LncRNA-MEG3 attenuates hyperglycemia-induced damage by enhancing mitochondrial translocation of HSP90A in the primary hippocampal neurons

Wanqing Zhou; Zhihua Wang; Yuanyuan Tao; Cheng Chen; Qian Zhang; Zhuoyi Liu; Longyan Li; Pingping Xia; Zhi Ye

doi:10.1016/j.yexcr.2022.113320

LncRNA-MEG3 attenuates hyperglycemia-induced damage by enhancing mitochondrial translocation of HSP90A in the primary hippocampal neurons

Exp Cell Res. 2022 Oct 15;419(2):113320. doi: 10.1016/j.yexcr.2022.113320. Epub 2022 Aug 23.

Authors

Wanqing Zhou¹, Zhihua Wang², Yuanyuan Tao¹, Cheng Chen¹, Qian Zhang¹, Zhuoyi Liu³, Longyan Li³, Pingping Xia³, Zhi Ye⁴

Affiliations

¹ , Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, 410008, Hunan Province, China.
² , Department of Anesthesiology, Hainan General Hospital, Haikou, Hainan Province, China.
³ , Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, 410008, Hunan Province, China; , National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan Province, China.
⁴ , Department of Anesthesiology, Xiangya Hospital of Central South University, Changsha, 410008, Hunan Province, China; , National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, Hunan Province, China. Electronic address: yezhi523@csu.edu.cn.

PMID: 35998683
DOI: 10.1016/j.yexcr.2022.113320

Abstract

The diabetic cognitive impairments are associated with high-glucose (HG)-induced mitochondrial dysfunctions in the brain. Our previous studies demonstrated that long non-coding RNA (lncRNA)-MEG3 alleviates diabetic cognitive impairments. However, the underlying mechanism has still remained elusive. Therefore, this study was designed to investigate whether the mitochondrial translocation of HSP90A and its phosphorylation are involved in lncRNA-MEG3-mediated neuroprotective effects of mitochondrial functions in HG-treated primary hippocampal neurons and diabetic rats. The primary hippocampal neurons were exposed to 75 mM glucose for 72 h to establish a HG model in vitro. Firstly, the RNA pull-down and RNA immunoprecipitation (RIP) assays clearly indicated that lncRNA-MEG3-associated mitochondrial proteins were Annexin A2, HSP90A, and Plectin. Although HG promoted the mitochondrial translocation of HSP90A and Annexin A2, lncRNA-MEG3 over-expression only enhanced the mitochondrial translocation of HSP90A, rather than Annexin A2, in the primary hippocampal neurons treated with or without HG. Meanwhile, Plectin mediated the mitochondrial localization of lncRNA-MEG3 and HSP90A. Furthermore, HSP90A threonine phosphorylation participated in regulating mitochondrial translocation of HSP90A, and lncRNA-MEG3 also enhanced mitochondrial translocation of HSP90A through suppressing HSP90A threonine phosphorylation. Finally, the anti-apoptotic role of mitochondrial translocation of HSP90A was found to be associated with inhibiting death receptor 5 (DR5) in HG-treated primary hippocampal neurons and diabetic rats. Taken together, lncRNA-MEG3 could improve mitochondrial functions in HG-exposed primary hippocampal neurons, and the underlying mechanisms were involved in enhanced mitochondrial translocation of HSP90A via suppressing HSP90A threonine phosphorylation, which may reveal a potential therapeutic target for diabetic cognitive impairments.

Keywords: Diabetic cognitive impairments; HSP90A; Hyperglycemia; LncRNA-MEG3; Mitochondrial functions.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Annexin A2* / metabolism
Apoptosis
Diabetes Mellitus, Experimental* / genetics
Glucose / pharmacology
HSP90 Heat-Shock Proteins / metabolism
Hippocampus / metabolism
Hyperglycemia* / genetics
Neurons / metabolism
Plectin
RNA, Long Noncoding / genetics*
RNA, Long Noncoding / metabolism
Rats
Threonine / pharmacology

Substances

Annexin A2
HSP90 Heat-Shock Proteins
MEG3 non-coding RNA, rat
Plectin
RNA, Long Noncoding
Threonine
Glucose