[en] Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme of the tricarboxylic acid (TCA) cycle. Here we show that the deglycase DJ-1 (encoded by PARK7, a key familial Parkinson's disease gene) is a pacemaker regulating PDH activity in CD4(+) regulatory T cells (T(reg) cells). DJ-1 binds to PDHE1-β (PDHB), inhibiting phosphorylation of PDHE1-α (PDHA), thus promoting PDH activity and oxidative phosphorylation (OXPHOS). Park7 (Dj-1) deletion impairs T(reg) survival starting in young mice and reduces T(reg) homeostatic proliferation and cellularity only in aged mice. This leads to increased severity in aged mice during the remission of experimental autoimmune encephalomyelitis (EAE). Dj-1 deletion also compromises differentiation of inducible T(reg) cells especially in aged mice, and the impairment occurs via regulation of PDHB. These findings provide unforeseen insight into the complicated regulatory machinery of the PDH complex. As T(reg) homeostasis is dysregulated in many complex diseases, the DJ-1-PDHB axis represents a potential target to maintain or re-establish T(reg) homeostasis.
Disciplines :
Neurologie
Auteur, co-auteur :
Danileviciute, Egle
Zeng, Ni
Capelle, Christophe M.
Paczia, Nicole
Gillespie, Mark A.
KURNIAWAN, Henry ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
Benzarti, Mohaned
Merz, Myriam P.
COOWAR, Djalil ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services
Fritah, Sabrina
Vogt Weisenhorn, Daniela Maria
GOMEZ GIRO, Gemma ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
GRUSDAT, Melanie ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Immunology and Genetics
BARON, Alexandre ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
Guerin, Coralie
Franchina, Davide G.
Léonard, Cathy
Domingues, Olivia
Delhalle, Sylvie
Wurst, Wolfgang
TURNER, Jonathan ; University of Luxembourg > Faculty of Science, Technology and Communication (FSTC)
SCHWAMBORN, Jens Christian ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
MEISER, Johannes ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
KRÜGER, Rejko ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
Ranish, Jeff
BRENNER, Dirk ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Immunology and Genetics
LINSTER, Carole ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Enzymology and Metabolism
Smeitink, J., van den Heuvel, L. & DiMauro, S. The genetics and pathology of oxidative phosphorylation. Nat. Rev. Genet. 2, 342–352 (2001). DOI: 10.1038/35072063
O’Neill, L. A., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553–565 (2016). DOI: 10.1038/nri.2016.70
Abou-Sleiman, P. M., Muqit, M. M. & Wood, N. W. Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nat. Rev. Neurosci. 7, 207–219 (2006). DOI: 10.1038/nrn1868
Mizuno, Y. et al. Deficiencies in complex I subunits of the respiratory chain in Parkinson’s disease. Biochem. Biophys. Res. Commun. 163, 1450–1455 (1989). DOI: 10.1016/0006-291X(89)91141-8
Schapira, A. H. et al. Mitochondrial complex I deficiency in Parkinson’s disease. J. Neurochem. 54, 823–827 (1990). DOI: 10.1111/j.1471-4159.1990.tb02325.x
González-Rodríguez, P. et al. Disruption of mitochondrial complex I induces progressive parkinsonism. Nature 599, 650–656 (2021). DOI: 10.1038/s41586-021-04059-0
Bonifati, V. et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 299, 256–259 (2003). DOI: 10.1126/science.1077209
Hayashi, T. et al. DJ-1 binds to mitochondrial complex I and maintains its activity. Biochem. Biophys. Res. Commun. 390, 667–672 (2009). DOI: 10.1016/j.bbrc.2009.10.025
Irrcher, I. et al. Loss of the Parkinson’s disease-linked gene DJ-1 perturbs mitochondrial dynamics. Hum. Mol. Genet. 19, 3734–3746 (2010). DOI: 10.1093/hmg/ddq288
Krebiehl, G. et al. Reduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson’s disease-associated protein DJ-1. PLoS ONE 5, e9367 (2010). DOI: 10.1371/journal.pone.0009367
Hao, L. Y., Giasson, B. I. & Bonini, N. M. DJ-1 is critical for mitochondrial function and rescues PINK1 loss of function. Proc. Natl Acad. Sci. USA 107, 9747–9752 (2010). DOI: 10.1073/pnas.0911175107
