Mitochondria Contribute to LPS-induced MAPK Activation Via Uncoupling Protein UCP2 in Macrophages

Overview

Journal Biochem J

Specialty Biochemistry

Date 2006 Nov 1

PMID 17073824

Citations 81

Authors

Yalin Emre

Corinne Hurtaud

Tobias Nubel

Francois Criscuolo

Daniel Ricquier

Anne-Marie Cassard-Doulcier

Affiliations

Soon will be listed here.

Abstract

The mitochondrion is a major organelle contributing to energy metabolism but also a main site of ROS (reactive oxygen species) production. LPS (lipopolysaccharide)-induced ROS signalling is a critical event in macrophage activation. In the present paper we report that part of LPS-mediated ROS signalling comes from mitochondria inside a signal amplification loop that enhances MAPK (mitogen-activated protein kinase) activation. More precisely, we have identified the inner mitochondrial membrane UCP2 (uncoupling protein 2) as a physiological brake on ROS signalling. Stimulation of murine bone marrow-derived macrophages by LPS quickly down-regulated UCP2 through the JNK (c-Jun N-terminal kinase) and p38 pathways. UCP2 down-regulation was shown to be necessary to increase mitochondrial ROS production in order to potentiate MAPK activation. Consistent with this, UCP2-deficient macrophages exhibit an enhanced inflammatory state characterized by increased nitric oxide production and elevated migration ability. Additionally, we found that the absence of UCP2 renders macrophages more resistant to nitric oxide-induced apoptosis.

Citing Articles

Renin-angiotensin system inhibitors positively impact on multiple aging regulatory pathways: Could they be used to protect against human aging?.

de Cavanagh E, Inserra F, Ferder L Physiol Rep. 2024; 12(12):e16094.

PMID: 38924381 PMC: 11200104. DOI: 10.14814/phy2.16094.

Cellular heterogeneity and plasticity during NAFLD progression.

Park H, Choi J, Kim H, Yang D, An T, Lee E Front Mol Biosci. 2023; 10:1221669.

PMID: 37635938 PMC: 10450943. DOI: 10.3389/fmolb.2023.1221669.

Fatty Acid-Binding Protein 4 is Essential for the Inflammatory and Metabolic Response of Microglia to Lipopolysaccharide.

Kagawa Y, Low Y, Pyun J, Doglione U, Short J, Pan Y J Neuroimmune Pharmacol. 2023; 18(3):448-461.

PMID: 37555918 PMC: 10577108. DOI: 10.1007/s11481-023-10079-6.

The protective effect of the mitochondrial-derived peptide MOTS-c on LPS-induced septic cardiomyopathy.

Wu J, Xiao D, Yu K, Shalamu K, He B, Zhang M Acta Biochim Biophys Sin (Shanghai). 2023; 55(2):285-294.

PMID: 36786072 PMC: 10157545. DOI: 10.3724/abbs.2023006.

UCP2 as a Cancer Target through Energy Metabolism and Oxidative Stress Control.

Luby A, Alves-Guerra M Int J Mol Sci. 2022; 23(23).

PMID: 36499405 PMC: 9735768. DOI: 10.3390/ijms232315077.

References

Li Q, Pedersen C, Day B, Patel M . Dependence of excitotoxic neurodegeneration on mitochondrial aconitase inactivation. J Neurochem. 2001; 78(4):746-55. DOI: 10.1046/j.1471-4159.2001.00457.x. View

Horvath T, Diano S, Miyamoto S, Barry S, Gatti S, Alberati D . Uncoupling proteins-2 and 3 influence obesity and inflammation in transgenic mice. Int J Obes Relat Metab Disord. 2003; 27(4):433-42. DOI: 10.1038/sj.ijo.0802257. View

Forman H, Torres M . Redox signaling in macrophages. Mol Aspects Med. 2001; 22(4-5):189-216. DOI: 10.1016/s0098-2997(01)00010-3. View

Medzhitov R . Toll-like receptors and innate immunity. Nat Rev Immunol. 2002; 1(2):135-45. DOI: 10.1038/35100529. View

Gardner P . Aconitase: sensitive target and measure of superoxide. Methods Enzymol. 2002; 349:9-23. DOI: 10.1016/s0076-6879(02)49317-2. View

