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LncRNA TUG1 compromised neuronal mitophagy in cerebral ischemia/reperfusion injury by targeting sirtuin 1.
- Source :
-
Cell biology and toxicology [Cell Biol Toxicol] 2022 Dec; Vol. 38 (6), pp. 1121-1136. Date of Electronic Publication: 2022 Mar 28. - Publication Year :
- 2022
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Abstract
- Background: Mitophagy protects against cerebral ischemia/reperfusion (CI/R)-induced neuronal apoptosis via mitochondrial clearance. Although taurine-upregulated gene 1 (lncRNA TUG1) has been proposed to be involved in the neuronal apoptosis evoked by CI/R, its specific role in mitophagy during the progression of CI/R injury remains unknown.<br />Methods: The CI/R rat model was established using middle cerebral artery occlusion/reperfusion (MCAO/R). Human neuroblastoma cell line SH-SY5Y was subjected to oxygen-glucose deprivation and reoxygenation (OGD/R). Ubiquitination assay, co-immunoprecipitation assay, RNA pull-down, and RNA immunoprecipitation were used to determine the interplay among TUG1, sirtuin 1 (SIRT1), and F-box and WD repeat domain-containing 7 (FBXW7).<br />Results: The upregulation of the TUG1 level and downregulation of the mitophagy were observed in both MCAO/R-treated rats and OGD/R-treated cells. The administration of si-TUG1 (a siRNA directed against TUG1) potentiated mitophagy and suppressed neuronal apoptosis in OGD/R-treated cells. However, the neuroprotective effect of si-TUG1 was reversed by mitophagy inhibitor or SIRT1 knockdown in vitro. Functionally, TUG1 enhanced FBXW7-mediated SIRT1 ubiquitination by upregulating FBXW7 expression. The overexpression of FBXW7 abrogated the si-TUG1-reinforced mitophagy by decreasing SIRT1 expression, thus aggravating neuronal apoptosis in the OGD/R+si-TUG1-treated cells. In rats with MCAO/R, the interference of TUG1 clearly decreased neuronal apoptosis, lessened the infarct volume, and relieved the neurological deficits.<br />Conclusion: TUG1 knockdown promotes SIRT1-induced mitophagy by suppressing FBXW7-mediated SIRT1 degradation, thus relieving the neuronal apoptosis induced by CI/R injury. LncRNA TUG1 promotes neuronal apoptosis through inhibition of mitophagy. TUG1 decreased SIRT1 expression by promoting FBXW7-mediated SIRT1 ubiquitination. FBXW7/SIRT1 axis mediated the effect of TUG1 on OGD/R-induced neuronal apoptosis by regulating mitophagy.<br /> (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)
- Subjects :
- Humans
Rats
Animals
Sirtuin 1 genetics
Sirtuin 1 metabolism
Mitophagy
F-Box-WD Repeat-Containing Protein 7 metabolism
Apoptosis genetics
Glucose metabolism
RNA, Long Noncoding genetics
RNA, Long Noncoding metabolism
Neuroblastoma
Reperfusion Injury genetics
Reperfusion Injury metabolism
Brain Ischemia genetics
MicroRNAs genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1573-6822
- Volume :
- 38
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cell biology and toxicology
- Publication Type :
- Academic Journal
- Accession number :
- 35348966
- Full Text :
- https://doi.org/10.1007/s10565-022-09700-w