title: The regulation of neuronal mitochondrial metabolism by calcium.
abstract: Calcium signalling is fundamental to the function of the nervous system, in association with changes in ionic gradients across the membrane. Although restoring ionic gradients is energetically costly, a rise in intracellular Ca(2+) acts through multiple pathways to increase ATP synthesis, matching energy supply to demand. Increasing cytosolic Ca(2+) stimulates metabolite transfer across the inner mitochondrial membrane through activation of Ca(2+) -regulated mitochondrial carriers, whereas an increase in matrix Ca(2+) stimulates the citric acid cycle and ATP synthase. The aspartate-glutamate exchanger Aralar/AGC1 (Slc25a12), a component of the malate-aspartate shuttle (MAS), is stimulated by modest increases in cytosolic Ca(2+) and upregulates respiration in cortical neurons by enhancing pyruvate supply into mitochondria. Failure to increase respiration in response to small (carbachol) and moderate (K(+) -depolarization) workloads and blunted stimulation of respiration in response to high workloads (veratridine) in Aralar/AGC1 knockout neurons reflect impaired MAS activity and limited mitochondrial pyruvate supply. In response to large workloads (veratridine), acute stimulation of respiration occurs in the absence of MAS through Ca(2+) influx through the mitochondrial calcium uniporter (MCU) and a rise in matrix [Ca(2+) ]. Although the physiological importance of the MCU complex in work-induced stimulation of respiration of CNS neurons is not yet clarified, abnormal mitochondrial Ca(2+) signalling causes pathology. Indeed, loss of function mutations in MICU1, a regulator of MCU complex, are associated with neuromuscular disease. In patient-derived MICU1 deficient fibroblasts, resting matrix Ca(2+) is increased and mitochondria fragmented. Thus, the fine tuning of Ca(2+) signals plays a key role in shaping mitochondrial bioenergetics.
authors: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-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, Madrid, Spain.
authors: I
authors: I
authors: Llorente-Folch
authors: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-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, Madrid, Spain.
authors: C B
authors: CB
authors: Rueda
authors: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-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, Madrid, Spain.
authors: B
authors: B
authors: Pardo
authors: Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK.|Department of Biomedical Sciences, University of Padua and Consiglio Nazionale delle Ricerche Neuroscience Institute, Padua, Italy.
authors: G
authors: G
authors: Szabadkai
authors: Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK.
authors: M R
authors: MR
authors: Duchen
authors: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-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, Madrid, Spain.
authors: J
authors: J
authors: Satrustegui
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; C034703:mitochondrial calcium uniporter; D000255:Adenosine Triphosphate