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Adenylate Kinase in Human Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 6196

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Guest Editor
1. Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami Kogushi 1-1-1, Ube Yamaguchi 755-8505, Japan
2. Department of Environmental Oncology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan
Interests: adenylate kinase; liver fibrosis; energy metabolism; regenerative medicine
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Special Issue Information

Dear Colleagues,

Large amounts of energy are required for various cell activities. ATP as energy currency is produced in glycolysis or oxidative phosphorylation, conveyed to energy consumption sites and used. Cellular energy metabolism and related enzymes have been evaluated as important biochemical matter.

Adenylate kinase (AK) is an enzyme that regulates adenine nucleotide metabolism in a wide range of organisms, by catalyzing the interconversion reaction: ATP + AMP ⇌ 2 ADP. To date, nine different kinds of human AK isozymes have been reported. An efficient transfer mechanism of high-energy phosphate within the cell has been proposed; however, this mechanism is not fully elucidated. It is reported that AK deficiency is associated with disease. AK1 deficiency causes a hematological abnormality in humans, and AK2 deficiency in humans causes reticular dysgenesis and sensorineural deafness. In recent advances AK is reported to be related to hypoxia responses, aging, metastasis, cell stemness, differentiation, drug resistance, cancer progressive markers, etc.

In this Special Issue, we aimed to address the energy metabolism and the importance of AK- or energy-metabolism-related enzymes such as creatine kinases or nucleoside diphosphate kinases in various life phenomena.

Dr. Koichi Fujisawa
Guest Editor

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Keywords

  • ATP
  • adenylate kinase
  • creatine kinases
  • nucleoside diphosphate kinases
  • cellular energy metabolism
  • adenine nucleotide metabolism
  • hematological abnormality
  • reticular dysgenesis
  • sensorineural deafness

Published Papers (3 papers)

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Research

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15 pages, 3616 KiB  
Article
The Effect of Heterozygous Mutation of Adenylate Kinase 2 Gene on Neutrophil Differentiation
by Taigo Horiguchi, Ayako Tanimura, Keiko Miyoshi, Hiroko Hagita, Hisanori Minami and Takafumi Noma
Int. J. Mol. Sci. 2022, 23(24), 16089; https://doi.org/10.3390/ijms232416089 - 17 Dec 2022
Cited by 3 | Viewed by 1508
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Adenylate Kinase in Human Health and Disease)
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12 pages, 2967 KiB  
Article
Adenylate Kinase Isozyme 3 Regulates Mitochondrial Energy Metabolism and Knockout Alters HeLa Cell Metabolism
by Koichi Fujisawa, Maina Wakazaki, Aya Matsuzaki, Toshihiko Matsumoto, Naoki Yamamoto, Takafumi Noma and Taro Takami
Int. J. Mol. Sci. 2022, 23(8), 4316; https://doi.org/10.3390/ijms23084316 - 13 Apr 2022
Cited by 4 | Viewed by 1936
Abstract
The balance between oxidative phosphorylation and glycolysis is important for cancer cell growth and survival, and changes in energy metabolism are an emerging therapeutic target. Adenylate kinase (AK) regulates adenine nucleotide metabolism, maintaining intracellular nucleotide metabolic homeostasis. In this study, we focused on [...] Read more.
The balance between oxidative phosphorylation and glycolysis is important for cancer cell growth and survival, and changes in energy metabolism are an emerging therapeutic target. Adenylate kinase (AK) regulates adenine nucleotide metabolism, maintaining intracellular nucleotide metabolic homeostasis. In this study, we focused on AK3, the isozyme localized in the mitochondrial matrix that reversibly mediates the following reaction: Mg2+ GTP + AMP ⇌ Mg2+ GDP + ADP. Additionally, we analyzed AK3-knockout (KO) HeLa cells, which showed reduced proliferation and were detected at an increased number in the G1 phase. A metabolomic analysis showed decreased ATP; increased glycolytic metabolites such as glucose 6 phosphate (G6P), fructose 6 phosphate (F6P), and phosphoenolpyruvate (PEP); and decreased levels of tricarboxylic acid (TCA) cycle metabolites in AK3KO cells. An intracellular ATP evaluation of AK3KO HeLa cells transfected with ATeam plasmid, an ATP sensor, showed decreased whole cell levels. Levels of mitochondrial DNA (mtDNA), a complementary response to mitochondrial failure, were increased in AK3KO HeLa cells. Oxidative stress levels increased with changes in gene expression, evidenced as an increase in related enzymes such as superoxide dismutase 2 (SOD2) and SOD3. Phosphoenolpyruvate carboxykinase 2 (PCK2) expression and PEP levels increased, whereas PCK2 inhibition affected AK3KO HeLa cells more than wild-type (WT) cells. Therefore, we concluded that increased PCK2 expression may be complementary to increased GDP, which was found to be deficient through AK3KO. This study demonstrated the importance of AK3 in mitochondrial matrix energy metabolism. Full article
(This article belongs to the Special Issue Adenylate Kinase in Human Health and Disease)
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Review

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10 pages, 253 KiB  
Review
Integration of Eukaryotic Energy Metabolism: The Intramitochondrial and Cytosolic Energy States ([ATP]f/[ADP]f[Pi])
by David F. Wilson and Franz M. Matschinsky
Int. J. Mol. Sci. 2022, 23(10), 5550; https://doi.org/10.3390/ijms23105550 - 16 May 2022
Cited by 8 | Viewed by 1806
Abstract
Maintaining a robust, stable source of energy for doing chemical and physical work is essential to all living organisms. In eukaryotes, metabolic energy (ATP) production and consumption occurs in two separate compartments, the mitochondrial matrix and the cytosol. As a result, understanding eukaryotic [...] Read more.
Maintaining a robust, stable source of energy for doing chemical and physical work is essential to all living organisms. In eukaryotes, metabolic energy (ATP) production and consumption occurs in two separate compartments, the mitochondrial matrix and the cytosol. As a result, understanding eukaryotic metabolism requires knowledge of energy metabolism in each compartment and how metabolism in the two compartments is coordinated. Central to energy metabolism is the adenylate energy state ([ATP]/[ADP][Pi]). ATP is synthesized by oxidative phosphorylation (mitochondrial matrix) and glycolysis (cytosol) and each compartment provides the energy to do physical work and to drive energetically unfavorable chemical syntheses. The energy state in the cytoplasmic compartment has been established by analysis of near equilibrium metabolic reactions localized in that compartment. In the present paper, analysis is presented for energy-dependent reactions localized in the mitochondrial matrix using data obtained from both isolated mitochondria and intact tissues. It is concluded that the energy state ([ATP]f/[ADP]f[Pi]) in the mitochondrial matrix, calculated from the free (unbound) concentrations, is not different from the energy state in the cytoplasm. Corollaries are: (1) ADP in both the cytosol and matrix is selectively bound and the free concentrations are much lower than the total measured concentrations; and (2) under physiological conditions, the adenylate energy states in the mitochondrial matrix and cytoplasm are not substantially different. Full article
(This article belongs to the Special Issue Adenylate Kinase in Human Health and Disease)
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