Pearce, E. L. & Pearce, E. J. Metabolic pathways in immune cell activation and quiescence. Immunity 38, 633–643 (2013).
Mills, E. L., Kelly, B. & O’Neill, L. A. J. Mitochondria are the powerhouses of immunity. Nat. Immunol. 18, 488–498 (2017).
Verdin, E. NAD+ in aging, metabolism, and neurodegeneration. Science 350, 1208–1213 (2015).
Katsyuba, E. & Auwerx, J. Modulating NAD+ metabolism, from bench to bedside. EMBO J. 36, 2670–2683 (2017).
Yang, Y. & Sauve, A. A. NAD+ metabolism: bioenergetics, signaling and manipulation for therapy. Biochim. Biophys. Acta 1864, 1787–1800 (2016).
Belenky, P., Bogan, K. L. & Brenner, C. NAD+ metabolism in health and disease. Trends Biochem. Sci. 32, 12–19 (2007).
Camacho-Pereira, J. et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 23, 1127–1139 (2016).
Imai, S. & Guarente, L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 24, 464–471 (2014).
Grahnert, A. et al. Review: NAD+: a modulator of immune functions. Innate Immun. 17, 212–233 (2011).
Yeung, A. W., Terentis, A. C., King, N. J. & Thomas, S. R. Role of indoleamine 2,3-dioxygenase in health and disease. Clin. Sci. 129, 601–672 (2015).
Munn, D. H. & Mellor, A. L. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 34, 137–143 (2013).
Opitz, C. A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011).
Mellor, A. L. et al. Prevention of T cell-driven complement activation and inflammation by tryptophan catabolism during pregnancy. Nat. Immunol. 2, 64–68 (2001).
Prendergast, G. C., Malachowski, W. P., DuHadaway, J. B. & Muller, A. J. Discovery of IDO1 inhibitors: from bench to bedside. Cancer Res. 77, 6795–6811 (2017).
Bender, D. A. & Olufunwa, R. Utilization of tryptophan, nicotinamide and nicotinic acid as precursors for nicotinamide nucleotide synthesis in isolated rat liver cells. Br. J. Nutr. 59, 279–287 (1988).
Nishizuka, Y. & Hayaishi, O. Studies on the biosynthesis of nicotinamide adenine dinucleotide. I. Enzymic synthesis of niacin ribonucleotides from 3-hydroxyanthranilic acid in mammalian tissues. J. Biol. Chem. 238, 3369–3377 (1963).
Liu, L. et al. Quantitative analysis of NAD synthesis-breakdown fluxes. Cell Metab. 27, 1067–1080 (2018).
Pellicciari, R. et al. α-Amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) inhibitors as novel modulators of de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis. J. Med. Chem. 61, 745–759 (2018).
Baban, B. et al. Indoleamine 2,3-dioxygenase expression is restricted to fetal trophoblast giant cells during murine gestation and is maternal genome specific. J. Reprod. Immunol. 61, 67–77 (2004).
Hou, D. Y. et al. Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res. 67, 792–801 (2007).
Malik, S. S., Patterson, D. N., Ncube, Z. & Toth, E. A. The crystal structure of human quinolinic acid phosphoribosyltransferase in complex with its inhibitor phthalic acid. Proteins 82, 405–414 (2014).
Mills, E. L. et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167, 457–470.e413 (2016).
Ryan, D. G. & O’Neill, L. A. J. Krebs cycle rewired for macrophage and dendritic cell effector functions. FEBS Lett. 591, 2992–3006 (2017).
O’Neill, L. A. J., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553–565 (2016).
Kelly, B. & O’Neill, L. A. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 25, 771–784 (2015).
Ahn, B. H. et al. A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis. Proc. Natl Acad. Sci. USA 105, 14447–14452 (2008).
Guerrero-Castillo, S. et al. The assembly pathway of mitochondrial respiratory chain complex I. Cell Metab. 25, 128–139 (2017).
Qiu, X., Brown, K., Hirschey, M. D., Verdin, E. & Chen, D. Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation. Cell Metab. 12, 662–667 (2010).
Bell, E. L., Emerling, B. M., Ricoult, S. J. H. & Guarente, L. SirT3 suppresses hypoxia inducible factor 1α and tumor growth by inhibiting mitochondrial ROS production. Oncogene 30, 2986–2996 (2011).
Liu, P. S. et al. α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 18, 985–994 (2017).
Zwilling, D. et al. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell 145, 863–874 (2011).
