Skip to main content
SpringerLink
Log in

Mitochondrial metabolism, reactive oxygen species, and macrophage function-fishing for insights

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Metabolism and defense mechanisms that protect against pathogens are two fundamental requirements for the survival of multicellular organisms. Research into metabolic disease has revealed these core mechanisms are highly co-dependent. This emerging field of research, termed immunometabolism, focuses on understanding how metabolism influences immunological processes and vice versa. It is now accepted that obesity influences the immune system and that obesity-driven inflammation contributes to many diseases including type 2 diabetes, cardiovascular disease and Alzheimer’s disease. The immune response requires the reallocation of nutrients within immune cells to different metabolic pathways to satisfy energy demands and the production of necessary macromolecules. One aspect of immunometabolic research is understanding how these metabolic changes help regulate specific immune cell functions. It is hoped that further understanding of the pathways involved in managing this immunological-metabolic interface will reveal new ways to treat metabolic disease. Given their growing status as principle drivers of obesity-associated inflammation, monocytes/macrophages have received much attention when studying the consequences of inflammation within adipose tissue. Less is known regarding how metabolic changes within macrophages (metabolic reprogramming) influence their immune cell function. In this review, we focus on our current understanding of how monocytes/macrophages alter their intracellular metabolism during the immune response and how these changes dictate specific effector functions. In particular, the immunomodulatory functions of mitochondrial metabolism and mitochondrial reactive oxygen species. We also highlight how the attributes of the zebrafish model system can be exploited to reveal new mechanistic insights into immunometabolic processes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Pearce EL, Pearce EJ (2013) Metabolic pathways in immune cell activation and quiescence. Immunity 38:633–643

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. Biswas SK, Mantovani A (2012) Orchestration of metabolism by macrophages. Cell Metab 15:432–437

    Article  PubMed  CAS  Google Scholar 

  3. Mathis D, Shoelson SE (2011) Immunometabolism: an emerging frontier. Nat Rev Immunol 11:81

    Article  PubMed  CAS  Google Scholar 

  4. Schipper HS, Prakken B, Kalkhoven E, Boes M (2012) Adipose tissue-resident immune cells: key players in immunometabolism. Trends Endocrinol Metabolism TEM 23:407–415

    Article  CAS  Google Scholar 

  5. Ferrante AW Jr (2007) Obesity-induced inflammation: a metabolic dialogue in the language of inflammation. J Intern Med 262:408–414

    Article  PubMed  CAS  Google Scholar 

  6. Schipper HS, Prakken B, Kalkhoven E, Boes M (2012) Adipose tissue-resident immune cells: key players in immunometabolism. Trends Endocrinol Metab 23(407–415):7

    Google Scholar 

  7. Shapiro H, Lutaty A, Ariel A (2011) Macrophages, meta-inflammation, and immuno-metabolism. Sci World J 11:2509–2529

    Article  Google Scholar 

  8. Zick Y (2005) Ser/Thr phosphorylation of IRS proteins: a molecular basis for insulin resistance. Sci STKE 2005:pe4

    PubMed  Google Scholar 

  9. Paz K, Hemi R, LeRoith D, Karasik A, Elhanany E, Kanety H, Zick Y (1997) A molecular basis for insulin resistance. Elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation. J Biol Chem 272:29911–29918

    Article  PubMed  CAS  Google Scholar 

  10. Mothe I, Van Obberghen E (1996) Phosphorylation of insulin receptor substrate-1 on multiple serine residues, 612, 632, 662, and 731, modulates insulin action. J Biol Chem 271:11222–11227

    Article  PubMed  CAS  Google Scholar 

  11. Pederson TM, Kramer DL, Rondinone CM (2001) Serine/threonine phosphorylation of IRS-1 triggers its degradation: possible regulation by tyrosine phosphorylation. Diabetes 50:24–31

    Article  PubMed  CAS  Google Scholar 

  12. Palsson-McDermott EM, O’Neill LAJ (2013) The Warburg effect then and now: from cancer to inflammatory diseases. Bioessays 35:965–973

    Article  PubMed  CAS  Google Scholar 

  13. Warburg O (1923) Metabolism of tumours. Biochem Z 142:317–333

    CAS  Google Scholar 

  14. Biswas S, Lunec J, Bartlett K (2012) Non-glucose metabolism in cancer cells—is it all in the fat? Cancer Metastasis Rev 31:689–698

    Article  PubMed  CAS  Google Scholar 

  15. Mashima T, Seimiya H, Tsuruo T (2009) De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy. Br J Cancer 100:1369–1372

