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2. Heme-dependent recognition of 5-aminolevulinate synthase by the human mitochondrial molecular chaperone ClpX.

Author

Nomura K, Kitagawa Y, Aihara M, Ohki Y, Furuyama K, and Hirokawa T

Subjects
5-Aminolevulinate Synthetase chemistry, Adenosine Diphosphate metabolism, Adenosine Triphosphate metabolism, Amino Acid Motifs, Amino Acid Sequence, Hemin metabolism, Humans, Intrinsically Disordered Proteins metabolism, Models, Biological, Protein Binding, 5-Aminolevulinate Synthetase metabolism, Endopeptidase Clp metabolism, Heme metabolism, Mitochondria metabolism, Molecular Chaperones metabolism
Abstract

The caseinolytic mitochondrial matrix peptidase chaperone subunit (ClpX) plays an important role in the heme-dependent regulation of 5-aminolevulinate synthase (ALAS1), a key enzyme in heme biosynthesis. However, the mechanisms underlying the role of ClpX in this process remain unclear. In this in vitro study, we confirmed the direct binding between ALAS1 and ClpX in a heme-dependent manner. The substitution of C 108 P 109 [CP motif 3 (CP3)] with A 108 A 109 in ALAS1 resulted in a loss of ability to bind ClpX. Computational disorder analyses revealed that CP3 was located in a potential intrinsically disordered protein region (IDPR). Thus, we propose that conditional disorder-to-order transitions in the IDPRs of ALAS1 may represent key mechanisms underlying the heme-dependent recognition of ALAS1 by ClpX., (© 2021 Federation of European Biochemical Societies.)

Published
2021
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3. Senescence caused by inactivation of the homeodomain transcription factor Pdx1 in adult pancreatic acinar cells in mice.

Author

Horiguchi M, Yoshida M, Hirata K, Furuyama K, Masui T, Uemoto S, and Kawaguchi Y

Subjects
Acinar Cells cytology, Acinar Cells metabolism, Animals, Cell Proliferation, Cellular Senescence, Gene Silencing, Mice, Microscopy, Electron, Mitochondria metabolism, Mitochondria ultrastructure, Pancreas metabolism, Pancreatic Elastase genetics, Pancreatic Elastase metabolism, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Pancreas cytology, Tamoxifen pharmacology, Trans-Activators genetics, Trans-Activators metabolism
Abstract

In this study, we used tamoxifen-inducible Elastase-Cre-mediated inactivation of pancreatic and duodenal homeobox1 (Pdx1), an indispensable gene during embryonic pancreatogenesis, to investigate the role of Pdx1 in adult pancreatic exocrine tissue. We found that Pdx1 depletion in approximately 50% of acinar cell mass did not show any macroscopic phenotype. Lineage tracing experiments revealed that the percentage of Pdx1-depleted cells did not change initially but gradually decreased, while the proliferation of Pdx1-preserved cells increased. Electron microscopic analysis showed the emergence of round-shaped mitochondria with less cristae, dilated ER lumen and increased number of autophagosomes but no apoptosis. Instead, Pdx1-depleted acinar cells became senescent. These findings indicate that intracellular stress caused by Pdx1 inactivation triggers the senescence-associated secretory phenotype to maintain organ homeostasis in this model., (© 2019 Federation of European Biochemical Societies.)

Published
2019
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4. Liver-specific Prox1 inactivation causes hepatic injury and glucose intolerance in mice.

Author

Goto T, Elbahrawy A, Furuyama K, Horiguchi M, Hosokawa S, Aoyama Y, Tsuboi K, Sakikubo M, Hirata K, Masui T, Kubo H, Sakai Y, Uemoto S, and Kawaguchi Y

Subjects
Animals, Blotting, Western, Cell Line, Tumor, Energy Metabolism genetics, Gene Expression, Glucose Intolerance genetics, Hepatocytes metabolism, Hepatocytes pathology, Hepatocytes ultrastructure, Homeodomain Proteins genetics, Humans, Liver pathology, Liver ultrastructure, Liver Diseases genetics, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Electron, Transmission, Microscopy, Fluorescence, Mitochondria, Liver metabolism, Mitochondria, Liver ultrastructure, Organ Specificity, RNA Interference, Reverse Transcriptase Polymerase Chain Reaction, Tumor Suppressor Proteins genetics, Prospero-Related Homeobox 1 Protein, Glucose Intolerance metabolism, Homeodomain Proteins metabolism, Liver metabolism, Liver Diseases metabolism, Tumor Suppressor Proteins metabolism
Abstract

Previous reports have revealed that Prospero-related homeobox 1 (Prox1) is required for the migration and differentiation of hepatoblasts during embryonic liver formation. However, the role of Prox1 in adults remains to be elucidated. We created liver-specific Prox1 knockout mice to verify the role of Prox1 in adult hepatocytes. The mutant mice exhibit hepatic injury and a nonobese, insulin-resistant diabetic phenotype in vivo. Hepatocyte injury is observed predominantly in the perivenous region and is characterized by the formation of vacuoles and emergence of round-shaped mitochondria, suggesting that the effect of Prox1 on the maintenance of adult hepatocytes is region dependent. Furthermore, glycolysis is suppressed, and both oxidative phosphorylation and autophagy are upregulated in the livers of Prox1 knockout mice, indicating that Prox1 has a role in regulating energy homeostasis in hepatocytes., (© 2017 Federation of European Biochemical Societies.)

Published
2017
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5. Enhancements of the production of bilirubin and the expression of β-globin by carbon monoxide during erythroid differentiation.

Author

Mu A, Li M, Tanaka M, Adachi Y, Tai TT, Liem PH, Izawa S, Furuyama K, and Taketani S

Subjects
Animals, Bone Marrow Cells, Cell Differentiation, Cells, Cultured, Erythroid Cells metabolism, Erythropoiesis, Gene Expression Regulation drug effects, Heme metabolism, Mice, Bilirubin metabolism, Carbon Monoxide pharmacology, Erythroid Cells cytology, beta-Globins metabolism
Abstract

Heme is degraded by heme oxygenase to form iron, carbon monoxide (CO), and biliverdin. However, information about the catabolism of heme in erythroid cells is limited. In this study, we showed the production and export of bilirubin in murine erythroleukemia (MEL) cells. The production of bilirubin by MEL cells was enhanced when heme synthesis was induced. When mouse bone marrow cells were induced with erythropoietin to differentiate into erythroid cells, the synthesis of bilirubin increased. The expression of β-globin was enhanced by CO at the transcriptional level. These results indicate that constant production of CO from heme regulates erythropoiesis., (© 2016 Federation of European Biochemical Societies.)

Published
2016
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