PT  - JOURNAL ARTICLE
AU  - Carlos B. Rueda
AU  - Javier Traba
AU  - Ignacio Amigo
AU  - Irene Llorente-Folch
AU  - Paloma González-Sánchez
AU  - Beatriz Pardo
AU  - José A. Esteban
AU  - Araceli del Arco
AU  - Jorgina Satrústegui
TI  - Mitochondrial ATP-Mg/Pi Carrier SCaMC-3/Slc25a23 Counteracts PARP-1-Dependent Fall in Mitochondrial ATP Caused by Excitotoxic Insults in Neurons
AID  - 10.1523/JNEUROSCI.2702-14.2015
DP  - 2015 Feb 25
TA  - The Journal of Neuroscience
PG  - 3566--3581
VI  - 35
IP  - 8
4099  - http://www.jneurosci.org/content/35/8/3566.short
4100  - http://www.jneurosci.org/content/35/8/3566.full
SO  - J. Neurosci.2015 Feb 25; 35
AB  - 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.