Calcium signalling in mitochondria and insulin/leptin signalling during ageing

Research summary:

Ca2+ entry in mitochondria through the Ca2+ uniporter is important in cell Ca2+ signaling, but its persistence in mitochondria is associated with mitochondrial dysfunction and cell death. We are interested in the study of systems for Ca2+ signaling in mitochondria that do not require Ca2+ entry in the organelle: the mitochondrial carriers of aspartate-glutamate carriers (AGC) aralar and citrin, components of the malate aspartate shuttle (MAS), and those of ATP-Mg/Pi, or Short CaMCs (SCaMCs) which sense extramitochondrial Ca2+ to regulate metabolite transport and mitochondrial functionality. We focus on their role in regulating respiration in intact cells and in the regulation of brain aspartate and glutamate levels and traffic.
We found that these transporters, particularly AGC1/Aralar, are essential for basal mitochondrial respiration of intact cultured neurons and for the Ca2+ dependent stimulation of respiration in response to different workloads.

The AGC1/Aralar KO mouse recapitulates many features of human AGC1 deficiency including very low levels of brain N-acetyl-aspartate, hypomyelination and seizures. We proposed that in brain, glial glutamate and glutamine synthesis requires aspartate produced in neurons, and we have now verified this proposal within the retina, finding that glutamine synthesis in Müller glial cells depends on the transcellular flux of aspartate from photoreceptors. These new functions of AGC1/Aralar-MAS in intra- and intercellular traffic of amino acids may set the basis for new therapeutic strategies in this and other brain disorders.
Aging is characterized by insulin and leptin resistance, and cardiovascular disease. We focuses our work in two aspects: 1) Changes in heart function in aged rats fed ad libitum or after 3-months of moderate caloric restriction; and 2) Changes in CCK satiating and insulin sensitizing effects looking for possible mechanisms involved in the development of insulin resistance with aging and its reversion.
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Mitochondrial Calcium Uniporter (MCU) and Ca2+-regulated mitochondrial carriers, SCaMCs and AGCs, mediate Ca2+-signalling to mitochondria. MCU and SCaMCs are activated by cytosolic [Ca2+] at uM range whereas that AGCs require lower cytosolic [Ca2+] about 100-300 nM for activation.

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Representative images of WT and SCaMC-3 KO neurons transfected with the mitochondrial FRET-based ATP probe GO-ATeam-2 to monitor changes in mitochondrial ATP levels after NMDA exposure.

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Last nameNameLaboratoryExt.*e-mailProfessional category
Bogónez PeláezElena3214622ebogonez(at)cbm.csic.esProfesor Titular Universidad, GA
Carrascosa BaezaJosé Mª3214651jmcarrascosa(at)cbm.csic.esCatedrático Universidad, GA
Contreras BalsaLaura3214651lcontreras(at)cbm.csic.esTitulado Sup.de Actividades Técn. y Profes. GP1
González MorenoLuis3214651lgmoreno(at)cbm.csic.esContrato Predoctoral
Juaristi SantosInés3214651ijuaristi(at)cbm.csic.esInvestigador
Pardo MerinoBeatriz3214635bpardo(at)cbm.csic.esProfesor Titular Universidad, GA
Richter Emma3214651Becario Erasmus
Romeral BuzónAlejandro4651Estudiante TFG
Santamaría CanoAndrea 3214651asantamaria(at)cbm.csic.esContrato Predoctoral
Satrústegui Gil-DelgadoJorgina3214621jsatrustegui(at)cbm.csic.esEmérito
Sesé CobosBárbara3214651bsese(at)cbm.csic.esE.Ayudantes De Invest. De Los Oo.Publicos De Investigacion
Von-Kobbe AlonsoCayetano-Alfonso114.44809cvonkobbe(at)cbm.csic.esE.Científicos Titulares de Organismos Públicos de Investigación

Relevant publications:

  • Civera-Tregón A, Domínguez L, Martínez-Valero P, Serrano C, Vallmitjana A, Benítez R, Hoenicka J, Satrústegui J, Palau F. (2021) Mitochondria and calcium defects correlate with axonal dysfunction in GDAP1-related Charcot-Marie-Tooth mouse model. Neurobiol Dis. 152:105300. doi: 10.1016/j.nbd.2021.
  • Pérez-Liébana I, Casarejos MJ, Alcaide A, Herrada-Soler E, Llorente-Folch I, Contreras L, Satrústegui J, Pardo B. (2020) βOHB Protective Pathways in Aralar-KO Neurons and Brain: An Alternative to Ketogenic Diet. J Neurosci. 40:9293-9305. doi: 10.1523/JNEUROSCI.0711-20.2020
  • Rubio C, Puerto M, García-Rodríquez JJ, Lu VB, García-Martínez I, Alén R, Sanmartín-Salinas P, Toledo-Lobo MV, Saiz J, Ruperez J, Barbas C, Menchén L, Gribble FM, Reimann F, Guijarro LG, Carrascosa JM, Valverde ÁM. (2020) Impact of global PTP1B deficiency on the gut barrier permeability during NASH in mice. Mol Metab. 35:100954. doi: 10.1016/j.molmet.2020.01.018
  • Juaristi I, Llorente-Folch I, Satrústegui J, Del Arco A. (2019) Extracellular ATP and glutamate drive pyruvate production and energy demand to regulate mitochondrial respiration in astrocytes. Glia 67:759-774. doi: 10.1002/glia.23574.
  • Puertas-Frías G, Del Arco A, Pardo B, Satrústegui J, Contreras L (2019) Mitochondrial movement in Aralar/Slc25a12/AGC1 deficient cortical neurons. Int. 131:104541. doi: 10.1016/j.neuint.2019.104541.
  • von Kobbe C (2019) Targeting senescent cells: approaches, opportunities, challenges. Aging (Albany NY) 11: 12844–12861. doi: 10.18632/aging.102557.
  • Remacha L, Comino-Méndez I, Richter S, Contreras L, Currás-Freixes M, Pita G, Letón R, Galarreta A, Torres-Pérez R, Honrado E, Jiménez S, Maestre L, Moran S, Esteller M, Satrústegui J, Eisenhofer G, Robledo M, Cascón A. (2017) Targeted Exome Sequencing of Krebs Cycle Genes Reveals Candidate Cancer-Predisposing Mutations in Pheochromocytomas and Paragangliomas. Clin Cancer Res. 23:6315-6324. doi: 10.1158/1078-0432.CCR-16-2250.
  • González-Sánchez P, Del Arco A, Esteban JA, Satrústegui J. (2017) Store-Operated Calcium Entry Is Required for mGluR-Dependent Long Term Depression in Cortical Neurons. Front Cell Neurosci. 11:363. doi: 10.3389/fncel.2017.00363.
  • Writzl K, Maver A, Kovačič L, Martinez-Valero P, Contreras L, Satrustegui J, Castori M, Faivre L, Lapunzina P, van Kuilenburg ABP, Radović S, Thauvin-Robinet C, Peterlin B, Del Arco A, Hennekam RC. (2017) De Novo Mutations in SLC25A24 Cause a Disorder Characterized by Early Aging, Bone Dysplasia, Characteristic Face, and Early Demise. Am J Hum Genet. 101:844-855. doi: 10.1016/j.ajhg.2017.09.017.
  • Juaristi I, García-Martín ML, Rodrigues TB, Satrústegui J, Llorente-Folch I, Pardo B. (2017) ARALAR/AGC1 deficiency, a neurodevelopmental disorder with severe impairment of neuronal mitochondrial respiration, does not produce a primary increase in brain lactate. J Neurochem. 142:132-139. doi: 10.1111/jnc.14047.
  • González-Sánchez P, Pla-Martín D, Martínez-Valero P, Rueda CB, Calpena E, Del Arco A, Palau F, Satrústegui J. (2017) CMT-linked loss-of-function mutations in GDAP1 impair store-operated Ca2+ entry-stimulated respiration. Sci Rep. 7:42993. doi: 10.1038/srep42993.
  • Rueda, C.B., Traba, J., Amigo, I., Llorente-Folch, I., González-Sánchez, P., Pardo, B., Esteban, J.A., del Arco, A. and Satrústegui, J. (2015) Mitochondrial ATP-Mg/Pi carrier SCaMC-3/Slc25a23 counteracts PARP-1- dependent fall in mitochondrial ATP caused by excitotoxic insults in neurons. J. Neurosci. 35, 3566-3581.
  • Llorente-Folch, I., Rueda, C.B., Pardo, B., Szabadkai, G., Duchen, M.R. and Satrustegui, J. (2015) The regulation of neuronal mitochondrial metabolism by calcium. J. Physiol. 593, 3447-3462.
  • Llorente-Folch, I., Rueda, C.B., Perez-Liebana, I., Satrústegui, J. and Pardo, B. (2016) L-Lactate-Mediated Neuroprotection against Glutamate-Induced Excitotoxicity Requires Aralar/AGC1. J. Neurosci. 36, 4443-4456.
  • Amigo, I., Traba, J., González-Barroso, MM., Rueda, CB., Fernández, M., Rial, E., Sánchez, A, Satrústegui, J. and del Arco, A. (2013) Glucagon regulation of oxidative phosphorylation requires an increase in matrix adenine nucleotide content through Ca2+ activation of the mitochondrial ATP-Mg/Pi carrier SCaMC-3. J. Biol. Chem. 288, 7791-7802.
  • Llorente-Folch, I., Rueda, CB., Amigo, I., del Arco, A., Saheki, T., Pardo, B. and Satrústegui, J. (2013) Calcium-regulation of mitochondrial respiration maintains ATP homeostasis and requires ARALAR/AGC1-malate aspartate shuttle in intact cortical neurons. J. Neurosci. 33, 13957-13971.
  • Lindsay, KJ., Du, J., Sloat, SR., Contreras, L., Linton, JD., Turner, SJ., Sadilek, M., Satrústegui, J. and Hurley, JB. (2014) Pyruvate kinase and aspartate-glutamate carrier distributions reveal key metabolic links between neurons and glia in retina. Proc. Natl. Acad. Sci. U. S. A. 111, 15579-15584.
  • Llorente-Folch, I., Sahún, I., Contreras, L., Casarejos, MJ., Grau JM, Saheki, T., Mena, MA., Satrústegui, J., Dierssen M. and Pardo, B. (2013) AGC1-malate aspartate shuttle activity is critical for dopamine handling in the nigrostriatal pathway. J. Neurochem. 124, 347-362.

