Mutations in succinate dehydrogenase B (SDHB) enhance neutrophil survival independent of HIF-1α expression

Neutrophils are unusual in their reliance on glycolysis to maintain their energy requirements 1 despite the presence of mitochondria and TCA cycle intermediaries 2 .This metabolic adaptation is thought in part to underpin their survival and anti-microbial function in tissues that are typically hypoxic [3][4][5] .Despite their unique metabolism, little is known about the importance of flux between metabolic pathways in determining neutrophil survival responses.Recent work has demonstrated the importance of the HIF/PHD oxygen-sensing pathway in this regard, identifying both HIF-1α and PHD3 as critical regulators of neutrophil survival in hypoxia 6,7 , with the extended survival of neutrophils in hypoxia being dependent upon HIF-1α expression.In parallel, an expanding body of work has addressed the role of HIF-1α in coordinating macrophage functional responses to pro-inflammatory mediators [8][9][10][11] .This work led to the observation that, in macrophages, LPS causes an intracellular increase in succinate levels resulting in HIF-1α stabilization and enhanced IL-1β signaling 11 .Subsequently, the metabolic re-wiring of anti-microbial (M1) and tissue repair (M2) macrophages has been elucidated, with important consequences of TCA cycle activity and integrity for regulation of NO and N-glycosylation signaling respectively 12 .Whether TCA cycle activity and succinate accumulation regulates HIF-1α activity and hypoxic survival in neutrophils is unknown.