Guillemin, G. J. Quinolinic acid, the inescapable neurotoxin. FEBS J. 279, 1356–1365 (2012).
Kim, H. et al. Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression. J. Clin. Invest. 122, 2940–2954 (2012).
Giorgini, F. et al. Targeted deletion of kynurenine 3-monooxygenase in mice: a new tool for studying kynurenine pathway metabolism in periphery and brain. J. Biol. Chem. 288, 36554–36566 (2013).
Heyes, M. P. et al. Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. Brain 115, 1249–1273 (1992).
O’Connor, J. C. et al. Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol. Psychiatry 14, 511–522 (2009).
Schwarcz, R. & Stone, T. W. The kynurenine pathway and the brain: challenges, controversies and promises. Neuropharmacology 112, 237–247 (2017).
Jha, A. K. et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419–430 (2015).
Lampropoulou, V. et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab. 24, 158–166 (2016).
Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013).
Wang, Z. et al. Quinolinate phosphoribosyltransferase is an antiviral host factor against hepatitis C virus infection. Sci. Rep. 7, 5876 (2017).
Youn, H. S. et al. Structural insights into the quaternary catalytic mechanism of hexameric human quinolinate phosphoribosyltransferase, a key enzyme in de novo NAD biosynthesis. Sci. Rep. 6, 19681 (2016).
Liu, H. et al. Structural and kinetic characterization of quinolinate phosphoribosyltransferase (hQPRTase) from Homo sapiens. J. Mol. Biol. 373, 755–763 (2007).
Heyes, M. P. et al. Human microglia convert l-tryptophan into the neurotoxin quinolinic acid. Biochem. J. 320, 595–597 (1996).
Heyes, M. P. et al. Elevated cerebrospinal fluid quinolinic acid levels are associated with region-specific cerebral volume loss in HIV infection. Brain 124, 1033–1042 (2001).
Biswas, S. K. & Mantovani, A. Orchestration of metabolism by macrophages. Cell Metab. 15, 432–437 (2012).
Ganeshan, K. & Chawla, A. Metabolic regulation of immune responses. Annu. Rev. Immunol. 32, 609–634 (2014).
Brown, K. et al. SIRT3 reverses aging-associated degeneration. Cell Rep. 3, 319–327 (2013).
Bonkowski, M. S. & Sinclair, D. A. Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat. Rev. Mol. Cell Biol. 17, 679–690 (2016).
Chiarugi, A., Dölle, C., Felici, R. & Ziegler, M. The NAD metabolome: a key determinant of cancer cell biology. Nat. Rev. Cancer 12, 741–752 (2012).
Johansson, J. U. et al. Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models. J. Clin. Invest. 125, 350–364 (2015).
Woodling, N. S. et al. Cyclooxygenase inhibition targets neurons to prevent early behavioural decline in Alzheimer’s disease model mice. Brain 139, 2063–2081 (2016).
Su, X., Lu, W. & Rabinowitz, J. D. Metabolite spectral accuracy on orbitraps. Anal. Chem. 89, 5940–5948 (2017).
Zhang, Z., Chen, L., Liu, L., Su, X. & Rabinowitz, J. D. Chemical basis for deuterium labeling of fat and NADPH. J. Am. Chem. Soc. 139, 14368–14371 (2017).
Hui, S. et al. Glucose feeds the TCA cycle via circulating lactate. Nature 551, 115–118 (2017).
Nijtmans, L. G., Henderson, N. S. & Holt, I. J. Blue native electrophoresis to study mitochondrial and other protein complexes. Methods 26, 327–334 (2002).
Schägger, H. & von Jagow, G. Blue native electrophoresis for isolation of membrane protein complexes in enzymatically active form. Anal. Biochem. 199, 223–231 (1991).
Piening, B. D. et al. Integrative personal omics profiles during periods of weight gain and loss. Cell Syst. 6, 157–170.e8 (2018).
Contrepois, K., Jiang, L. & Snyder, M. Optimized analytical procedures for the untargeted metabolomic profiling of human urine and plasma by combining hydrophilic interaction (HILIC) and reverse-phase liquid chromatography (RPLC)-mass spectrometry. Mol. Cell. Proteomics 14, 1684–1695 (2015).
López-Ibáñez, J., Pazos, F. & Chagoyen, M. MBROLE 2.0: functional enrichment of chemical compounds. Nucleic Acids Res. 44, W201–W204 (2016).