{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T16:59:36Z","timestamp":1762102776699,"version":"build-2065373602"},"reference-count":30,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T00:00:00Z","timestamp":1671235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Aid for Young Scientists (B)","award":["17K12900","19K10090"],"award-info":[{"award-number":["17K12900","19K10090"]}]},{"name":"Aid for Scientific Research (C)","award":["17K12900","19K10090"],"award-info":[{"award-number":["17K12900","19K10090"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mitochondrial ATP production plays an important role in most cellular activities, including growth and differentiation. Previously we reported that Adenylate kinase 2 (AK2) is the main ADP supplier in the mitochondrial intermembrane space in hematopoietic cells, especially in the bone marrow. AK2 is crucial for the production of neutrophils and T cells, and its deficiency causes reticular dysgenesis. However, the relationship between ADP supply by AK2 and neutrophil differentiation remains unclear. In this study, we used CRISPR\/Cas9 technology to establish two heterozygous AK2 knock-out HL-60 clones as models for reticular dysgenesis. Their AK2 activities were about half that in the wild-type (WT). Furthermore, neutrophil differentiation was impaired in one of the clones. In silico analysis predicted that the obtained mutations might cause a structural change in AK2. Time course microarray analysis of the WT and mutants revealed that similar gene clusters responded to all-trans retinoic acid treatment, but their expression was lower in the mutants than in WT. Application of fructose partially restored neutrophil differentiation in the heterozygous knock-out HL-60 clone after all-trans retinoic acid treatment. Collectively, our study suggests that the mutation of N-terminal region in AK2 might play a role in AK2-dependent neutrophil differentiation and fructose could be used to treat AK2 deficiency.<\/jats:p>","DOI":"10.3390\/ijms232416089","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T05:25:46Z","timestamp":1671427546000},"page":"16089","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Effect of Heterozygous Mutation of Adenylate Kinase 2 Gene on Neutrophil Differentiation"],"prefix":"10.3390","volume":"23","author":[{"given":"Taigo","family":"Horiguchi","sequence":"first","affiliation":[{"name":"Department of Oral Bioscience, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayako","family":"Tanimura","sequence":"additional","affiliation":[{"name":"Division of Food & Health Environmental Sciences, Department of Environmental & Symbiotic Sciences, Faculty of Environmental & Symbiotic Sciences, Prefectural University of Kumamoto, 3-1-100, Tsukide, Higashi-ku, Kumamoto 862-8502, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6910-4172","authenticated-orcid":false,"given":"Keiko","family":"Miyoshi","sequence":"additional","affiliation":[{"name":"Department of Oral Bioscience, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroko","family":"Hagita","sequence":"additional","affiliation":[{"name":"Department of Oral Bioscience, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hisanori","family":"Minami","sequence":"additional","affiliation":[{"name":"Division of Applied Nutrition, Faculty of Nutrition, Kobe Gakuin University, 518 Arise, Ikawadani-cho, Nishi-ku, Kobe 651-2180, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takafumi","family":"Noma","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health Promotion, Faculty of Human Life Studies, Hiroshima Jogakuin University, 4-13-1 Ushita-Higashi, Higashi-ku, Hiroshima 732-0063, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Tanimura, A., Horiguchi, T., Miyoshi, K., Hagita, H., and Noma, T. 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