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.

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.


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.


* For external calls please dial 34 91196 followed by the extension number
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 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
Romeral BuzónAlejandro4651Estudiante TFG
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:

  • 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.

NOTE! This site uses cookies and similar technologies.

If you not change browser settings, you agree to it. Learn more

I understand


What are cookies?

A cookie is a file that is downloaded to your computer when you access certain web pages. Cookies allow a web page, among other things, to store and retrieve information about the browsing habits of a user or their equipment and, depending on the information they contain and the way they use their equipment, they can be used to recognize the user.

Types of cookies

Classification of cookies is made according to a series of categories. However, it is necessary to take into account that the same cookie can be included in more than one category.

  1. Cookies according to the entity that manages them

    Depending on the entity that manages the computer or domain from which the cookies are sent and treat the data obtained, we can distinguish:

    • Own cookies: those that are sent to the user's terminal equipment from a computer or domain managed by the editor itself and from which the service requested by the user is provided.
    • Third party cookies: those that are sent to the user's terminal equipment from a computer or domain that is not managed by the publisher, but by another entity that processes the data obtained through the cookies. When cookies are installed from a computer or domain managed by the publisher itself, but the information collected through them is managed by a third party, they cannot be considered as own cookies.

  2. Cookies according to the period of time they remain activated

    Depending on the length of time that they remain activated in the terminal equipment, we can distinguish:

    • Session cookies: type of cookies designed to collect and store data while the user accesses a web page. They are usually used to store information that only is kept to provide the service requested by the user on a single occasion (e.g. a list of products purchased).
    • Persistent cookies: type of cookies in which the data is still stored in the terminal and can be accessed and processed during a period defined by the person responsible for the cookie, which can range from a few minutes to several years.

  3. Cookies according to their purpose

    Depending on the purpose for which the data obtained through cookies are processed, we can distinguish between:

    • Technical cookies: those that allow the user to navigate through a web page, platform or application and the use of different options or services that exist in it, such as controlling traffic and data communication, identifying the session, access to restricted access parts, remember the elements that make up an order, perform the purchase process of an order, make a registration or participation in an event, use security elements during navigation, store content for the broadcast videos or sound or share content through social networks.
    • Personalization cookies: those that allow the user to access the service with some predefined general characteristics based on a series of criteria in the user's terminal, such as the language, the type of browser through which the user accesses the service, the regional configuration from where you access the service, etc.
    • Analytical cookies: those that allow the person responsible for them to monitor and analyse the behaviour of the users of the websites to which they are linked. The information collected through this type of cookies is used in the measurement of the activity of the websites, applications or platforms, and for the elaboration of navigation profiles of the users of said sites, applications and platforms, in order to introduce improvements in the analysis of the data of use made by the users of the service.

Cookies used on our website

The CBMSO website uses Google Analytics. Google Analytics is a simple and easy to use tool that helps website owners to measure how users interact with the content of the site. You can consult more information about the cookies used by Google Analitycs in this link.

Acceptance of the Cookies Policy

The CBMSO assumes that you accept the use of cookies if you continue browsing, considering that it is a conscious and positive action from which the user's consent is inferred. In this regard, you are previously informed that such behaviour will be interpreted that you accept the installation and use of cookies.

Knowing this information, it is possible to carry out the following actions:

  • Accept cookies: if the user presses the acceptance button, this warning will not be displayed again when accessing any page of the portal.
  • Review the cookies policy: the user can access to this page in which the use of cookies is detailed, as well as links to modify the browser settings.

How to modify the configuration of cookies

Using your browser you can restrict, block or delete cookies from any web page. In each browser the process is different, here we show you links on this particular of the most used browsers: