Loss-of-function mutations in the human adenylate kinase 2 (AK2 ) gene cause a rare genetic disorder called reticular dysgenesis (RD), characterized by severe combined immunodeficiency, primarily T and B lymphocyte deficiencies and neutrophil maturation arrest, and progressive sensorineural hearing loss. This severe immunodeficiency, if left untreated by hematopoietic stem cell (HSC) transplantation, makes patients vulnerable to life-threatening infectious diseases. While HSC transplantation is a solution, it does not improve hearing loss and is not without risk of failure or complications. As such, researchers continue to seek novel therapeutic approaches for RD treatment.

AK2 is an enzyme regulating cellular energy homeostasis, and its deficiency is believed to cause oxidative stress that impairs hematopoietic precursor cell functions, including their proper differentiation and maturation into various blood cell lineages. Previous work led by Professor Megumu K. Saito, using hemo-angiogenic progenitor cells (HAPCs) derived from RD patient-specific iPS cells, revealed an abnormal intracellular distribution of ATP, the principal fuel used for various cellular processes. A key hypothesis is that AK2 deficiency inhibits ATP efflux from mitochondria, thus leading to an inadequate ATP supply in the cytoplasm and nucleus. In a recent study, Saito and his research team tested whether reduced mitochondrial transport of pyruvate, the primary substrate for aerobic ATP production inside the mitochondria, could shift cellular energy production toward anaerobic glycolysis and elevate cytoplasmic and nuclear ATP concentrations to enhance neutrophil maturation.

To this end, the researchers treated RD patient-specific iPS cells with UK-5099, a small molecule inhibitor of the mitochondrial pyruvate carrier (MPC), during hematopoietic differentiation. Remarkably, they observed an intermediate dose of UK-5099 to enhance neutrophil maturation significantly. They further confirmed the beneficial effects of UK-5099 on terminal differentiation of neutrophils using AK2-deleted iPS cells and embryonic stem (ES) cells generated by CRISPR/Cas9-based genome editing. Notably, unlike previous studies using zebrafish, the researchers did not observe increased oxidative stress, as measured by reactive oxygen species (ROS) generation, in AK2-deficient HAPCs. Moreover, the intermediate dose of UK-5099 that enhanced neutrophil maturation did not affect ROS levels, thus suggesting that its antioxidant effects may not be required for its positive influence on neutrophil differentiation.

While the researchers demonstrated the beneficial effects of MPC inhibition on neutrophil maturation, further efforts are necessary for elucidating the underlying molecular mechanisms and in vivo safety of this novel therapeutic approach. The research team hopes this study is the first step toward a curative treatment for the severe immunodeficiencies affecting RD patients.

• doi: 10.1016/j.bbrc.2023.149211