PMID- 24595818
OWN - NLM
STAT- MEDLINE
DCOM- 20141229
LR  - 20140512
IS  - 1096-0929 (Electronic)
IS  - 1096-0929 (Linking)
VI  - 139
IP  - 2
DP  - 2014 Jun
TI  - The mixture of "ecstasy" and its metabolites impairs mitochondrial fusion/fission 
      equilibrium and trafficking in hippocampal neurons, at in vivo relevant 
      concentrations.
PG  - 407-20
LID - 10.1093/toxsci/kfu042 [doi]
AB  - 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. Neuronal mitochondrial 
      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 
      depletion 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 six of its major in vivo metabolites, each compound at 10muM, 
      impaired mitochondrial trafficking and increased the fragmentation of axonal 
      mitochondria in cultured hippocampal neurons. Furthermore, the overexpression 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 overexpressing 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.
FAU - Barbosa, Daniel Jose
AU  - Barbosa DJ
AD  - REQUIMTE (Rede de Quimica e Tecnologia), Toxicology Laboratory, Department of 
      Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Jorge Viterbo 
      Ferreira 228, 4050-313 Porto, Portugal.
FAU - Serrat, Roman
AU  - Serrat R
FAU - Mirra, Serena
AU  - Mirra S
FAU - Quevedo, Marti
AU  - Quevedo M
FAU - de Barreda, Elena Gomez
AU  - de Barreda EG
FAU - Avila, Jesus
AU  - Avila J
FAU - Ferreira, Luisa Maria
AU  - Ferreira LM
FAU - Branco, Paula Serio
AU  - Branco PS
FAU - Fernandes, Eduarda
AU  - Fernandes E
FAU - Lourdes Bastos, Maria de
AU  - Lourdes Bastos Md
FAU - Capela, Joao Paulo
AU  - Capela JP
FAU - Soriano, Eduardo
AU  - Soriano E
FAU - Carvalho, Felix
AU  - Carvalho F
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140304
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 3.6.1.- (GTP Phosphohydrolases)
RN  - EC 3.6.1.- (Mfn2 protein, mouse)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Animals
MH  - Axonal Transport/*drug effects
MH  - Calcium/metabolism
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Dose-Response Relationship, Drug
MH  - GTP Phosphohydrolases/metabolism
MH  - Hippocampus/*drug effects/metabolism
MH  - Mice
MH  - Mitochondrial Dynamics/*drug effects
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*metabolism/*toxicity
MH  - Neurons/*drug effects/metabolism
MH  - Neurotoxicity Syndromes/etiology/metabolism
MH  - Rats
OTO - NOTNLM
OT  - 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy")
OT  - MDMA's metabolites
OT  - mitochondrial dysfunction
OT  - mitochondrial fusion/fission
OT  - mitochondrial trafficking
OT  - neurotoxicity
EDAT- 2014/03/07 06:00
MHDA- 2014/12/30 06:00
CRDT- 2014/03/06 06:00
PHST- 2014/03/06 06:00 [entrez]
PHST- 2014/03/07 06:00 [pubmed]
PHST- 2014/12/30 06:00 [medline]
AID - kfu042 [pii]
AID - 10.1093/toxsci/kfu042 [doi]
PST - ppublish
SO  - Toxicol Sci. 2014 Jun;139(2):407-20. doi: 10.1093/toxsci/kfu042. Epub 2014 Mar 4.