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Published on: January 10, 2025
LncRNA TUG1 compromised neuronal mitophagy in cerebral ischemia/reperfusion injury by targeting sirtuin 1
Long-Xing Xue1, Song-Feng Chen2, Shi-Xing Xue3
1Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1 JianShe Road, Zhengzhou, 450052, Henan Province, People's Republic of China.
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.
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).
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.
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.
Insights
Taurine-upregulated gene 1 (TUG1) inhibition promotes mitophagy and protects neurons from cerebral ischemia/reperfusion injury. TUG1 aggravates neuronal apoptosis by suppressing mitophagy via the FBXW7/SIRT1 pathway.
Area of Science:
- Neuroscience
- Molecular Biology
- Cellular Biology
Background:
- Cerebral ischemia/reperfusion (CI/R) injury causes neuronal apoptosis.
- Mitophagy is a protective mechanism against CI/R-induced neuronal apoptosis.
- The role of long non-coding RNA taurine-upregulated gene 1 (lncRNA TUG1) in CI/R-induced mitophagy and neuronal apoptosis is unclear.
Purpose of the Study:
- To investigate the role of lncRNA TUG1 in mitophagy during CI/R injury.
- To elucidate the molecular mechanisms by which TUG1 affects neuronal apoptosis and mitophagy in CI/R.
- To determine the interplay between TUG1, SIRT1, and FBXW7 in the context of CI/R.
Main Methods:
- Establishment of a middle cerebral artery occlusion/reperfusion (MCAO/R) rat model for CI/R.
- Oxygen-glucose deprivation and reoxygenation (OGD/R) model using human neuroblastoma SH-SY5Y cells.
- Assays including ubiquitination, co-immunoprecipitation, RNA pull-down, and RNA immunoprecipitation to analyze molecular interactions.
Main Results:
- TUG1 levels were upregulated, while mitophagy was downregulated in both MCAO/R rats and OGD/R cells.
- si-TUG1 administration enhanced mitophagy and reduced neuronal apoptosis, an effect reversed by mitophagy inhibitors or SIRT1 knockdown.
- TUG1 promotes FBXW7-mediated SIRT1 ubiquitination and degradation, thereby inhibiting mitophagy and exacerbating neuronal apoptosis.
Conclusions:
- TUG1 knockdown promotes SIRT1-induced mitophagy by suppressing FBXW7-mediated SIRT1 degradation, alleviating CI/R-induced neuronal apoptosis.
- lncRNA TUG1 promotes neuronal apoptosis by inhibiting mitophagy through the FBXW7/SIRT1 axis.
- Targeting TUG1 represents a potential therapeutic strategy for mitigating CI/R injury.
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