Mitochondrial ATP-Mg/pi carrier SCaMC-3/Slc25a23 counteracts PARP-1-dependent fall in mitochondrial ATP caused by excitotoxic insults in neurons
EntityUAM. Departamento de Biología Molecular
PublisherSociety for Neuroscience
10.1523/JNEUROSCI.2702-14.2015Journal of Neuroscience 35.8 (2015): 3566 –3581
ISSN0270-6474 (print); 1520-2401 (online)
Funded byThis 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.
ProjectComunidad de Madrid. S2010/BMD-2402/MITOLAB
SubjectsATP-Mg/Pi carrier; Calcium; Excitotoxicity; Mitochondria; PARP-1; SCaMC-3; Biología y Biomedicina / Biología
Rights© 2015 the authors
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
Google Scholar:Rueda, Carlos - Traba, Javier - Amigo, Ignacio - Llorente-Folch, Irene - González-Sánchez, Paloma - Pardo Merino, Beatriz - Esteban, José A. - Arco, Araceli del - Satrustegui Gil Delgado, Jorgina
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