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Liu Y (2006) Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer. Prostate Cancer Prostatic Dis 9:230–234

    Article  PubMed  CAS  Google Scholar 

  17. Murray PJ, Wynn TA (2011) Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11:723–737

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Shi C, Pamer EG (2011) Monocyte recruitment during infection and inflammation. Nat Rev Immunol 11:762–774

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Biswas SK, Mantovani A (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11:889–896

    Article  PubMed  CAS  Google Scholar 

  20. Martinez FO, Gordon S, Locati M, Mantovani A (2006) Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol 177:7303–7311

    Article  PubMed  CAS  Google Scholar 

  21. Drapier JC, Hibbs JB Jr (1988) Differentiation of murine macrophages to express nonspecific cytotoxicity for tumor cells results in L-arginine-dependent inhibition of mitochondrial iron-sulfur enzymes in the macrophage effector cells. J Immunol (Baltimore, Md: 1950) 140:2829–2838

    CAS  Google Scholar 

  22. Schnyder J, Baggiolini M (1978) Role of phagocytosis in the activation of macrophages. J Exp Med 148:1449–1457

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. Aktan F (2004) iNOS-mediated nitric oxide production and its regulation. Life Sci 75:639–653

    Article  PubMed  CAS  Google Scholar 

  24. Haschemi A, Kosma P, Gille L, Evans CR, Burant CF, Starkl P, Knapp B, Haas R, Schmid JA, Jandl C et al (2012) The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab 15:813–826

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Imtiyaz HZ, Simon MC (2010) Hypoxia-inducible factors as essential regulators of inflammation. Curr Top Microbiol Immunol 345:105–120

    PubMed  CAS  PubMed Central  Google Scholar 

  26. Glass CK, Ogawa S (2006) Combinatorial roles of nuclear receptors in inflammation and immunity. Nat Rev Immunol 6:44–55

    Article  PubMed  CAS  Google Scholar 

  27. Nagy L, Szanto A, Szatmari I, Szeles L (2012) Nuclear hormone receptors enable macrophages and dendritic cells to sense their lipid environment and shape their immune response. Physiol Rev 92:739–789

    Article  PubMed  CAS  Google Scholar 

  28. Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Red Eagle A, Vats D, Brombacher F, Ferrante AW et al (2007) Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 447:1116–1120

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A, Vats D, Morel CR, Goforth MH, Subramanian V, Mukundan L, Ferrante AW, Chawla A (2008) Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab 7:496–507

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Kang K, Reilly SM, Karabacak V, Gangl MR, Fitzgerald K, Hatano B, Lee CH (2008) Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity. Cell Metab 7:485–495

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Vats D, Mukundan L, Odegaard JI, Zhang L, Smith KL, Morel CR, Wagner RA, Greaves DR, Murray PJ, Chawla A (2006) Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab 4:13–24

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. West AP, Shadel GS, Ghosh S (2011) Mitochondria in innate immune responses. Nat Rev Immunol 11:389–402

    Article  PubMed  CAS  Google Scholar 

  33. Li X, Fang P, Mai J, Choi ET, Wang H, Yang XF (2013) Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. J Hematol Oncol 6:19

    Article  PubMed  PubMed Central  Google Scholar 

  34. Sena LA, Chandel NS (2012) Physiological roles of mitochondrial reactive oxygen species. Mol Cell 48:158–167

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Brand MD (2010) The sites and topology of mitochondrial superoxide production. Exp Gerontol 45:466–472

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, Walsh MC, Choi Y, Shadel GS, Ghosh S (2011) TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 472:476–480

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Hall CJ, Boyle RH, Astin JW, Flores MV, Oehlers SH, Sanderson LE, Ellett F, Lieschke GJ, Crosier KE, Crosier PS (2013) Immunoresponsive gene 1 augments bactericidal activity of macrophage-lineage cells by regulating beta-oxidation-dependent mitochondrial ROS production. Cell Metab 18:265–278

    Article  PubMed  CAS  Google Scholar 

  38. Sonoda J, Laganiere J, Mehl IR, Barish GD, Chong LW, Li X, Scheffler IE, Mock DC, Bataille AR, Robert F et al (2007) Nuclear receptor ERR alpha and coactivator PGC-1 beta are effectors of IFN-gamma-induced host defense. Genes Dev 21:1909–1920

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Roca FJ, Ramakrishnan L (2013) TNF dually mediates resistance and susceptibility to mycobacteria via mitochondrial reactive oxygen species. Cell 153:521–534

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Schroder K, Tschopp J (2010) The inflammasomes. Cell 140:821–832

