The metabolic basis of inherited neutropenias

Neutrophils are the shortest-lived blood cells, which requires a prodigious degree of proliferation and differentiation to sustain physiologically sufficient numbers and be poised to respond quickly to infectious emergencies. More than 107 neutrophils are produced every minute in an adult bone marrow-a process that is tightly regulated by a small group of cytokines and chemical mediators and dependent on nutrients and energy. Like granulocyte colony-stimulating factor, the primary growth factor for granulopoiesis, they stimulate signalling pathways, some affecting metabolism. Nutrient or energy deficiency stresses the survival, proliferation, and differentiation of neutrophils and their precursors. Thus, it is not surprising that monogenic disorders related to metabolism exist that result in neutropenia. Among these are pathogenic mutations in HAX1, G6PC3, SLC37A4, TAFAZZIN, SBDS, EFL1 and the mitochondrial disorders. These mutations perturb carbohydrate, lipid and/or protein metabolism. We hypothesize that metabolic disturbances may drive the pathogenesis of a subset of inherited neutropenias just as defects in DNA damage response do in Fanconi anaemia, telomere maintenance in dyskeratosis congenita and ribosome formation in Diamond-Blackfan anaemia. Greater understanding of metabolic pathways in granulopoiesis will identify points of vulnerability in production and may point to new strategies for the treatment of neutropenias. Greater than 107 neutrophils are produced per minute in the bone marrow. Given the high nutrient demand for this process, a subset of congenital neutropenias results from defects in cellular metabolism stemming from monogenic disorders. These genes affect mitochondrial/tricarboxylic acid (TCA) function, carbohydrate metabolism and proteostasis through defective ribosomal assembly and altered protein synthesis. We speculate that these metabolic abnormalities promote stress responses such as senescence and autophagy.image

Automated summary

Neutrophils, the shortest-lived blood cells, require extensive proliferation and differentiation to maintain sufficient numbers and respond quickly to infections. Defects in cellular metabolism resulting from monogenic disorders can lead to congenital neutropenias. Understanding metabolic pathways could identify new strategies for treating neutropenias.