Human AK2 links intracellular bioenergetic redistribution to the fate of hematopoietic progenioptors

Recent studies have linked bioenergetic regulation to cellular differentiation. However, the contribution of metabolic communication among subcellular components to the fate of progenitor cells remains unclear. Adenylate kinase 2 (AK2) is an adenylate phosphotransferase localized in the mitochondrial intermembrane space. Although AK2 mutations in human can cause a severe combined immunodeficiency with neutropenia, named reticular dysgenesis (RD), underlying mechanisms have not yet been elucidated. To address these questions, we established induced pluripotent stem cells (iPSCs) from two RD patients. Metabolic flux analysis revealed that AK2 mediates the distribution of glycolytic metabolites into the tricarbon acid cycle in mitochondria. Hematopoietic differentiation from RD-iPSCs was profoundly impaired. Intriguingly, RD-iPSC-derived hematopoietic progenitors exhibited an immature mitochondrial morphology, discordant ATP distribution among the mitochondria and nucleus, and alteration of global transcriptional profiles. These results highlight the importance of stage-specific intracellular energy communication for controlling the fate of multipotential progenitors. We compared expression profiles of ES cells, AK2-deficient and AK2-supplemented clones during four sequential developmental stages: undifferentiated pluripotent stem cells, day 6 CD34+KDR+ hemoangiogenic progenitors, day 13 CD34+CD45+ myeloid progenitor cells and day 22 neutrophils