    Article  PubMed  CAS  Google Scholar 

  41. Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469:221–225

    Article  PubMed  CAS  Google Scholar 

  42. Kamata H, Honda S-I, Maeda S, Chang L, Hirata H, Karin M (2005) Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120:649–661

    Article  PubMed  CAS  Google Scholar 

  43. Bulua AC, Simon A, Maddipati R, Pelletier M, Park H, Kim K-Y, Sack MN, Kastner DL, Siegel RM (2011) Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med 208:519–533

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Woo CH, Lim JH, Kim JH (2004) 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 173:6973–6980

    Article  PubMed  CAS  Google Scholar 

  45. Shipley JM, Wesselschmidt RL, Kobayashi DK, Ley TJ, Shapiro SD (1996) Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proc Natl Acad Sci U S A 93:3942–3946

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  46. Henry KM, Loynes CA, Whyte MKB, Renshaw SA (2013) Zebrafish as a model for the study of neutrophil biology. J Leukoc Biol 94:633–642

    Article  PubMed  CAS  Google Scholar 

  47. Renshaw SA, Trede NS (2012) A model 450 million years in the making: zebrafish and vertebrate immunity. Dis Models Mech 5:38–47

    Article  CAS  Google Scholar 

  48. Herbomel P, Thisse B, Thisse C (1999) Ontogeny and behaviour of early macrophages in the zebrafish embryo. Development 126:3735–3745

    PubMed  CAS  Google Scholar 

  49. Lieschke GJ, Oates AC, Crowhurst MO, Ward AC, Layton JE (2001) Morphologic and functional characterization of granulocytes and macrophages in embryonic and adult zebrafish. Blood 98:3087–3096

    Article  PubMed  CAS  Google Scholar 

  50. Bertrand JY, Kim AD, Violette EP, Stachura DL, Cisson JL, Traver D (2007) Definitive hematopoiesis initiates through a committed erythromyeloid progenitor in the zebrafish embryo. Development 134:4147–4156

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  51. Herbomel P, Thisse B, Thisse C (2001) Zebrafish early macrophages colonize cephalic mesenchyme and developing brain, retina, and epidermis through a M-CSF receptor-dependent invasive process. Dev Biol 238:274–288

    Article  PubMed  CAS  Google Scholar 

  52. Hall C, Flores MV, Storm T, Crosier K, Crosier P (2007) The zebrafish lysozyme C promoter drives myeloid-specific expression in transgenic fish. BMC Dev Biol 7:42

    Article  PubMed  PubMed Central  Google Scholar 

  53. Ellett F, Pase L, Hayman JW, Andrianopoulos A, Lieschke GJ (2011) mpeg1 promoter transgenes direct macrophage-lineage expression in zebrafish. Blood 117:e49–e56

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  54. Renshaw SA, Loynes CA, Trushell DM, Elworthy S, Ingham PW, Whyte MK (2006) A transgenic zebrafish model of neutrophilic inflammation. Blood 108:3976–3978

    Article  PubMed  CAS  Google Scholar 

  55. Mathias JR, Perrin BJ, Liu TX, Kanki J, Look AT, Huttenlocher A (2006) Resolution of inflammation by retrograde chemotaxis of neutrophils in transgenic zebrafish. J Leukoc Biol 80:1281–1288

    Article  PubMed  CAS  Google Scholar 

  56. Gray C, Loynes CA, Whyte MK, Crossman DC, Renshaw SA, Chico TJ (2011) Simultaneous intravital imaging of macrophage and neutrophil behaviour during inflammation using a novel transgenic zebrafish. Thromb Haemost 105:811–819

    Article  PubMed  CAS  Google Scholar 

  57. Hall C, Flores MV, Chien A, Davidson A, Crosier K, Crosier P (2009) Transgenic zebrafish reporter lines reveal conserved Toll-like receptor signaling potential in embryonic myeloid leukocytes and adult immune cell lineages. J Leukoc Biol 85:751–765

    Article  PubMed  CAS  Google Scholar 

  58. Niethammer P, Grabher C, Look AT, Mitchison TJ (2009) A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature 459:996–999

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  59. Hall CJ, Flores MV, Oehlers SH, Sanderson LE, Lam EY, Crosier KE, Crosier PS (2012) Infection-responsive expansion of the hematopoietic stem and progenitor cell compartment in zebrafish is dependent upon inducible nitric oxide. Cell Stem Cell 10:198–209

