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

Journal Article · Thu Mar 15 04:00:00 EDT 2018 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2018.02.139· OSTI ID:23137304

Oshima, Koichi; Saiki, Norikazu ^[1]; Tanaka, Michihiro ^[2]; Imamura, Hiromi ^[3]; Niwa, Akira ^[1]; others, and

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1. Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Kyoto, 6068507 (Japan)
2. Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Kyoto, 6068507 (Japan)
3. The Hakubi Center for Advanced Research, Kyoto University, Kyoto, Kyoto, 6068501 (Japan)

Highlights: • RD-patient derived iPSCs can recapitulate disease phenotype which can be rescued by AK2 overexpression. • RD-iPSC-derived CD34 + KDR + HAPCs are impaired in differentiation propensity to hematopoietic lineage. • Dysfunction of AK2 causes intracellular ATP misdistribution which leads to a relative shortage of ATP in the nuclei of HAPCs. • AK2(-) HAPCs have altered transcriptional profile associated with hematopoiesis. AK2 is an adenylate phosphotransferase that localizes at the intermembrane spaces of the mitochondria, and its mutations cause a severe combined immunodeficiency with neutrophil maturation arrest named reticular dysgenesis (RD). Although the dysfunction of hematopoietic stem cells (HSCs) has been implicated, earlier developmental events that affect the fate of HSCs and/or hematopoietic progenitors have not been reported. Here, we used RD-patient-derived induced pluripotent stem cells (iPSCs) as a model of AK2-deficient human cells. Hematopoietic differentiation from RD-iPSCs was profoundly impaired. RD-iPSC-derived hemoangiogenic progenitor cells (HAPCs) showed decreased ATP distribution in the nucleus and altered global transcriptional profiles. Thus, AK2 has a stage-specific role in maintaining the ATP supply to the nucleus during hematopoietic differentiation, which affects the transcriptional profiles necessary for controlling the fate of multipotential HAPCs. Our data suggest that maintaining the appropriate energy level of each organelle by the intracellular redistribution of ATP is important for controlling the fate of progenitor cells.

• OSTI ID: 23137304
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 2 Vol. 497; ISSN BBRCA9; ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ATP
BLOOD FORMATION
MITOCHONDRIA
NEUTROPHILS
PHOSPHOTRANSFERASES
STEM CELLS