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The Effect of Heterozygous Mutation of Adenylate Kinase 2 Gene on Neutrophil Differentiation

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...

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Autores principales: Horiguchi, Taigo, Tanimura, Ayako, Miyoshi, Keiko, Hagita, Hiroko, Minami, Hisanori, Noma, Takafumi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9786915/
https://www.ncbi.nlm.nih.gov/pubmed/36555730
http://dx.doi.org/10.3390/ijms232416089
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author Horiguchi, Taigo
Tanimura, Ayako
Miyoshi, Keiko
Hagita, Hiroko
Minami, Hisanori
Noma, Takafumi
author_facet Horiguchi, Taigo
Tanimura, Ayako
Miyoshi, Keiko
Hagita, Hiroko
Minami, Hisanori
Noma, Takafumi
author_sort Horiguchi, Taigo
collection PubMed
description 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.
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spelling pubmed-97869152022-12-24 The Effect of Heterozygous Mutation of Adenylate Kinase 2 Gene on Neutrophil Differentiation Horiguchi, Taigo Tanimura, Ayako Miyoshi, Keiko Hagita, Hiroko Minami, Hisanori Noma, Takafumi Int J Mol Sci Article 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. MDPI 2022-12-17 /pmc/articles/PMC9786915/ /pubmed/36555730 http://dx.doi.org/10.3390/ijms232416089 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Horiguchi, Taigo
Tanimura, Ayako
Miyoshi, Keiko
Hagita, Hiroko
Minami, Hisanori
Noma, Takafumi
The Effect of Heterozygous Mutation of Adenylate Kinase 2 Gene on Neutrophil Differentiation
title The Effect of Heterozygous Mutation of Adenylate Kinase 2 Gene on Neutrophil Differentiation
title_full The Effect of Heterozygous Mutation of Adenylate Kinase 2 Gene on Neutrophil Differentiation
title_fullStr The Effect of Heterozygous Mutation of Adenylate Kinase 2 Gene on Neutrophil Differentiation
title_full_unstemmed The Effect of Heterozygous Mutation of Adenylate Kinase 2 Gene on Neutrophil Differentiation
title_short The Effect of Heterozygous Mutation of Adenylate Kinase 2 Gene on Neutrophil Differentiation
title_sort effect of heterozygous mutation of adenylate kinase 2 gene on neutrophil differentiation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9786915/
https://www.ncbi.nlm.nih.gov/pubmed/36555730
http://dx.doi.org/10.3390/ijms232416089
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