Burbulla, L. F. et al. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science 357, 1255–1261 (2017). DOI: 10.1126/science.aam9080
Ariga, H. et al. Neuroprotective function of DJ-1 in Parkinson’s disease. Oxid. Med. Cell. Longev. 2013, 683920 (2013). DOI: 10.1155/2013/683920
Pisetsky, D. S. The role of mitochondria in immune-mediated disease: the dangers of a split personality. Arthritis Res. Ther. 18, 169 (2016). DOI: 10.1186/s13075-016-1063-5
Mosley, R. L., Hutter-Saunders, J. A., Stone, D. K. & Gendelman, H. E. Inflammation and adaptive immunity in Parkinson’s disease. Cold Spring Harb. Perspect. Med. 2, a009381 (2012). DOI: 10.1101/cshperspect.a009381
Waak, J. et al. Regulation of astrocyte inflammatory responses by the Parkinson’s disease-associated gene DJ-1. FASEB J. 23, 2478–2489 (2009). DOI: 10.1096/fj.08-125153
Kim, J. H. et al. DJ-1 facilitates the interaction between STAT1 and its phosphatase, SHP-1, in brain microglia and astrocytes: a novel anti-inflammatory function of DJ-1. Neurobiol. Dis. 60, 1–10 (2013). DOI: 10.1016/j.nbd.2013.08.007
Amatullah, H. et al. DJ-1/PARK7 impairs bacterial clearance in sepsis. Am. J. Respir. Crit. Care Med. 195, 889–905 (2017). DOI: 10.1164/rccm.201604-0730OC
Liu, W. et al. Park7 interacts with p47phox to direct NADPH oxidase-dependent ROS production and protect against sepsis. Cell Res. 25, 691–706 (2015). DOI: 10.1038/cr.2015.63
Singh, Y. et al. Differential effect of DJ-1/PARK7 on development of natural and induced regulatory T cells. Sci. Rep. 5, 17723 (2015). DOI: 10.1038/srep17723
Sakaguchi, S., Miyara, M., Costantino, C. M. & Hafler, D. A. FOXP3+ regulatory T cells in the human immune system. Nat. Rev. Immunol. 10, 490–500 (2010). DOI: 10.1038/nri2785
Reeve, A., Simcox, E. & Turnbull, D. Ageing and Parkinson’s disease: why is advancing age the biggest risk factor? Ageing Res. Rev. 14, 19–30 (2014). DOI: 10.1016/j.arr.2014.01.004
He, F. et al. PLAU inferred from a correlation network is critical for suppressor function of regulatory T cells. Mol. Syst. Biol. 8, 624 (2012). DOI: 10.1038/msb.2012.56
Bras, J., Guerreiro, R. & Hardy, J. SnapShot: genetics of Parkinson’s disease. Cell 160, 570 (2015). DOI: 10.1016/j.cell.2015.01.019
Gillis, J. & Pavlidis, P. The role of indirect connections in gene networks in predicting function. Bioinformatics 27, 1860–1866 (2011). DOI: 10.1093/bioinformatics/btr288
Pham, T. T. et al. DJ-1-deficient mice show less TH-positive neurons in the ventral tegmental area and exhibit non-motoric behavioural impairments. Genes Brain Behav. 9, 305–317 (2010). DOI: 10.1111/j.1601-183X.2009.00559.x
Jagger, A., Shimojima, Y., Goronzy, J. J. & Weyand, C. M. Regulatory T cells and the immune aging process: a mini-review. Gerontology 60, 130–137 (2014). DOI: 10.1159/000355303
Zeng, N. et al. DJ-1 depletion prevents immunoaging in T-cell compartments. EMBO Rep. 23, e53302 (2022). DOI: 10.15252/embr.202153302
Kohm, A. P., Carpentier, P. A., Anger, H. A. & Miller, S. D. Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J. Immunol. 169, 4712–4716 (2002). DOI: 10.4049/jimmunol.169.9.4712
Mak, T. W. et al. Glutathione primes T cell metabolism for inflammation. Immunity 46, 675–689 (2017). DOI: 10.1016/j.immuni.2017.03.019
Gray, D. H. et al. Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood 108, 3777–3785 (2006). DOI: 10.1182/blood-2006-02-004531
Zemmour, D. et al. Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR. Nat. Immunol. 19, 291–301 (2018). DOI: 10.1038/s41590-018-0051-0
Xu, J. et al. The Parkinson’s disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis. Hum. Mol. Genet. 14, 1231–1241 (2005). DOI: 10.1093/hmg/ddi134
Holling, T. M., Schooten, E. & van Den Elsen, P. J. Function and regulation of MHC class II molecules in T-lymphocytes: of mice and men. Hum. Immunol. 65, 282–290 (2004). DOI: 10.1016/j.humimm.2004.01.005
van der Brug, M. P. et al. RNA binding activity of the recessive parkinsonism protein DJ-1 supports involvement in multiple cellular pathways. Proc. Natl Acad. Sci. USA 105, 10244–10249 (2008). DOI: 10.1073/pnas.0708518105
Weyand, C. M., Goronzy, J. & Fathman, C. G. Modulation of CD4 by antigenic activation. J. Immunol. 138, 1351–1354 (1987).
