Mitochondrial biology in immune modulation

We offer a position for a student to carry out his TFM working on the role of mitochondrial biology in immune regulation.

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, detoxification of ROS or regulation of cell death. Emerging functions of the mitochondria in disease include their role as damage-associated molecular patterns (DAMPs), which are important for immune activation. In this context, release of mitochondrial components, such as mitochondrial DNA, may activate several pathways that lead to the secretion of pro-inflammatory cytokines. Among them, the most studied pathway is the NLRP3 inflammasome, a cytosolic complex that senses the presence oxidized mitochondrial DNA 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, into active mature peptides.

Our research has shown that nutrient restriction blunts the activation of the inflammasome in macrophages, and that this effect depends partially on the activation of the NAD⁺-dependent mitochondrial deacetylase enzyme Sirtuin 3 (SIRT3). Nutrient restriction leads to higher levels of intracellular NAD⁺, which activates sirtuin proteins like SIRT3 that require NAD⁺ as a cosubstrate to function. 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.

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

- 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.

-Evaluate whether NAD⁺ precursors blunt inflammation in a psoriatic mouse model via augmentation of mitochondrial function, fidelity and quality control programs.

References:

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).