UK-5099, a mitochondrial pyruvate carrier inhibitor, recovers impaired neutrophil maturation caused by AK2 deficiency in human pluripotent stem cell models

Jingxin Wang; Norikazu Saiki; Ayako Tanimura; Takafumi Noma; Akira Niwa; Tastutoshi Nakahata; Megumu K Saito

doi:10.1016/j.bbrc.2023.149211

UK-5099, a mitochondrial pyruvate carrier inhibitor, recovers impaired neutrophil maturation caused by AK2 deficiency in human pluripotent stem cell models

Biochem Biophys Res Commun. 2023 Dec 20:687:149211. doi: 10.1016/j.bbrc.2023.149211. Epub 2023 Nov 3.

Authors

Jingxin Wang¹, Norikazu Saiki², Ayako Tanimura³, Takafumi Noma⁴, Akira Niwa¹, Tastutoshi Nakahata⁵, Megumu K Saito⁶

Affiliations

¹ Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan.
² Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan; Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan.
³ Division of Food and Health Environmental Sciences, Department of Environmental and Symbiotic Sciences, Faculty of Environmental and Symbiotic Sciences, Prefectural University of Kumamoto, Kumamoto, 862-8502, Japan; Department of Health and Nutrition, Faculty of Nursing and Nutrition, The University of Shimane, Izumo, 693-8550, Japan.
⁴ Department of Nutrition and Health, Faculty of Human Life Studies, Hiroshima Jogakuin University, Hiroshima, 732-0063, Japan.
⁵ Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan; Central Institute for Experimental Animals, Kawasaki, 210-0821, Japan.
⁶ Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan. Electronic address: [email protected].

PMID: 37949028
DOI: 10.1016/j.bbrc.2023.149211

Abstract

Reticular dysgenesis (RD) is a rare genetic disease caused by gene mutations in the ATP:AMP phosphotransferase, adenylate kinase 2 (AK2). Patients with RD suffer from severe combined immunodeficiency with neutrophil maturation arrest. Although hematopoietic stem cell transplantation can be a curative option, it is invasive, and complications of agranulocytosis-induced infection worsen the prognosis. Here, we report that the use of UK-5099, an inhibitor of the mitochondrial pyruvate carrier (MPC), on hemo-angiogenic progenitor cells (HAPCs) derived from AK2-deficient induced pluripotent stem cells improved neutrophil maturation. Reactive oxygen species (ROS) levels in AK2-deficient HAPCs remained unchanged throughout all experiments, implying that UK-5099 improved the phenotype without affecting ROS levels. Overall, our results suggest that the MPC is a potential therapeutic target for the treatment of neutrophil maturation defects in RD.

Keywords: Adenylate kinase 2; Induced pluripotent stem cells; Neutrophils; Reticular dysgenesis; UK-5099.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenylate Kinase / metabolism
Humans
Leukopenia
Monocarboxylic Acid Transporters*
Neutrophils / metabolism
Pluripotent Stem Cells* / metabolism
Reactive Oxygen Species / metabolism
Severe Combined Immunodeficiency

Substances

2-cyano-3-(1-phenylindol-3-yl)acrylate
Monocarboxylic Acid Transporters
Reactive Oxygen Species
Adenylate Kinase

Supplementary concepts

Reticular dysgenesis