Abstract B08: Metabolic adaption in inflammatory macrophages through the modulation of Fe-S cluster biogenesis factors
Authors: Tong Wing-Hang , Maio Nunziata , Rouault Tracey A. 
Published: May 2016

Macrophages are among the most abundant normal cells in the tumor microenvironment, and the mechanistic overlap in the metabolic changes in glycolytic cancer cells and inflammatory immune cells suggest that insights into the mechanisms underlying the metabolic changes could be useful in the treatment of both cancers and inflammatory diseases. Metabolic choices in immune cells are tightly linked to cell fate and function. Inflammatory immune cells, such as M1 macrophages and T-helper 17 cells, undergo a shift from OXPHOS to enhanced glucose uptake, glycolysis and the pentose phosphate pathway, whereas anti-inflammatory cells, such as M2 macrophages and regulatory T cells have lower glycolytic rates and higher levels of oxidative metabolism. The metabolic switch from OXPHOS to aerobic glycolysis (Warburg effect) in Toll-like receptor (TLR)-stimulated myeloid cells has been shown to result from the activation of glycolysis through the action of AKT and HIF-1α signaling, with mitochondrial respiration passively decreasing due to NF-kB mediated induction of inducible nitric oxide synthase (iNOS), which produces the toxic gas nitric oxide that damages the Fe-S cluster cofactors that are essential for mitochondrial electron transport. The results reported here indicate that the pro-inflammatory activation of macrophages also involved the active suppression of mitochondrial pyruvate catabolism and respiration through the down-regulation of several genes in the Fe-S cluster biogenesis pathway. A decrease in Fe-S cluster biogenesis/repair not only resulted in a decrease in the activities of Fe-S cluster dependent enzymes including the respiratory complexes I and II, mitochondrial and cytosolic aconitases, and ferrochelatase, but also reduced lipoylation in the E2 subunit of pyruvate dehydrogenase (PDH) complex, thereby inhibiting pyruvate catabolism through the TCA cycle. Inhibition of glycolytic metabolism limited the TLR-stimulated repression of Fe-S cluster biogenesis factors, consistent with a vital survival function of Fe-S cluster biogenesis in cells that depend on mitochondrial ATP production. Activation of AMPK, inhibition of mTOR, and inhibition of Nf-kB all resulted in reduced TLR-induced suppression of Fe-S cluster biogenesis factors. These results suggested that the regulation of Fe-S cluster biogenesis factors are highly sensitive to cellular metabolic needs and are subject to the regulation of metabolic regulators AMPK and mTOR and inflammation modulator Nf-kB. Our results suggested that, in addition to iNOS induction, repression of Fe-S cluster biogenesis/repair may serve to suppress OXPHOS to promote the production of mitochondrial ROS for host defense, and to drive prolonged glycolytic metabolism to produce ATP, NADPH, and biosynthetic precursors to meet the metabolic and anabolic demands of host defense.

Citation Format: Wing-Hang Tong, Nunziata Maio, Tracey A. Rouault. Metabolic adaption in inflammatory macrophages through the modulation of Fe-S cluster biogenesis factors. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B08.