Fig. 1

ATP-producing metabolic pathways in distinct immune cell subsets. Glucose oxidation to pyruvate via glycolysis is a fast reaction generating 2 mol of ATP per mol glucose. This aerobic glycolysis is complemented by the PPP that can produce further metabolic precursor molecules and is involved in ROS production. Pyruvate can be converted to lactate or can be further oxidized to acetyl-CoA entering the mitochondrial TCA cycle (yellow box). The TCA cycle (red box) generates reducing equivalents NADH and FADH₂ which are utilized in the mitochondrial respiratory chain to build up the proton gradient across the mitochondrial inner membrane by complexes I–IV of the respiratory chain. As a by-product, ROS and RNS are produced. Oxidative phosphorylation produces larger amounts of ATP (36–38 mol/mol glucose) by complex V. Immune cells are also able to utilize substrates such as glutamine, which enters these pathways via the TCA metabolite α-ketoglutarate, and fatty acids, which are oxidized to acetyl-CoA via β-oxidation. Granulocytes and M1 macrophages have a highly glycolytic metabolism (yellow box) even when oxygen is available. Their TCA cycle and respiratory chain activity is kept at low level. T_n, T_m, and T_reg cells as well as monocytes and M2 macrophages primarily perform OXPHOS and are also able to metabolize fatty acids and glutamine in order to fuel the TCA cycle (red box). T_eff cells have a highly active metabolism including all of the pathways described (green box). These pathways do not only culminate in ATP production but also provide other biosynthetic pathways with metabolic precursors thus supporting different functional necessities of the immune cell populations. Abbreviations: ADP, adenosine diphosphate; ATP, adenosine triphosphate; CoA, coenzyme A; FADH₂/FAD, flavin adenine dinucleotide in its reduced/oxidized form; IMS, intermembrane space; MM, mitochondrial membrane; NADH/NAD⁺, nicotinamide adenine dinucleotide in its reduced/oxidized form; OXPHOS, oxidative phosphorylation; PPP, pentose phosphate pathway; ROS, reactive oxygen species; RNS, reactive nitrogen species; TCA, tricarboxylic acid cycle; T_eff, effector T cell; T_n, naïve T cell; T_m, memory T cell; T_reg, regulatory T cell