Mitochondrial biology in immune modulation

Research summary:

Mitochondria are known as the powerhouses of the cell, and yet their functions are much more complex. In addition to energy conversion, they are also involved in heat production, calcium signaling and storage, signaling through and detoxification of reactive oxygen species (ROS), synthesis of heme and other molecules, and regulation of cell death. Emerging functions of the mitochondria in disease include their role as damage-associated molecular patterns (DAMPs), which are important for innate and adaptive immune activation. In this context, release of mitochondrial components of bacterial origin, such as mitochondrial DNA, may activate several pathways that lead to the secretion of pro-inflammatory cytokines (Fig. 1), a phenomenon called sterile inflammation. Among them, the most studied pathway is the NLRP3 inflammasome, a cytosolic multiprotein complex that senses the presence oxidized mitochondrial DNA (mtDNA) in the cytosol (and thus acts as a sensor for mitochondrial dysfunction) and in turn activates caspase-1, an enzyme that cleaves other proteins, including the precursors of the inflammatory cytokines interleukin 1β and interleukin 18, as well as the pyroptosis inducer Gasdermin D, into active mature peptides. The NLRP3 inflammasome thus plays a central role in immunity as an inflammatory response initiator and is associated with a broad range of degenerative diseases associated with aging, including Alzheimer's, asthma, gout, ischemia/reperfusion, hypertension, diabetes or psoriasis.

Mitochondria are also being recognized as important nutrient-sensing organelles which functionally adapt in a nutrient-dependent manner. Nutrient restriction leads to activation of several pathways and to higher levels of intracellular nicotinamide adenine dinucleotide (NAD+), which activates sirtuin proteins, a group of enzymes possessing deacetylase activity that require NAD+ as a cosubstrate to function, and thus are considered metabolic and energy sensors.

Our research has shown that nutrient restriction blunted the activation of the inflammasome in  macrophages, and that this effect depended partially on the activation of the NAD+-dependent mitochondrial deacetylase enzyme Sirtuin 3 (SIRT3). The mechanism of action of SIRT3 is very intriguing: by modulating the acetylation status and activity of mitochondrial superoxide dismutase (SOD2), and thus mitochondrial ROS levels, it finely controls the extrusion of oxidized mtDNA into the cytosol, where it acts as an NLRP3 agonist (Fig. 2). In addition, we have found that nicotinamide riboside (NR), an intermediate precursor of NAD+ synthesis in the salvage pathway, functions as a fasting mimetic and blunts monocyte/macrophage IL-1β production and reduces T helper 1 (Th1) and 17 (Th17) cell activation. Interestingly, a mouse model of psoriasis, a chronic inflammatory skin disease linked to hyperactivation of Th17 cells,  displayed downregulation of the SIRT3 gene and decreased mitochondrial SOD2 activity, and thus can be considered a functional SIRT3 knockdown. The downregulation of this gene might be involved in the hyperinflammatory phenotype observed in some of its tissues. It is also known that NLRP3 inflammasome activation and IL-1β signaling are associated with psoriasis progression. Given our findings of the role of SIRT3 in immune-modulation, a question arising is whether NAD+ precursors could mimic caloric restriction effects and ameliorate an inflammatory disease. Psoriasis, a prototypic Th17 disease, appears to be an appealing candidate disease to test this hypothesis. 

The main lines of research of our group are the following:

  1. Expand our studies into the fundamental role of mtDNA in innate inflammatory pathways regulated by the mitochondrial protein SIRT3, the main deacetylase in the mitochondria.
  2. Evaluate whether NAD+ precursors blunt inflammation in a psoriatic mouse model via augmentation of mitochondrial function, fidelity and quality control programs.
Image

Fig.1: Release of mtDNA during mitochondrial dysfunction triggers at least three distinct pathways linked to inflammation: the endosomal TLR9 pathway, the NLRP3 inflammasome and the cGAS-STING pathway.

Image

Fig. 2: Mechanism of action of SIRT3 in immune modulation: nutrient restriction increases the levels of NAD+, which activates the mitochondrial deacetylase SIRT3, that in turn deacetylates and activates SOD2. SOD2 decreases mitochondrial levels of superoxide, and therefore protects  mitochondrial DNA from oxidation and release to the cytosol, where it might act as an agonist of NLRP3.

Image


* For external calls please dial 34 91196 followed by the extension number
Last nameNameLaboratoryExt.*e-mailProfessional category
Traba DomínguezJavier3214651jtraba(at)cbm.csic.esInvestigador

Relevant publications:

  • Traba J., Waldmann T.A., Anton O.M. (2020) Analysis of human Natural Killer Cell metabolism. J Vis Exp (160), doi: 10.3791/61466.
  • Anton O.M., Peterson M.E., Hollander M.J., Dorward D.W., Arora G., Traba J., Rajagopalan S., Snapp E., Garcia K.C., Waldmann T.A., Long E.O. (2020) Trans-endocytosis of intact IL-15Rα-IL-15 complex from presenting cells into NK cells favors signaling for proliferation. Proc Natl Acad Sci USA 117, 522-531.
  • Akkaya M.1, Traba J.1, Roesler A.S., Miozzo P., Akkaya B., Theall B.P., Sohn H., Pena M., Smelkinson M., Kabat J., Dahlstrom E., Dorward D., Sack M.N., Pierce S.K. (2018) Second signals rescue B cells from activation-induced mitochondrial dysfunction and death. Nat Immunology 19, 871-884. (1: Equal contribution).
  • Traba J., Geiger S.S., Kwarteng-Siaw M., Han K., Ra O.H., Siegel R.M, Gius D., Sack M.N. (2017) Prolonged fasting suppresses mitochondrial NLRP3 inflammasome assembly and execution via SIRT3 mediated activation of SOD2. J Biol Chem 292, 12153-12164.
  • Traba J., Sack M.N. (2017) The role of caloric load and mitochondrial homeostasis in the regulation of the NLRP3 inflammasome. Cell Mol Life Sci 74, 1777-1791.
  • Traba J., Kwarteng-Siaw M., Okoli T.C, Li J., Huffstutler R.D., Bray A., Waclawiw M.A., Han K., Pelletier M., Sauve A.A., Siegel R.M, Sack M.N. (2015) Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects. J Clin Invest 125, 4592-4600.  
  • Rueda C.1, Traba J.1, Amigo I.1, Llorente-Folch I., Gonzalez-Sanchez P., Pardo B., Esteban J.A., del Arco A., and Satrustegui 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. (1: Equal contribution).
  • Webster B.R., Scott I., Traba J., Han K., and Sack M.N. (2014) Caloric Restriction, Acetylation and the Regulation of Autophagy and Mitophagy. Biochim Biophys Acta 1841, 525-534.
  • Traba J., del Arco A., Duchen M.R., Szabadkai G. and Satrústegui J. (2012) SCaMC-1 promotes cancer cell survival by desensitizing mitochondrial permeability transition via ATP/ADP-mediated matrix Ca2+ buffering. Cell Death Differ 19, 650-660.
  • Traba J.1, Satrústegui J. and del Arco A. (2011) Adenine nucleotide transporters in organelles: novel genes and functions. Cell Mol Life Sci 68, 1183–1206. (1: Corresponding author).

Funding:

  • Ministerio de Ciencia e Innovación (MICINN) :
    • Ramón y Cajal 2018 (RYC2018-026050-I)
    • Programa Estatal de I+D+i Orientada a los Retos de la Sociedad (PID2019-105665RA-I00)

NOTE! This site uses cookies and similar technologies.

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

I understand

COOKIES POLICY

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: