Wednesday, 13th December 2017

Molecular Neuropathology

    Calcium signalling in mitochondria and insulin/leptin signalling during ageing

 


 Lab 321 Grupo Jorgina Satrustegui 400

 


Jorgina Satrústegui

DSciStaff

DPublications

 

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.

 Jorgina Satrustegui Fig01 300 ------

 

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.

 

Jorgina Satrustegui Fig02 300

 
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.  

 

 

 

 
   

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.


 

Publications:

  • 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.
  • 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.
  • Du, J., Cleghorn, W., Contreras, L, Linton, JD., Chan, GC., Chertov, AO., Saheki, T., Govindaraju, V., Sadilek, M., Satrústegui J, Hurley JB. (2013) Cytosolic reducing power preserves glutamate in retina. Proc. Natl. Acad. Sci. U. S. A. 110, 18501-18506.
  • Pla-Martín, D., Rueda, CB., Estela, A., Sánchez-Piris, M., González-Sánchez, P., Traba, J., de la Fuente, S., Scorrano, L., Renau-Piqueras, J., Alvarez, J., Satrústegui, J. and Palau, F. (2013) Silencing of the Charcot-Marie-Tooth disease-associated gene GDAP1 induces abnormal mitochondrial distribution and affects Ca2+ homeostasis by reducing store-operated Ca2+ entry. Neurobiol. Dis. 55, 140-151.
    • Du J, Cleghorn WM, Contreras L, Lindsay K, Rountree AM, Chertov AO, Turner SJ, Sahaboglu A, Linton J, Sadilek M, Satrústegui J, Sweet IR, Paquet-Durand F, Hurley JB. (2013) Inhibition of mitochondrial pyruvate transport by zaprinast causes massive accumulation of aspartate at the expense of glutamate in the retina. J. Biol. Chem. 288, 36129-36140.
    • Pardo B, Contreras L, Satrústegui J. (2013) De novo Synthesis of Glial Glutamate and Glutamine in Young Mice Requires Aspartate Provided by the Neuronal Mitochondrial Aspartate-Glutamate Carrier Aralar/AGC1. Front. Endocrinol. 4, 149.
    • Rueda, CB., Llorente-Folch, I., Amigo, I., Contreras, L., González-Sánchez, P., Martínez-Valero, P., Juaristi, I., Pardo, B., del Arco, A. and Satrústegui J. (2014) Ca(2+) regulation of mitochondrial function in neurons. Biochim. Biophys. Acta 1837, 1617-1624.
    • 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.
    • Granado, M., Rubio, C., Amor, S., Monge, L., Fernández, N., Carreño-Tarragona, G., Carrascosa, JM. and García-Villalón ÁL. (2014) Effects of age and caloric restriction on the cardiac and coronary response to endothelin-1 in rats. Exp. Gerontol. 60, 183-189.

    Capítulos de libros:

    del Arco, A. and Satrústegui, J. (March 2013) Mitochondrial Carriers. In: eLS. John Wiley & Sons, Ltd: Chichester.


 

Doctoral theses:

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

Irene Llorente Folch (2013). “New roles of aralar, the brain mitochondrial aspartate/glutamate carrier in dopamine handling glutamate excitotoxicity and regulation of mitocondrial respiration”. UAM. Jorgina Satrústegui y Beatriz Pardo.

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.