title: Glutamate excitotoxicity and Ca2+-regulation of respiration: Role of the Ca2+ activated mitochondrial transporters (CaMCs).
abstract: Glutamate elicits Ca(2+) signals and workloads that regulate neuronal fate both in physiological and pathological circumstances. Oxidative phosphorylation is required in order to respond to the metabolic challenge caused by glutamate. In response to physiological glutamate signals, cytosolic Ca(2+) activates respiration by stimulation of the NADH malate-aspartate shuttle through Ca(2+)-binding to the mitochondrial aspartate/glutamate carrier (Aralar/AGC1/Slc25a12), and by stimulation of adenine nucleotide uptake through Ca(2+) binding to the mitochondrial ATP-Mg/Pi carrier (SCaMC-3/Slc25a23). In addition, after Ca(2+) entry into the matrix through the mitochondrial Ca(2+) uniporter (MCU), it activates mitochondrial dehydrogenases. In response to pathological glutamate stimulation during excitotoxicity, Ca(2+) overload, reactive oxygen species (ROS), mitochondrial dysfunction and delayed Ca(2+) deregulation (DCD) lead to neuronal death. Glutamate-induced respiratory stimulation is rapidly inactivated through a mechanism involving Poly (ADP-ribose) Polymerase-1 (PARP-1) activation, consumption of cytosolic NAD(+), a decrease in matrix ATP and restricted substrate supply. Glutamate-induced Ca(2+)-activation of SCaMC-3 imports adenine nucleotides into mitochondria, counteracting the depletion of matrix ATP and the impaired respiration, while Aralar-dependent lactate metabolism prevents substrate exhaustion. A second mechanism induced by excitotoxic glutamate is permeability transition pore (PTP) opening, which critically depends on ROS production and matrix Ca(2+) entry through the MCU. By increasing matrix content of adenine nucleotides, SCaMC-3 activity protects against glutamate-induced PTP opening and lowers matrix free Ca(2+), resulting in protracted appearance of DCD and protection against excitotoxicity in vitro and in vivo, while the lack of lactate protection during in vivo excitotoxicity explains increased vulnerability to kainite-induced toxicity in Aralar +/- mice. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi.
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Spain; Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Spain.
authors.forename: Carlos B
authors.initials: CB
authors.lastname: Rueda
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Spain; Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Llorente-Folch
authors.affiliation: Cardiovascular and Pulmonary Branch, NHLBI, NIH, 20892 Bethesda, MD, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Traba
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, 13560-970 São Paulo, Brazil.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Amigo
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Spain; Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Gonzalez-Sanchez
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Spain; Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Contreras
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Spain; Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: Juaristi
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Spain; Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Martinez-Valero
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Spain; Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pardo
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Spain; Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Spain; Facultad de Ciencias Ambientales y Bioquímica, Universidad de Castilla la Mancha, Toledo 45071, Spain.
authors.forename: Araceli
authors.initials: A
authors.lastname: Del Arco
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Universidad Autónoma de Madrid-Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain; CIBER de Enfermedades Raras (CIBERER), Spain; Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD), Spain.
authors.forename: Jorgina
authors.initials: J
authors.lastname: Satrustegui
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017920:Antiporters / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D019069:Cell Respiration / Q000187:drug effects; D015870:Gene Expression; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C086357:ATP-Mg-Pi carrier proteins, mitochondria; D017920:Antiporters; D015220:Calcium Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C491956:Slc25a12 protein, mouse; C034703:mitochondrial calcium uniporter; D018698:Glutamic Acid; 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; Aralar; Aspartate/glutamate carrier; Calcium; Excitotoxicity; Mitochondria; PARP-1; SCaMC-3