A1  - Soriano, Eduardo
A1  - Carvalho, Felix
SP  - 407
EP  - 420
VL  - 139
IS  - 2
N2  - 3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy"), is a potentially neurotoxic recreational drug of abuse. Though the mechanisms involved are still not completely understood, formation of reactive metabolites and mitochondrial dysfunction contribute to MDMA-related neurotoxicity. Mitochondrial neuronal trafficking, and their targeting to synapses, is essential for proper neuronal function and survival, rendering neurons particularly vulnerable to mitochondrial dysfunction. Indeed, MDMA-associated disruption of Ca(2+) homeostasis and ATP depletions have been described in neurons, thus suggesting possible MDMA interference on mitochondrial dynamics. In this study, we performed real-time functional experiments of mitochondrial trafficking to explore the role of in situ mitochondrial dysfunction in MDMA's neurotoxic actions. We show that the mixture of MDMA and its 6 major in vivo metabolites, each compound at 10 μM, impaired mitochondrial trafficking and increased the fragmentation of axonal mitochondria in cultured hippocampal neurons. Furthermore, the over-expression of mitofusin 2 (Mfn2) or dynamin-related protein 1 (Drp1) K38A constructs almost completely rescued the trafficking deficits caused by this mixture. Finally, in hippocampal neurons over-expressing a Mfn2 mutant, Mfn2 R94Q, with impaired fusion and transport properties, it was confirmed that a dysregulation of mitochondrial fission/fusion events greatly contributed to the reported trafficking phenotype. In conclusion, our study demonstrated, for the first time, that the mixture of MDMA and its metabolites, at concentrations relevant to the in vivo scenario, impaired mitochondrial trafficking and increased mitochondrial fragmentation in hippocampal neurons, thus providing a new insight in the context of "ecstasy"-induced neuronal injury.<p />  <p>Language: en</p>
LA  - en
SN  - 1096-6080
UR  - http://dx.doi.org/10.1093/toxsci/kfu042
ID  - ref1
ER  -