Mitochondrial ATP-Mg/pi carrier SCaMC-3/Slc25a23 counteracts PARP-1-dependent fall in mitochondrial ATP caused by excitotoxic insults in neurons
Entity
UAM. Departamento de Biología MolecularPublisher
Society for NeuroscienceDate
2015-01-01Citation
10.1523/JNEUROSCI.2702-14.2015
Journal of Neuroscience 35.8 (2015): 3566 –3581
ISSN
0270-6474 (print); 1520-2401 (online)DOI
10.1523/JNEUROSCI.2702-14.2015Funded by
This work was supported by Ministerio de Economía Grant BFU2011-30456, by Centro de Investigación Biomé dica en Red de Enfermedades Raras [an initiative of the Instituto de Salud Carlos III (ISCIII)], by Comunidad de Madrid Grant S2010/BMD-2402 MITOLAB-CM (to J.S.), by ISCIII Grant PI080610 (to A.d.A.), and by an institutional grant from the Fundación Ramón Areces to the Centro de Biología Molecular Severo Ochoa.Project
Comunidad de Madrid. S2010/BMD-2402/MITOLABEditor's Version
http://dx.doi.org/10.1523/JNEUROSCI.2702-14.2015Subjects
ATP-Mg/Pi carrier; Calcium; Excitotoxicity; Mitochondria; PARP-1; SCaMC-3; Biología y Biomedicina / BiologíaRights
© 2015 the authorsAbstract
Glutamate excitotoxicity is caused by sustained activation of neuronal NMDA receptors causing a large Ca2 and Na influx, activation
of poly(ADP ribose) polymerase-1 (PARP-1), and delayed Ca2 deregulation. Mitochondria undergo early changes in membrane potential
during excitotoxicity, but their precise role in these events is still controversial. Using primary cortical neurons derived from mice, we
show that NMDA exposure results in a rapid fall in mitochondrial ATP in neurons deficient in SCaMC-3/Slc25a23, a Ca2 -regulated
mitochondrial ATP-Mg/Pi carrier. This fall is associated with blunted increases in respiration and a delayed decrease in cytosolic ATP
levels, which are prevented by PARP-1 inhibitors or by SCaMC-3 activity promoting adenine nucleotide uptake into mitochondria.
SCaMC-3 KO neurons show an earlier delayed Ca2 deregulation, and SCaMC-3-deficient mitochondria incubated with ADP or ATP-Mg
had reduced Ca2 retention capacity, suggesting a failure to maintain matrix adenine nucleotides as a cause for premature delayed Ca2
deregulation. SCaMC-3 KO neurons have higher vulnerability to in vitro excitotoxicity, and SCaMC-3 KO mice are more susceptible to
kainate-induced seizures, showing that early PARP-1-dependent fall in mitochondrial ATP levels, counteracted by SCaMC-3, is an early
step in the excitotoxic cascade
Files in this item
Google Scholar:Rueda, Carlos
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Traba, Javier
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Amigo, Ignacio
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Llorente-Folch, Irene
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González-Sánchez, Paloma
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Pardo Merino, Beatriz
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Esteban, José A.
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Arco, Araceli del
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Satrustegui Gil Delgado, Jorgina
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