Switching gears in glutamine metabolism is key to red blood cell development and disease  

During mature red blood cell formation, a process called erythropoiesis, blood stem cells develop through many different stages. This fundamental biological process includes complex metabolic pathways, which are often dysregulated in blood disorders such as sickle cell disease and β-thalassemia. However, these metabolic pathways and how their dysfunction contributes to disease are not fully understood.

A collaborative research team led by Jian Xu, PhD, Department of Pathology and Center of Excellence for Leukemia Studies, and Min Ni, PhD, Department of Oncology, set out to understand the metabolic pathways regulating normal red blood cell maturation and how this might be altered in various disorders.

The scientists systematically profiled metabolic changes through each red blood cell maturation stage and identified a previously unrecognized role for the amino acid glutamine. The work, published in Science, reveals modulating glutamine metabolism is a potential therapeutic route for common red blood cell disorders. It may also serve as a tool for evaluating therapeutic efficacy. 

Early blood cell maturation processes break down glutamine as an energy source, but the researchers made a surprising finding about the amino acid’s metabolism in the later stages of development. “We found this process is completely reversed during later differentiation. The cells stop breaking down glutamine and begin synthesizing it by completely reversing the reaction,” Xu explained.

Heme is the main component of hemoglobin, the protein in red blood cells that carries oxygen. Red blood cell maturation depends on heme production, but ammonium (a heme production byproduct) can accumulate if not removed, causing oxidative stress. The researchers found red blood cells begin producing glutamine synthetase to facilitate ammonium’s removal by combining glutamate with the ammonium to produce glutamine. 

Through conditional inactivation of glutamine synthetase, the researchers identified a direct link between disruption of glutamine metabolism and red blood cell disorders, such as β-thalassemia. This link causes a metabolic phenotype resembling a glutamine synthetase deficiency, characterized by increased glutamate and ammonia levels and decreased glutamine levels. They identified glutamine synthetase oxidation as the cause of this metabolic phenotype in β-thalassemia and were able to treat the condition by restoring enzyme activity. 

The link between glutamine synthase deficiency and other red blood cell disorders in which the enzyme is inactivated is further supported by a recent report describing a selective impairment of erythropoiesis in a human patient with inherited glutamine synthetase deficiency, an ultra-rare inborn error of metabolism.

The researchers carried their study further, investigating how the drug luspatercept, currently used to treat β-thalassemia, works. They found the drug likely acts to restore glutamine levels. Similarly, the study suggests that the mechanisms behind other red blood cell disorder treatments, such as L-glutamine supplementation to alleviate sickle cell disease symptoms, likely involve fixing defective glutamine metabolism. 

Beyond its direct impact on treating red blood cell disorders, the findings suggest metabolic features, such as glutamine-to-glutamate ratios, can be used as biomarkers for these conditions, offering a means to diagnose, monitor disease progression and evaluate therapeutic efficacy. 

“Collaboration is key to this type of research,” said Ni. “At St. Jude, we are fortunate to have outstanding support and strong partnerships with collaborators, which are vital to success.”