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Melatonin-mediated FKBP4 downregulation protects against stress-induced neuronal mitochondria dysfunctions by blocking nuclear translocation of GR
The physiological crosstalk between glucocorticoid and melatonin maintains neuronal homeostasis in regulating circadian rhythms. However, the stress-inducing level of glucocorticoid triggers mitochondrial dysfunction including defective mitophagy by increasing the activity of glucocorticoid receptor...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9943853/ https://www.ncbi.nlm.nih.gov/pubmed/36810730 http://dx.doi.org/10.1038/s41419-023-05676-5 |
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author | Kim, Min Jeong Choi, Gee Euhn Chae, Chang Woo Lim, Jae Ryong Jung, Young Hyun Yoon, Jee Hyeon Park, Ji Yong Han, Ho Jae |
author_facet | Kim, Min Jeong Choi, Gee Euhn Chae, Chang Woo Lim, Jae Ryong Jung, Young Hyun Yoon, Jee Hyeon Park, Ji Yong Han, Ho Jae |
author_sort | Kim, Min Jeong |
collection | PubMed |
description | The physiological crosstalk between glucocorticoid and melatonin maintains neuronal homeostasis in regulating circadian rhythms. However, the stress-inducing level of glucocorticoid triggers mitochondrial dysfunction including defective mitophagy by increasing the activity of glucocorticoid receptors (GRs), leading to neuronal cell death. Melatonin then suppresses glucocorticoid-induced stress-responsive neurodegeneration; however, the regulatory mechanism of melatonin, i.e., associated proteins involved in GR activity, has not been elucidated. Therefore, we investigated how melatonin regulates chaperone proteins related to GR trafficking into the nucleus to suppress glucocorticoid action. In this study, the effects of glucocorticoid on suppressing NIX-mediated mitophagy, followed by mitochondrial dysfunction, neuronal cell apoptosis, and cognitive deficits were reversed by melatonin treatment by inhibiting the nuclear translocation of GRs in both SH-SY5Y cells and mouse hippocampal tissue. Moreover, melatonin selectively suppressed the expression of FKBP prolyl isomerase 4 (FKBP4), which is a co-chaperone protein that works with dynein, to reduce the nuclear translocation of GRs among the chaperone proteins and nuclear trafficking proteins. In both cells and hippocampal tissue, melatonin upregulated melatonin receptor 1 (MT1) bound to Gαq, which triggered the phosphorylation of ERK1. The activated ERK then enhanced DNA methyltransferase 1 (DNMT1)-mediated hypermethylation of FKBP52 promoter, reducing GR-mediated mitochondrial dysfunction and cell apoptosis, the effects of which were reversed by knocking down DNMT1. Taken together, melatonin has a protective effect against glucocorticoid-induced defective mitophagy and neurodegeneration by enhancing DNMT1-mediated FKBP4 downregulation that reduced the nuclear translocation of GRs. |
format | Online Article Text |
id | pubmed-9943853 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-99438532023-02-23 Melatonin-mediated FKBP4 downregulation protects against stress-induced neuronal mitochondria dysfunctions by blocking nuclear translocation of GR Kim, Min Jeong Choi, Gee Euhn Chae, Chang Woo Lim, Jae Ryong Jung, Young Hyun Yoon, Jee Hyeon Park, Ji Yong Han, Ho Jae Cell Death Dis Article The physiological crosstalk between glucocorticoid and melatonin maintains neuronal homeostasis in regulating circadian rhythms. However, the stress-inducing level of glucocorticoid triggers mitochondrial dysfunction including defective mitophagy by increasing the activity of glucocorticoid receptors (GRs), leading to neuronal cell death. Melatonin then suppresses glucocorticoid-induced stress-responsive neurodegeneration; however, the regulatory mechanism of melatonin, i.e., associated proteins involved in GR activity, has not been elucidated. Therefore, we investigated how melatonin regulates chaperone proteins related to GR trafficking into the nucleus to suppress glucocorticoid action. In this study, the effects of glucocorticoid on suppressing NIX-mediated mitophagy, followed by mitochondrial dysfunction, neuronal cell apoptosis, and cognitive deficits were reversed by melatonin treatment by inhibiting the nuclear translocation of GRs in both SH-SY5Y cells and mouse hippocampal tissue. Moreover, melatonin selectively suppressed the expression of FKBP prolyl isomerase 4 (FKBP4), which is a co-chaperone protein that works with dynein, to reduce the nuclear translocation of GRs among the chaperone proteins and nuclear trafficking proteins. In both cells and hippocampal tissue, melatonin upregulated melatonin receptor 1 (MT1) bound to Gαq, which triggered the phosphorylation of ERK1. The activated ERK then enhanced DNA methyltransferase 1 (DNMT1)-mediated hypermethylation of FKBP52 promoter, reducing GR-mediated mitochondrial dysfunction and cell apoptosis, the effects of which were reversed by knocking down DNMT1. Taken together, melatonin has a protective effect against glucocorticoid-induced defective mitophagy and neurodegeneration by enhancing DNMT1-mediated FKBP4 downregulation that reduced the nuclear translocation of GRs. Nature Publishing Group UK 2023-02-21 /pmc/articles/PMC9943853/ /pubmed/36810730 http://dx.doi.org/10.1038/s41419-023-05676-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Kim, Min Jeong Choi, Gee Euhn Chae, Chang Woo Lim, Jae Ryong Jung, Young Hyun Yoon, Jee Hyeon Park, Ji Yong Han, Ho Jae Melatonin-mediated FKBP4 downregulation protects against stress-induced neuronal mitochondria dysfunctions by blocking nuclear translocation of GR |
title | Melatonin-mediated FKBP4 downregulation protects against stress-induced neuronal mitochondria dysfunctions by blocking nuclear translocation of GR |
title_full | Melatonin-mediated FKBP4 downregulation protects against stress-induced neuronal mitochondria dysfunctions by blocking nuclear translocation of GR |
title_fullStr | Melatonin-mediated FKBP4 downregulation protects against stress-induced neuronal mitochondria dysfunctions by blocking nuclear translocation of GR |
title_full_unstemmed | Melatonin-mediated FKBP4 downregulation protects against stress-induced neuronal mitochondria dysfunctions by blocking nuclear translocation of GR |
title_short | Melatonin-mediated FKBP4 downregulation protects against stress-induced neuronal mitochondria dysfunctions by blocking nuclear translocation of GR |
title_sort | melatonin-mediated fkbp4 downregulation protects against stress-induced neuronal mitochondria dysfunctions by blocking nuclear translocation of gr |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9943853/ https://www.ncbi.nlm.nih.gov/pubmed/36810730 http://dx.doi.org/10.1038/s41419-023-05676-5 |
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