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

Overview

Journal Diabetes Metab Syndr Obes

Publisher Dove Medical Press

Specialty Endocrinology

Date 2021 Jan 25

PMID 33488104

Citations 6

Authors

Bo Wang

Yang Li

Chao You

Affiliations

Soon will be listed here.

Abstract

Introduction: 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.

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References

Cox D, Kovatchev B, Gonder-Frederick L, Summers K, McCall A, Grimm K . Relationships between hyperglycemia and cognitive performance among adults with type 1 and type 2 diabetes. Diabetes Care. 2004; 28(1):71-7. DOI: 10.2337/diacare.28.1.71. View

Guo J, Sang Y, Yin T, Wang B, Yang W, Li X . miR-1273g-3p participates in acute glucose fluctuation-induced autophagy, dysfunction, and proliferation attenuation in human umbilical vein endothelial cells. Am J Physiol Endocrinol Metab. 2016; 310(9):E734-43. DOI: 10.1152/ajpendo.00444.2015. View

Zhang K, Yan J, Wang L, Tian X, Zhang T, Guo L . The Pyk2/MCU pathway in the rat middle cerebral artery occlusion model of ischemic stroke. Neurosci Res. 2017; 131:52-62. DOI: 10.1016/j.neures.2017.09.002. View

De Stefani D, Raffaello A, Teardo E, Szabo I, Rizzuto R . A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature. 2011; 476(7360):336-40. PMC: 4141877. DOI: 10.1038/nature10230. View

Vishnoi A, Rani S . MiRNA Biogenesis and Regulation of Diseases: An Overview. Methods Mol Biol. 2016; 1509:1-10. DOI: 10.1007/978-1-4939-6524-3_1. View

Quagliaro L, Piconi L, Assaloni R, Martinelli L, Motz E, Ceriello A . Intermittent high glucose enhances apoptosis related to oxidative stress in human umbilical vein endothelial cells: the role of protein kinase C and NAD(P)H-oxidase activation. Diabetes. 2003; 52(11):2795-804. DOI: 10.2337/diabetes.52.11.2795. View

Quincozes-Santos A, Bobermin L, de Assis A, Goncalves C, Souza D . Fluctuations in glucose levels induce glial toxicity with glutamatergic, oxidative and inflammatory implications. Biochim Biophys Acta Mol Basis Dis. 2016; 1863(1):1-14. DOI: 10.1016/j.bbadis.2016.09.013. View

Prasai P, Shrestha B, Orr A, Pattillo C . Decreases in GSH:GSSG activate vascular endothelial growth factor receptor 2 (VEGFR2) in human aortic endothelial cells. Redox Biol. 2018; 19:22-27. PMC: 6086407. DOI: 10.1016/j.redox.2018.07.015. View

Wu D, Zhang Y, Lu J, Zheng Y . Effects of microRNA-129 and its target gene c-Fos on proliferation and apoptosis of hippocampal neurons in rats with epilepsy via the MAPK signaling pathway. J Cell Physiol. 2017; 233(9):6632-6643. DOI: 10.1002/jcp.26297. View

10.

Liu T, Pei Y, Peng Y, Chen J, Jiang S, Gong J . Oscillating high glucose enhances oxidative stress and apoptosis in human coronary artery endothelial cells. J Endocrinol Invest. 2014; 37(7):645-51. DOI: 10.1007/s40618-014-0086-5. View

11.

Tait S, Green D . Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol. 2010; 11(9):621-32. DOI: 10.1038/nrm2952. View

12.

Ott M, Robertson J, Gogvadze V, Zhivotovsky B, Orrenius S . Cytochrome c release from mitochondria proceeds by a two-step process. Proc Natl Acad Sci U S A. 2002; 99(3):1259-63. PMC: 122177. DOI: 10.1073/pnas.241655498. View

13.

Paupe V, Prudent J . New insights into the role of mitochondrial calcium homeostasis in cell migration. Biochem Biophys Res Commun. 2017; 500(1):75-86. PMC: 5930976. DOI: 10.1016/j.bbrc.2017.05.039. View

14.

Russo V, Higgins S, Werther G, Cameron F . Effects of fluctuating glucose levels on neuronal cells in vitro. Neurochem Res. 2012; 37(8):1768-82. DOI: 10.1007/s11064-012-0789-y. View

15.

Russo G, Tedesco I, Russo M, Cioppa A, Andreassi M, Picano E . Cellular adaptive response to chronic radiation exposure in interventional cardiologists. Eur Heart J. 2011; 33(3):408-14. DOI: 10.1093/eurheartj/ehr263. View

16.

Liu Z, Zhao W, Lei H, Xu H, Lai L, Xu R . High Glucose Enhances Bupivacaine-Induced Neurotoxicity via MCU-Mediated Oxidative Stress in SH-SY5Y Cells. Oxid Med Cell Longev. 2019; 2019:7192798. PMC: 6398017. DOI: 10.1155/2019/7192798. View

17.

Kohlhaas M, Liu T, Knopp A, Zeller T, Ong M, Bohm M . Elevated cytosolic Na+ increases mitochondrial formation of reactive oxygen species in failing cardiac myocytes. Circulation. 2010; 121(14):1606-13. PMC: 2946079. DOI: 10.1161/CIRCULATIONAHA.109.914911. View

18.

Liu D, Zhang R, Wu J, Pu Y, Yin X, Cheng Y . Interleukin-17A promotes esophageal adenocarcinoma cell invasiveness through ROS-dependent, NF-κB-mediated MMP-2/9 activation. Oncol Rep. 2017; 37(3):1779-1785. DOI: 10.3892/or.2017.5426. View

19.

Liu X, Kim C, Yang J, Jemmerson R, Wang X . Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996; 86(1):147-57. DOI: 10.1016/s0092-8674(00)80085-9. View

20.

Haorah J, Ramirez S, Schall K, Smith D, Pandya R, Persidsky Y . Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood-brain barrier dysfunction. J Neurochem. 2007; 101(2):566-76. DOI: 10.1111/j.1471-4159.2006.04393.x. View