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High glucose induces Drp1-mediated mitochondrial fission via the Orai1 calcium channel to participate in diabetic cardiomyocyte hypertrophy

Mitochondrial dysfunction and impaired Ca(2+) handling are involved in the development of diabetic cardiomyopathy (DCM). Dynamic relative protein 1 (Drp1) regulates mitochondrial fission by changing its level of phosphorylation, and the Orai1 (Ca(2+) release-activated calcium channel protein 1) calc...

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Autores principales: Wu, Qing-Rui, Zheng, Dan-Lin, Liu, Pei-Ming, Yang, Hui, Li, Lu-An, Kuang, Su-Juan, Lai, Ying-Yu, Rao, Fang, Xue, Yu-Mei, Lin, Ji-Jin, Liu, Shuang-Xin, Chen, Chun-Bo, Deng, Chun-Yu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910592/
https://www.ncbi.nlm.nih.gov/pubmed/33637715
http://dx.doi.org/10.1038/s41419-021-03502-4
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author Wu, Qing-Rui
Zheng, Dan-Lin
Liu, Pei-Ming
Yang, Hui
Li, Lu-An
Kuang, Su-Juan
Lai, Ying-Yu
Rao, Fang
Xue, Yu-Mei
Lin, Ji-Jin
Liu, Shuang-Xin
Chen, Chun-Bo
Deng, Chun-Yu
author_facet Wu, Qing-Rui
Zheng, Dan-Lin
Liu, Pei-Ming
Yang, Hui
Li, Lu-An
Kuang, Su-Juan
Lai, Ying-Yu
Rao, Fang
Xue, Yu-Mei
Lin, Ji-Jin
Liu, Shuang-Xin
Chen, Chun-Bo
Deng, Chun-Yu
author_sort Wu, Qing-Rui
collection PubMed
description Mitochondrial dysfunction and impaired Ca(2+) handling are involved in the development of diabetic cardiomyopathy (DCM). Dynamic relative protein 1 (Drp1) regulates mitochondrial fission by changing its level of phosphorylation, and the Orai1 (Ca(2+) release-activated calcium channel protein 1) calcium channel is important for the increase in Ca(2+) entry into cardiomyocytes. We aimed to explore the mechanism of Drp1 and Orai1 in cardiomyocyte hypertrophy caused by high glucose (HG). We found that Zucker diabetic fat rats induced by administration of a high-fat diet develop cardiac hypertrophy and impaired cardiac function, accompanied by the activation of mitochondrial dynamics and calcium handling pathway-related proteins. Moreover, HG induces cardiomyocyte hypertrophy, accompanied by abnormal mitochondrial morphology and function, and increased Orai1-mediated Ca(2+) influx. Mechanistically, the Drp1 inhibitor mitochondrial division inhibitor 1 (Mdivi-1) prevents cardiomyocyte hypertrophy induced by HG by reducing phosphorylation of Drp1 at serine 616 (S616) and increasing phosphorylation at S637. Inhibition of Orai1 with single guide RNA (sgOrai1) or an inhibitor (BTP2) not only suppressed Drp1 activity and calmodulin-binding catalytic subunit A (CnA) and phosphorylated-extracellular signal-regulated kinase (p-ERK1/2) expression but also alleviated mitochondrial dysfunction and cardiomyocyte hypertrophy caused by HG. In addition, the CnA inhibitor cyclosporin A and p-ERK1/2 inhibitor U0126 improved HG-induced cardiomyocyte hypertrophy by promoting and inhibiting phosphorylation of Drp1 at S637 and S616, respectively. In summary, we identified Drp1 as a downstream target of Orai1-mediated Ca(2+) entry, via activation by p-ERK1/2-mediated phosphorylation at S616 or CnA-mediated dephosphorylation at S637 in DCM. Thus, the Orai1–Drp1 axis is a novel target for treating DCM.
