miR-129-3p Targeting of MCU Protects Against Glucose Fluctuation-Mediated Neuronal Damage via a Mitochondrial-Dependent Intrinsic Apoptotic Pathway

Bo Wang,1,2 Yang Li,3 Chao You1 1Department of Neurosurgery, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People’s Republic of China; 2Department of Neurosurgery, Kunming Medical University First Affiliated Hospital, Kunming, Yunnan 6500...

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Autores principales:	Wang B, Li Y, You C
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	mir-129-3p mcu calcium ros，mitochondrion apoptosis oxidative stress Specialties of internal medicine RC581-951
Acceso en línea:	https://doaj.org/article/6fa51ae3f0e049cb805c583f4185c8da
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spelling	oai:doaj.org-article:6fa51ae3f0e049cb805c583f4185c8da2021-12-02T10:36:30ZmiR-129-3p Targeting of MCU Protects Against Glucose Fluctuation-Mediated Neuronal Damage via a Mitochondrial-Dependent Intrinsic Apoptotic Pathway1178-7007https://doaj.org/article/6fa51ae3f0e049cb805c583f4185c8da2021-01-01T00:00:00Zhttps://www.dovepress.com/mir-129-3p-targeting-of-mcu-protects-against-glucose-fluctuation-media-peer-reviewed-article-DMSOhttps://doaj.org/toc/1178-7007Bo Wang,1,2 Yang Li,3 Chao You1 1Department of Neurosurgery, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People’s Republic of China; 2Department of Neurosurgery, Kunming Medical University First Affiliated Hospital, Kunming, Yunnan 650032, People’s Republic of China; 3Intensive Care Unit, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People’s Republic of ChinaCorrespondence: Chao YouDepartment of Neurosurgery, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People’s Republic of ChinaTel +86 28-85422026Email youchaohuaxi@126.comIntroduction: Glucose fluctuations have an adverse effect on several diabetes-related complications, especially for the nervous system, but the underlying mechanisms are not clear. MicroRNAs are critical regulators of posttranscription in many physiological processes, such as apoptosis. Our study clarified the neuroprotective effects of miR-129-3p targeting mitochondrial calcium uniporter (MCU) in glucose fluctuation-mediated neuronal damage and the specific mechanisms involved.Methods: The expression of MCU and miR-129-3p was examined by real-time PCR and Western blot in the glucose fluctuation cell model. Dual-luciferase reporter assay was performed to confirm the transcriptional regulation of miR-129-3p by MCU. Fluorescent probe and assay kit assay was used to determine oxidative stress condition. Mitochondrial-dependent intrinsic apoptotic factors were examined by flow cytometry assay, enzyme-linked immunosorbent assay (ELISA), and gene and protein expression assays.Results: We found an upregulation of MCU and downregulation of miR-129-3p in glucose fluctuation-treated primary hippocampal neuronal cells, and miR-129-3p directly targeted MCU. miR-129-3p overexpression produced a dramatic reduction in calcium overload, reactive oxygen species (ROS) generation, GSH-to-GSSG ratio, MMP-2 expression in the mitochondrial-dependent intrinsic apoptosis pathway and an increase in MnSOD activity. Increasing MCU expression rescued the effects of miR-129-3p overexpression. miR-129-3p downregulation produced a significant increase in calcium overload, reactive oxygen species (ROS) generation, MMP-2 expression, cytochrome c release and cell apoptosis, and antioxidant N-acetyl cysteine (NAC) rescued the effects of miR-129-3p downregulation.Conclusion: Therefore, miR-129-3p suppressed glucose fluctuation-mediated neuronal damage by targeting MCU via a mitochondrial-dependent intrinsic apoptotic pathway. The miR-129-3p/MCU axis may be a promising therapeutic target for glucose fluctuation-mediated neuronal damage.Keywords: miR-129-3p, MCU, calcium, ROS, mitochondrion, apoptosis, oxidative stressWang BLi YYou CDove Medical Pressarticlemir-129-3pmcucalciumros，mitochondrionapoptosisoxidative stressSpecialties of internal medicineRC581-951ENDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy, Vol Volume 14, Pp 153-163 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	mir-129-3p mcu calcium ros，mitochondrion apoptosis oxidative stress Specialties of internal medicine RC581-951