Capítulos de libros:

  • del Arco, A. and Satrústegui, J. (March 2013) Mitochondrial Carriers. In: eLS. John Wiley & Sons, Ltd: Chichester.
  • José María Carrascosa Baeza, “Ciencia, ética y sostenibilidad: el papel de la Academia para alcanzar los Objetivos de Desarrollo Sostenible” Agenda 2030: Claves para la transformación sostenible / Margarita Alfaro (ed. lit.), Silvia Arias Careaga (ed. lit.), Ana Gamba Romero (ed. lit.), ISBN 9788490977071.

Doctoral theses:

  • Irene Pérez Liébana (2020) “The mitochondrial aspartate-glutamate carrier Aralar/AGC1 controls neuronal respiration and (beta)-Hydroxybutyrate rescues brain defects caused by AGC1 deficiency”. UAM. Jorgina Satrústegui y Beatriz Pardo.
  • Inés Juaristi Santos (2019) “Regulation of mitochondrial respiration in astrocytes: role of Ca2+, ATP demand and pyruvate production”. UAM. Jorgina Satrústegui y Araceli del Arco.
  • Carmen Rubio Caballero (2018) “Changes in gut microbiota associated with inflammation during ageing and non-alcoholic steatohepatitis”. UAM. José María Carrascosa Baeza y Ángela Martínez Valverde.
  • Paula Martínez Valero (2017) “Enfermedad de Charcot-Marie-Tooth asociada a Gadp1: alteraciones en nocicepción y señalización por calcio”. UAM. Jorgina Satrústegui, Laura Contreras y Carolina Roza.
  • Paloma González Sánchez (2017) “Store-operated calcium entry in neural cells. A role in Charcot-Marie-Tooth disease”. UAM. Jorgina Satrústegui y Araceli del Arco.
  • Carlos B. Rueda Díez (2014). “Ca2+ modulation of mitochondrial function under physiological and pathological stimulation: Role of the ATP-Mg/Pi carrier, SCaMC-3”. UAM. Jorgina Satrústegui, Beatriz Pardo y Araceli del Arco.
  • Irene Llorente Folch (2013). “New roles of aralar, the brain mitochondrial aspartate/glutamate carrier in dopamine handling glutamate excitotoxicity and regulation of mitochondrial respiration”. UAM. Jorgina Satrústegui y Beatriz Pardo.
  • Ignacio Amigo de la Huerga (2013). “Characterization of SCaMC-3, the mitochondrial ATP-Mg/Pi carrier present in liver and brain”. UAM. Jorgina Satrústegui y Araceli del Arco

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