2. Academic Validation
  3. LncRNA TUG1 compromised neuronal mitophagy in cerebral ischemia/reperfusion injury by targeting sirtuin 1

LncRNA TUG1 compromised neuronal mitophagy in cerebral ischemia/reperfusion injury by targeting sirtuin 1

  • Cell Biol Toxicol. 2022 Mar 28. doi: 10.1007/s10565-022-09700-w.
Long-Xing Xue  # 1,  Song-Feng Chen  # 2,  Shi-Xing Xue 3,  Pei-Dong Liu 4 5,  Hong-Bo Liu 6
Affiliations

Affiliations

  • 1 Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1 JianShe Road, Zhengzhou, 450052, Henan Province, People's Republic of China.
  • 2 Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
  • 3 Department of Neurology, Affiliated Xinhua Hospital of Dalian University, Dalian, 116021, China.
  • 4 Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA.
  • 5 Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, People's Republic of China.
  • 6 Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1 JianShe Road, Zhengzhou, 450052, Henan Province, People's Republic of China. [email protected].
  • # Contributed equally.
PMID: 35348966 DOI: 10.1007/s10565-022-09700-w
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.

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.

Keywords

Cerebral ischemia/reperfusion; LncRNA TUG1; Mitophagy; Neuronal apoptosis; SIRT1.

Figures
Products