Kizaki T, Suzuki K, Hitomi Y, Taniguchi N, Saitoh D, Watanabe K . Uncoupling protein 2 plays an important role in nitric oxide production of lipopolysaccharide-stimulated macrophages. Proc Natl Acad Sci U S A. 2002; 99(14):9392-7. PMC: 123151. DOI: 10.1073/pnas.142206299. View

Bhat N, Feinstein D, Shen Q, Bhat A . p38 MAPK-mediated transcriptional activation of inducible nitric-oxide synthase in glial cells. Roles of nuclear factors, nuclear factor kappa B, cAMP response element-binding protein, CCAAT/enhancer-binding protein-beta, and activating.... J Biol Chem. 2002; 277(33):29584-92. DOI: 10.1074/jbc.M204994200. View

Hu X, Herrero C, Li W, Antoniv T, Falck-Pedersen E, Koch A . Sensitization of IFN-gamma Jak-STAT signaling during macrophage activation. Nat Immunol. 2002; 3(9):859-66. DOI: 10.1038/ni828. View

Mattiasson G, Shamloo M, Gido G, Mathi K, Tomasevic G, Yi S . Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med. 2003; 9(8):1062-8. DOI: 10.1038/nm903. View

10.

Kim S, Kim J, Sharma R . Inhibition of p38 and ERK MAP kinases blocks endotoxin-induced nitric oxide production and differentially modulates cytokine expression. Pharmacol Res. 2004; 49(5):433-9. DOI: 10.1016/j.phrs.2003.11.004. View

11.

Lambeth J . NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol. 2004; 4(3):181-9. DOI: 10.1038/nri1312. View

12.

Ueda T, Watanabe-Fukunaga R, Fukuyama H, Nagata S, Fukunaga R . Mnk2 and Mnk1 are essential for constitutive and inducible phosphorylation of eukaryotic initiation factor 4E but not for cell growth or development. Mol Cell Biol. 2004; 24(15):6539-49. PMC: 444855. DOI: 10.1128/MCB.24.15.6539-6549.2004. View

13.

Engelhardt B, Wolburg H . Mini-review: Transendothelial migration of leukocytes: through the front door or around the side of the house?. Eur J Immunol. 2004; 34(11):2955-63. DOI: 10.1002/eji.200425327. View

14.

Kariko K, Weissman D, Welsh F . Inhibition of toll-like receptor and cytokine signaling--a unifying theme in ischemic tolerance. J Cereb Blood Flow Metab. 2004; 24(11):1288-304. DOI: 10.1097/01.WCB.0000145666.68576.71. View

15.

Woo C, Lim J, Kim J . Lipopolysaccharide induces matrix metalloproteinase-9 expression via a mitochondrial reactive oxygen species-p38 kinase-activator protein-1 pathway in Raw 264.7 cells. J Immunol. 2004; 173(11):6973-80. DOI: 10.4049/jimmunol.173.11.6973. View

16.

Bai Y, Onuma H, Bai X, Medvedev A, Misukonis M, Weinberg J . Persistent nuclear factor-kappa B activation in Ucp2-/- mice leads to enhanced nitric oxide and inflammatory cytokine production. J Biol Chem. 2005; 280(19):19062-9. PMC: 1382174. DOI: 10.1074/jbc.M500566200. View

17.

Criscuolo F, Gonzalez-Barroso M, Le Maho Y, Ricquier D, Bouillaud F . Avian uncoupling protein expressed in yeast mitochondria prevents endogenous free radical damage. Proc Biol Sci. 2005; 272(1565):803-10. PMC: 1599860. DOI: 10.1098/rspb.2004.3044. View

18.

Cakir Y, Ballinger S . Reactive species-mediated regulation of cell signaling and the cell cycle: the role of MAPK. Antioxid Redox Signal. 2005; 7(5-6):726-40. DOI: 10.1089/ars.2005.7.726. View

19.

Rousset S, Emre Y, Join-Lambert O, Hurtaud C, Ricquier D, Cassard-Doulcier A . The uncoupling protein 2 modulates the cytokine balance in innate immunity. Cytokine. 2006; 35(3-4):135-42. DOI: 10.1016/j.cyto.2006.07.012. View

20.

Weinstein S, Finn A, Dave S, Meng F, Lowell C, Sanghera J . Phosphatidylinositol 3-kinase and mTOR mediate lipopolysaccharide-stimulated nitric oxide production in macrophages via interferon-beta. J Leukoc Biol. 2000; 67(3):405-14. DOI: 10.1002/jlb.67.3.405. View