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Succinate induces aberrant mitochondrial fission in cardiomyocytes through GPR91 signaling
Altered mitochondrial metabolism acts as an initial cause for cardiovascular diseases and metabolic intermediate succinate emerges as a mediator of mitochondrial dysfunction. This work aims to investigate whether or not extracellular succinate accumulation and its targeted G protein-coupled receptor...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986788/ https://www.ncbi.nlm.nih.gov/pubmed/29867110 http://dx.doi.org/10.1038/s41419-018-0708-5 |
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author | Lu, Yi-Tong Li, Lan-Zhu Yang, Yi-Lin Yin, Xiaojian Liu, Qun Zhang, Lei Liu, Kang Liu, Baolin Li, Jia Qi, Lian-Wen |
author_facet | Lu, Yi-Tong Li, Lan-Zhu Yang, Yi-Lin Yin, Xiaojian Liu, Qun Zhang, Lei Liu, Kang Liu, Baolin Li, Jia Qi, Lian-Wen |
author_sort | Lu, Yi-Tong |
collection | PubMed |
description | Altered mitochondrial metabolism acts as an initial cause for cardiovascular diseases and metabolic intermediate succinate emerges as a mediator of mitochondrial dysfunction. This work aims to investigate whether or not extracellular succinate accumulation and its targeted G protein-coupled receptor-91 (GPR91) activation induce cardiac injury through mitochondrial impairment. The results showed that extracellular succinate promoted the translocation of dynamin-related protein 1 (Drp1) to mitochondria via protein kinase Cδ (PKCδ) activation, and induced mitochondrial fission factor (MFF) phosphorylation via extracellular signal-regulated kinases-1/2 (ERK1/2) activation in a GPR91-dependent manner. As a result, enhanced localization of MFF and Drp1 in mitochondria promoted mitochondrial fission, leading to mitochondrial dysfunction and cardiomyocyte apoptosis. We further showed that inhibition of succinate release and GPR91 signaling ameliorated oxygen–glucose deprivation-induced injury in cardiomyocytes and isoproterenol-induced myocardial ischemia injury in mice. Taken together, these results showed that in response to cardiac ischemia, succinate release activated GPR91 and induced mitochondrial fission via regulation of PKCδ and ERK1/2 signaling branches. These findings suggest that inhibition of extracellular succinate-mediated GPR91 activation might be a potential therapeutic strategy for protecting cardiomyocytes from ischemic injury. |
format | Online Article Text |
id | pubmed-5986788 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59867882018-06-05 Succinate induces aberrant mitochondrial fission in cardiomyocytes through GPR91 signaling Lu, Yi-Tong Li, Lan-Zhu Yang, Yi-Lin Yin, Xiaojian Liu, Qun Zhang, Lei Liu, Kang Liu, Baolin Li, Jia Qi, Lian-Wen Cell Death Dis Article Altered mitochondrial metabolism acts as an initial cause for cardiovascular diseases and metabolic intermediate succinate emerges as a mediator of mitochondrial dysfunction. This work aims to investigate whether or not extracellular succinate accumulation and its targeted G protein-coupled receptor-91 (GPR91) activation induce cardiac injury through mitochondrial impairment. The results showed that extracellular succinate promoted the translocation of dynamin-related protein 1 (Drp1) to mitochondria via protein kinase Cδ (PKCδ) activation, and induced mitochondrial fission factor (MFF) phosphorylation via extracellular signal-regulated kinases-1/2 (ERK1/2) activation in a GPR91-dependent manner. As a result, enhanced localization of MFF and Drp1 in mitochondria promoted mitochondrial fission, leading to mitochondrial dysfunction and cardiomyocyte apoptosis. We further showed that inhibition of succinate release and GPR91 signaling ameliorated oxygen–glucose deprivation-induced injury in cardiomyocytes and isoproterenol-induced myocardial ischemia injury in mice. Taken together, these results showed that in response to cardiac ischemia, succinate release activated GPR91 and induced mitochondrial fission via regulation of PKCδ and ERK1/2 signaling branches. These findings suggest that inhibition of extracellular succinate-mediated GPR91 activation might be a potential therapeutic strategy for protecting cardiomyocytes from ischemic injury. Nature Publishing Group UK 2018-06-04 /pmc/articles/PMC5986788/ /pubmed/29867110 http://dx.doi.org/10.1038/s41419-018-0708-5 Text en © The Author(s) 2018 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 Lu, Yi-Tong Li, Lan-Zhu Yang, Yi-Lin Yin, Xiaojian Liu, Qun Zhang, Lei Liu, Kang Liu, Baolin Li, Jia Qi, Lian-Wen Succinate induces aberrant mitochondrial fission in cardiomyocytes through GPR91 signaling |
title | Succinate induces aberrant mitochondrial fission in cardiomyocytes through GPR91 signaling |
title_full | Succinate induces aberrant mitochondrial fission in cardiomyocytes through GPR91 signaling |
title_fullStr | Succinate induces aberrant mitochondrial fission in cardiomyocytes through GPR91 signaling |
title_full_unstemmed | Succinate induces aberrant mitochondrial fission in cardiomyocytes through GPR91 signaling |
title_short | Succinate induces aberrant mitochondrial fission in cardiomyocytes through GPR91 signaling |
title_sort | succinate induces aberrant mitochondrial fission in cardiomyocytes through gpr91 signaling |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986788/ https://www.ncbi.nlm.nih.gov/pubmed/29867110 http://dx.doi.org/10.1038/s41419-018-0708-5 |
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