spellingShingle	mir-129-3p mcu calcium ros，mitochondrion apoptosis oxidative stress Specialties of internal medicine RC581-951 Wang B Li Y You C miR-129-3p Targeting of MCU Protects Against Glucose Fluctuation-Mediated Neuronal Damage via a Mitochondrial-Dependent Intrinsic Apoptotic Pathway
description	Bo Wang,1,2 Yang Li,3 Chao You1 1Department of Neurosurgery, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People’s Republic of China; 2Department of Neurosurgery, Kunming Medical University First Affiliated Hospital, Kunming, Yunnan 650032, People’s Republic of China; 3Intensive Care Unit, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People’s Republic of ChinaCorrespondence: Chao YouDepartment of Neurosurgery, West China School of Medicine/West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People’s Republic of ChinaTel +86 28-85422026Email youchaohuaxi@126.comIntroduction: Glucose fluctuations have an adverse effect on several diabetes-related complications, especially for the nervous system, but the underlying mechanisms are not clear. MicroRNAs are critical regulators of posttranscription in many physiological processes, such as apoptosis. Our study clarified the neuroprotective effects of miR-129-3p targeting mitochondrial calcium uniporter (MCU) in glucose fluctuation-mediated neuronal damage and the specific mechanisms involved.Methods: The expression of MCU and miR-129-3p was examined by real-time PCR and Western blot in the glucose fluctuation cell model. Dual-luciferase reporter assay was performed to confirm the transcriptional regulation of miR-129-3p by MCU. Fluorescent probe and assay kit assay was used to determine oxidative stress condition. Mitochondrial-dependent intrinsic apoptotic factors were examined by flow cytometry assay, enzyme-linked immunosorbent assay (ELISA), and gene and protein expression assays.Results: We found an upregulation of MCU and downregulation of miR-129-3p in glucose fluctuation-treated primary hippocampal neuronal cells, and miR-129-3p directly targeted MCU. miR-129-3p overexpression produced a dramatic reduction in calcium overload, reactive oxygen species (ROS) generation, GSH-to-GSSG ratio, MMP-2 expression in the mitochondrial-dependent intrinsic apoptosis pathway and an increase in MnSOD activity. Increasing MCU expression rescued the effects of miR-129-3p overexpression. miR-129-3p downregulation produced a significant increase in calcium overload, reactive oxygen species (ROS) generation, MMP-2 expression, cytochrome c release and cell apoptosis, and antioxidant N-acetyl cysteine (NAC) rescued the effects of miR-129-3p downregulation.Conclusion: Therefore, miR-129-3p suppressed glucose fluctuation-mediated neuronal damage by targeting MCU via a mitochondrial-dependent intrinsic apoptotic pathway. The miR-129-3p/MCU axis may be a promising therapeutic target for glucose fluctuation-mediated neuronal damage.Keywords: miR-129-3p, MCU, calcium, ROS, mitochondrion, apoptosis, oxidative stress
format	article
author	Wang B Li Y You C
author_facet	Wang B Li Y You C
author_sort	Wang B
title	miR-129-3p Targeting of MCU Protects Against Glucose Fluctuation-Mediated Neuronal Damage via a Mitochondrial-Dependent Intrinsic Apoptotic Pathway
title_short	miR-129-3p Targeting of MCU Protects Against Glucose Fluctuation-Mediated Neuronal Damage via a Mitochondrial-Dependent Intrinsic Apoptotic Pathway
title_full	miR-129-3p Targeting of MCU Protects Against Glucose Fluctuation-Mediated Neuronal Damage via a Mitochondrial-Dependent Intrinsic Apoptotic Pathway
title_fullStr	miR-129-3p Targeting of MCU Protects Against Glucose Fluctuation-Mediated Neuronal Damage via a Mitochondrial-Dependent Intrinsic Apoptotic Pathway
title_full_unstemmed	miR-129-3p Targeting of MCU Protects Against Glucose Fluctuation-Mediated Neuronal Damage via a Mitochondrial-Dependent Intrinsic Apoptotic Pathway
title_sort	mir-129-3p targeting of mcu protects against glucose fluctuation-mediated neuronal damage via a mitochondrial-dependent intrinsic apoptotic pathway
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/6fa51ae3f0e049cb805c583f4185c8da
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miR-129-3p Targeting of MCU Protects Against Glucose Fluctuation-Mediated Neuronal Damage via a Mitochondrial-Dependent Intrinsic Apoptotic Pathway

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