34 Chapter 2 then reoxidized by complex III, which also reduces cytochrome c, that in its turn will reduce complex IV. This complex then reduces molecular oxygen to water. The transfer of electrons that takes place in the respiratory chain provides the potential energy necessary to generate the proton-motive force required for ATP synthesis (59). Therefore, inhibition of succinate dehydrogenase by itaconate could also lead to decreased mitochondrial respiration in macrophages, providing a link between these two pathways, and leading to higher ROS production due to reverse electron transport to complex one, rather than complex III, that will receive the electrons from ubiquinol and generate NADH from NAD+ (60). Higher levels of succinate also lead to stabilization of transcription factor hypoxiainducible factor 1-alpha (HIF-1α) because succinate inhibits prolyl hydroxylase domain proteins, which normally hydroxylate HIF-1α leading to its ubiquitination and proteasomal degradation (61). The stabilization of HIF-1α will lead to its binding to hypoxia response elements on target genes and induce their expression. HIF-1α regulates expression of genes associated with angiogenesis, proliferation, inflammation, and cellular metabolism. HIF-1α in fact promotes the switch to glycolysis by inducing expression of glycolytic enzymes like hexokinase 2, glucose-6-phosphate isomerase, and pyruvate kinase M2. These are involved in the first, second, and tenth reactions of glycolysis respectively, to ensure these cells can continue to produce ATP when oxygen is limited. Glycolysis will also supply metabolic intermediates, like glucose-6-phosphate, to the pentose phosphate pathway to produce NADPH (62). This can then be used by the enzyme NADPH oxidase to produce ROS. Members of the oxidative phase of the pentose phosphate pathway (from the entrance of glycolytic glucose-6-phosphate to the production of ribulose-5-phosphate) are all upregulated in classically activated macrophages (63), while members of the nonoxidative phase are downregulated due to downregulation of sedoheptulose kinase, which converts sedoheptulose in sedoheptulose-7phosphate (64). HIF-1α also promotes expression of lactate dehydrogenase, which metabolizes pyruvate to lactate (65) and expression of pyruvate dehydrogenase kinase 1. The latter inhibits pyruvate dehydrogenase, therefore inhibiting the conversion of pyruvate in acetyl-CoA, repressing mitochondrial function even more (66). In summary, highly active glycolysis combined with increased glucose uptake results in improved availability of glycolytic intermediates, meeting one of the requirements of an inflammatory response, such as an increased demand for energy (67).
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