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spelling pubmed-79105922021-03-04 High glucose induces Drp1-mediated mitochondrial fission via the Orai1 calcium channel to participate in diabetic cardiomyocyte hypertrophy Wu, Qing-Rui Zheng, Dan-Lin Liu, Pei-Ming Yang, Hui Li, Lu-An Kuang, Su-Juan Lai, Ying-Yu Rao, Fang Xue, Yu-Mei Lin, Ji-Jin Liu, Shuang-Xin Chen, Chun-Bo Deng, Chun-Yu Cell Death Dis Article Mitochondrial dysfunction and impaired Ca(2+) handling are involved in the development of diabetic cardiomyopathy (DCM). Dynamic relative protein 1 (Drp1) regulates mitochondrial fission by changing its level of phosphorylation, and the Orai1 (Ca(2+) release-activated calcium channel protein 1) calcium channel is important for the increase in Ca(2+) entry into cardiomyocytes. We aimed to explore the mechanism of Drp1 and Orai1 in cardiomyocyte hypertrophy caused by high glucose (HG). We found that Zucker diabetic fat rats induced by administration of a high-fat diet develop cardiac hypertrophy and impaired cardiac function, accompanied by the activation of mitochondrial dynamics and calcium handling pathway-related proteins. Moreover, HG induces cardiomyocyte hypertrophy, accompanied by abnormal mitochondrial morphology and function, and increased Orai1-mediated Ca(2+) influx. Mechanistically, the Drp1 inhibitor mitochondrial division inhibitor 1 (Mdivi-1) prevents cardiomyocyte hypertrophy induced by HG by reducing phosphorylation of Drp1 at serine 616 (S616) and increasing phosphorylation at S637. Inhibition of Orai1 with single guide RNA (sgOrai1) or an inhibitor (BTP2) not only suppressed Drp1 activity and calmodulin-binding catalytic subunit A (CnA) and phosphorylated-extracellular signal-regulated kinase (p-ERK1/2) expression but also alleviated mitochondrial dysfunction and cardiomyocyte hypertrophy caused by HG. In addition, the CnA inhibitor cyclosporin A and p-ERK1/2 inhibitor U0126 improved HG-induced cardiomyocyte hypertrophy by promoting and inhibiting phosphorylation of Drp1 at S637 and S616, respectively. In summary, we identified Drp1 as a downstream target of Orai1-mediated Ca(2+) entry, via activation by p-ERK1/2-mediated phosphorylation at S616 or CnA-mediated dephosphorylation at S637 in DCM. Thus, the Orai1–Drp1 axis is a novel target for treating DCM. Nature Publishing Group UK 2021-02-26 /pmc/articles/PMC7910592/ /pubmed/33637715 http://dx.doi.org/10.1038/s41419-021-03502-4 Text en © The Author(s) 2021 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/.
spellingShingle Article
Wu, Qing-Rui
Zheng, Dan-Lin
Liu, Pei-Ming
Yang, Hui
Li, Lu-An
Kuang, Su-Juan
Lai, Ying-Yu
Rao, Fang
Xue, Yu-Mei
Lin, Ji-Jin
Liu, Shuang-Xin
Chen, Chun-Bo
Deng, Chun-Yu
High glucose induces Drp1-mediated mitochondrial fission via the Orai1 calcium channel to participate in diabetic cardiomyocyte hypertrophy
title High glucose induces Drp1-mediated mitochondrial fission via the Orai1 calcium channel to participate in diabetic cardiomyocyte hypertrophy
title_full High glucose induces Drp1-mediated mitochondrial fission via the Orai1 calcium channel to participate in diabetic cardiomyocyte hypertrophy
title_fullStr High glucose induces Drp1-mediated mitochondrial fission via the Orai1 calcium channel to participate in diabetic cardiomyocyte hypertrophy
title_full_unstemmed High glucose induces Drp1-mediated mitochondrial fission via the Orai1 calcium channel to participate in diabetic cardiomyocyte hypertrophy
title_short High glucose induces Drp1-mediated mitochondrial fission via the Orai1 calcium channel to participate in diabetic cardiomyocyte hypertrophy
title_sort high glucose induces drp1-mediated mitochondrial fission via the orai1 calcium channel to participate in diabetic cardiomyocyte hypertrophy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910592/
https://www.ncbi.nlm.nih.gov/pubmed/33637715
http://dx.doi.org/10.1038/s41419-021-03502-4
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