Neutrophils are unusual in their reliance on glycolysis to maintain their energy requirements1 despite the presence of mitochondria and tricarboxylic acid (TCA) cycle intermediaries. 2 This metabolic adaptation is thought in part to underpin their survival and antimicrobial function in tissues that are typically hypoxic. 3-5 Despite their unique metabolism, little is known about the importance offlux between metabolic pathways in determining neutrophil survival responses. Recent work has demonstrated the importance of the hypoxia-inducible factor (HIF)/prolyl hydroxylase domain (PHD)–containing enzyme oxygen-sensing pathway in this regard, identifying both HIF-1a and PHD3 as critical regulators of neutrophil survival in hypoxia, 6, 7 with the extended survival of neutrophils in hypoxia being dependent on HIF-1a expression. In parallel, an expanding body of work has addressed the role of HIF-1a in coordinating macrophage functional responses to proinflammatory mediators. 8-11 This work led to the observation that, in macrophages, lipopolysaccharide (LPS) causes an intracellular increase in succinate levels, resulting in HIF-1a stabilization and enhanced interleukin-1b signaling. 11 Subsequently, the metabolic rewiring of antimicrobial (M1) and tissue repair (M2) macrophages has been elucidated, with important consequences of TCA cycle activity and integrity for regulation of nitric oxide and N-glycosylation signaling, respectively. 12 Whether TCA cycle activity and succinate accumulation regulates HIF-1a and hypoxic survival in neutrophils is unknown.

Patients with rare germ line mutations in genes encoding the TCA cycle enzyme succinate dehydrogenase (SDH) allow us to directly question the role of the TCA cycle and mitochondrial respiratory chain in neutrophil survival responses. SDH oxidizes succinate to fumarate in the TCA cycle and is a ubiquinone oxidoreductase, also functioning in complex II of the respiratory chain. 13 SDH comprises four subunits (AD), with inherited mutations of each of the subunits linked to the development of pheochromocytoma (PHEO) and paraganglioma (PGL) after somatic