    Article  PubMed  CAS  Google Scholar 

  60. Ellis JM, Frahm JL, Li LO, Coleman RA (2010) Acyl-coenzyme A synthetases in metabolic control. Curr Opin Lipidol 21:212–217

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  61. Thumser AE, Storch J (2007) Characterization of a BODIPY-labeled fluorescent fatty acid analogue. Binding to fatty acid-binding proteins, intracellular localization, and metabolism. Mol Cell Biochem 299:67–73

    Article  PubMed  CAS  Google Scholar 

  62. Semova I, Carten JD, Stombaugh J, Mackey LC, Knight R, Farber SA, Rawls JF (2012) Microbiota regulate intestinal absorption and metabolism of fatty acids in the zebrafish. Cell Host Microbe 12:277–288

    Article  PubMed  CAS  Google Scholar 

  63. Walters JW, Anderson JL, Bittman R, Pack M, Farber SA (2012) Visualization of lipid metabolism in the zebrafish intestine reveals a relationship between NPC1L1-mediated cholesterol uptake and dietary fatty acid. Chem Biol 19:913–925

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  64. Carten JD, Bradford MK, Farber SA (2011) Visualizing digestive organ morphology and function using differential fatty acid metabolism in live zebrafish. Dev Biol 360:276–285

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  65. Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, Romero IL, Carey MS, Mills GB, Hotamisligil GS et al (2011) Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 17:1498–1503

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  66. Davis JM, Ramakrishnan L (2009) The role of the granuloma in expansion and dissemination of early tuberculous infection. Cell 136:37–49

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  67. Volkman HE, Pozos TC, Zheng J, Davis JM, Rawls JF, Ramakrishnan L (2010) Tuberculous granuloma induction via interaction of a bacterial secreted protein with host epithelium. Science 327:466–469

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  68. Yang CT, Cambier CJ, Davis JM, Hall CJ, Crosier PS, Ramakrishnan L (2012) Neutrophils exert protection in the early tuberculous granuloma by oxidative killing of mycobacteria phagocytosed from infected macrophages. Cell Host Microbe 12:301–312

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  69. Cambier CJ, Takaki KK, Larson RP, Hernandez RE, Tobin DM, Urdahl KB, Cosma CL, Ramakrishnan L (2014) Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids. Nature 505:218–222

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  70. Chen B, Zhang D, Pollard JW (2003) Progesterone regulation of the mammalian ortholog of methylcitrate dehydratase (immune response gene 1) in the uterine epithelium during implantation through the protein kinase C pathway. Mol Endocrinol 17:2340–2354

    Article  PubMed  CAS  Google Scholar 

  71. Hall CJ, Boyle RH, Sun X, Wicker SM, Misa JP, Krissansen GW, Print CG, Crosier KE, Crosier PS (2014) Epidermal cells help coordinate leukocyte migration during inflammation through fatty acid-fuelled matrix metalloproteinase production. Nat Commun 5:3880

    Article  PubMed  Google Scholar 

  72. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2007) Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 297:842–857

    Article  PubMed  CAS  Google Scholar 

  73. Cocheme HM, Quin C, McQuaker SJ, Cabreiro F, Logan A, Prime TA, Abakumova I, Patel JV, Fearnley IM, James AM et al (2011) Measurement of H2O2 within living Drosophila during aging using a ratiometric mass spectrometry probe targeted to the mitochondrial matrix. Cell Metab 13:340–350

    Article  PubMed  CAS  Google Scholar 

  74. Murphy MP, Holmgren A, Larsson N-G, Halliwell B, Chang CJ, Kalyanaraman B, Rhee SG, Thornalley PJ, Partridge L, Gems D et al (2011) Unraveling the biological roles of reactive oxygen species. Cell Metab 13:361–366

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

C.J.H, K.E.C, and P.S.C are supported by a grant awarded to PC from the Ministry of Business, Innovation and Employment, New Zealand. L.E.S. is supported by a University of Auckland Doctoral Scholarship.

Conflict of interest

The authors declare that they have no conflict of interests.

Author information

Authors and Affiliations

  1. Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand

    Christopher J. Hall, Leslie E. Sanderson, Kathryn E. Crosier & Philip S. Crosier

Authors
  1. Christopher J. Hall
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leslie E. Sanderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kathryn E. Crosier
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Philip S. Crosier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Philip S. Crosier.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hall, C.J., Sanderson, L.E., Crosier, K.E. et al. Mitochondrial metabolism, reactive oxygen species, and macrophage function-fishing for insights. J Mol Med 92, 1119–1128 (2014). https://doi.org/10.1007/s00109-014-1186-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-014-1186-6

Keywords

Search

Navigation