title: Ca(2+) regulation of mitochondrial function in neurons.
abstract: Calcium is thought to regulate respiration but it is unclear whether this is dependent on the increase in ATP demand caused by any Ca(2+) signal or to Ca(2+) itself. [Na(+)]i, [Ca(2+)]i and [ATP]i dynamics in intact neurons exposed to different workloads in the absence and presence of Ca(2+) clearly showed that Ca(2+)-stimulation of coupled respiration is required to maintain [ATP]i levels. Ca(2+) may regulate respiration by activating metabolite transport in mitochondria from outer face of the inner mitochondrial membrane, or after Ca(2+) entry in mitochondria through the calcium uniporter (MCU). Two Ca(2+)-regulated mitochondrial metabolite transporters are expressed in neurons, the aspartate-glutamate exchanger ARALAR/AGC1/Slc25a12, a component of the malate-aspartate shuttle, and the ATP-Mg/Pi exchanger SCaMC-3/APC2/Slc25a23, with S0.5 for Ca(2+) of 300nM and 3.4μM, respectively. The lack of SCaMC-3 results in a smaller Ca(2+)-dependent stimulation of respiration only at high workloads, as caused by veratridine, whereas the lack of ARALAR reduced by 46% basal OCR in intact neurons using glucose as energy source and the Ca(2+)-dependent responses to all workloads: a reduction of about 65-70% in the response to the high workload imposed by veratridine, and completely suppression of the OCR responses to moderate (K(+)-depolarization) and small (carbachol) workloads, effects reverted by pyruvate supply. For K(+)-depolarization, this occurs in spite of the presence of large [Ca(2+)]mit signals and increased formation of mitochondrial NAD(P)H. These results show that ARALAR-MAS is a major contributor of Ca(2+)-stimulated respiration in neurons by providing increased pyruvate supply to mitochondria. In its absence and under moderate workloads, matrix Ca(2+) is unable to stimulate pyruvate metabolism and entry in mitochondria suggesting a limited role of MCU in these conditions. This article was invited for a Special Issue entitled: 18th European Bioenergetic Conference.
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Departamento de Investigaciones-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), ISCIII, Madrid, Spain.
authors.forename: Carlos B
authors.initials: CB
authors.lastname: Rueda
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Departamento de Investigaciones-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), ISCIII, Madrid, Spain.
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 Departamento de Investigaciones-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), ISCIII, Madrid, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Amigo
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Departamento de Investigaciones-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), ISCIII, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Contreras
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Departamento de Investigaciones-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), ISCIII, Madrid, Spain.
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 Departamento de Investigaciones-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), ISCIII, Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Martínez-Valero
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Departamento de Investigaciones-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), ISCIII, Madrid, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: Juaristi
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Departamento de Investigaciones-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), ISCIII, Madrid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pardo
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), ISCIII, Madrid, Spain; Centro regional de Investigaciones Biomédicas, Facultad de Ciencias Ambientales y Bioquímica, Universidad de Castilla La Mancha, 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 Departamento de Investigaciones-Universidad Autónoma de Madrid (CSIC-UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain; Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), ISCIII, Madrid, Spain. Electronic address: jsatrustegui@cbm.csic.es.
authors.forename: Jorgina
authors.initials: J
authors.lastname: Satrústegui
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D026922:Amino Acid Transport Systems, Acidic / Q000378:metabolism; D000818:Animals; D017920:Antiporters / Q000378:metabolism; D002118:Calcium / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D017136:Ion Transport; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D019289:Pyruvic Acid / Q000378:metabolism
chemical_list: D026922:Amino Acid Transport Systems, Acidic; D017920:Antiporters; C051046:aspartate-glutamate carrier; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D002118:Calcium
keywords: ATP-Mg/Pi transporter; Aspartate–glutamate transporter; Calcium; Calcium-regulated transport; Mitochondrion; Neuronal respiration