Vandenbon, A. et al. Immuno-Navigator, a batch-corrected coexpression database, reveals cell type-specific gene networks in the immune system. Proc. Natl Acad. Sci. USA 113, E2393–E2402 (2016). DOI: 10.1073/pnas.1604351113
Patel, M. S. & Roche, T. E. Molecular biology and biochemistry of pyruvate dehydrogenase complexes. FASEB J. 4, 3224–3233 (1990). DOI: 10.1096/fasebj.4.14.2227213
Desdin-Mico, G. et al. T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science 368, 1371–1376 (2020). DOI: 10.1126/science.aax0860
Wang, R. & Green, D. R. Metabolic checkpoints in activated T cells. Nat. Immunol. 13, 907–915 (2012).
Zhou, Z. H., McCarthy, D. B., O’Connor, C. M., Reed, L. J. & Stoops, J. K. The remarkable structural and functional organization of the eukaryotic pyruvate dehydrogenase complexes. Proc. Natl Acad. Sci. USA 98, 14802–14807 (2001). DOI: 10.1073/pnas.011597698
Zachar, Z. et al. Non-redox-active lipoate derivates disrupt cancer cell mitochondrial metabolism and are potent anticancer agents in vivo. J. Mol. Med. 89, 1137–1148 (2011). DOI: 10.1007/s00109-011-0785-8
Polansky, J. K. et al. DNA methylation controls Foxp3 gene expression. Eur. J. Immunol. 38, 1654–1663 (2008). DOI: 10.1002/eji.200838105
Benayoun, B. A., Pollina, E. A. & Brunet, A. Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat. Rev. Mol. Cell Biol. 16, 593–610 (2015). DOI: 10.1038/nrm4048
Gerriets, V. A. et al. Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J. Clin. Invest. 125, 194–207 (2015). DOI: 10.1172/JCI76012
Richard, A. J., Hang, H. & Stephens, J. M. Pyruvate dehydrogenase complex (PDC) subunits moonlight as interaction partners of phosphorylated STAT5 in adipocytes and adipose tissue. J. Biol. Chem. 292, 19733–19742 (2017). DOI: 10.1074/jbc.M117.811794
Patel, K. P., O’Brien, T. W., Subramony, S. H., Shuster, J. & Stacpoole, P. W. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol. Genet. Metab. 106, 385–394 (2012). DOI: 10.1016/j.ymgme.2012.03.017
Olahova, M. et al. Biallelic mutations in ATP5F1D, which encodes a subunit of ATP synthase, cause a metabolic disorder. Am. J. Hum. Genet. 102, 494–504 (2018). DOI: 10.1016/j.ajhg.2018.01.020
Probst-Kepper, M. et al. GARP: a key receptor controlling FOXP3 in human regulatory T cells. J. Cell. Mol. Med. 13, 3343–3357 (2009). DOI: 10.1111/j.1582-4934.2009.00782.x
Tyanova, S. et al. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat. Methods 13, 731–740 (2016). DOI: 10.1038/nmeth.3901
