title: Mitochondrial ATP-Mg/Pi carrier SCaMC-3/Slc25a23 counteracts PARP-1-dependent fall in mitochondrial ATP caused by excitotoxic insults in neurons.
abstract: Glutamate excitotoxicity is caused by sustained activation of neuronal NMDA receptors causing a large Ca(2+) and Na(+) influx, activation of poly(ADP ribose) polymerase-1 (PARP-1), and delayed Ca(2+) 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 Ca(2+)-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 Ca(2+) deregulation, and SCaMC-3-deficient mitochondria incubated with ADP or ATP-Mg had reduced Ca(2+) retention capacity, suggesting a failure to maintain matrix adenine nucleotides as a cause for premature delayed Ca(2+) 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.
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, 28006 Madrid, Spain, and.
authors.forename: Carlos B
authors.identifier: http://orcid.org/0000-0002-3876-612X
authors.initials: CB
authors.lastname: Rueda
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, 28006 Madrid, Spain, and.
authors.forename: Javier
authors.initials: J
authors.lastname: Traba
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, 28006 Madrid, Spain, and.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Amigo
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, 28006 Madrid, Spain, and.
authors.forename: Irene
authors.initials: I
authors.lastname: Llorente-Folch
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, 28006 Madrid, Spain, and.
authors.forename: Paloma
authors.initials: P
authors.lastname: González-Sánchez
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, 28006 Madrid, Spain, and.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pardo
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Esteban
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, 28006 Madrid, Spain, and Centro Regional de Investigaciones Biomédicas, Facultad de Ciencias Ambientales y Bioquímica, Universidad de Castilla La Mancha, 45600 Toledo, Spain.
authors.forename: Araceli
authors.initials: A
authors.lastname: del Arco
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras, 28029 Madrid, Spain, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, 28006 Madrid, Spain, and jsatrustegui@cbm.csic.es.
authors.forename: Jorgina
authors.initials: J
authors.lastname: Satrústegui
mesh_terms: D000200:Action Potentials; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D019069:Cell Respiration; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D012640:Seizures / Q000378:metabolism
chemical_list: C086357:ATP-Mg-Pi carrier proteins, mitochondria; D017920:Antiporters; D024101:Mitochondrial Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D016202:N-Methylaspartate; D000255:Adenosine Triphosphate; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D002118:Calcium
keywords: ATP-Mg/Pi carrier; PARP-1; SCaMC-3; calcium; excitotoxicity; mitochondria