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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...

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Autores principales: Lu, Yi-Tong, Li, Lan-Zhu, Yang, Yi-Lin, Yin, Xiaojian, Liu, Qun, Zhang, Lei, Liu, Kang, Liu, Baolin, Li, Jia, Qi, Lian-Wen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
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.
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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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