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

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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.

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.

Graphical abstract

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.

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Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Funding

This work was supported by the Medical Science and Technology Program of Henan Province of China (No. SB201901018), Joint Funds of the National Natural Science Foundation of China (No. U2004128), and Joint Project of Medical Science and Technology Program of Henan Province of China (No. 2018020070).

Author information

Author notes

  1. Long-xing Xue and Song-feng Chen contributed equally to this work.

Authors and 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

    Long-xing Xue & Hong-bo Liu

  2. Department of Orthopaedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Song-feng Chen

  3. Department of Neurology, Affiliated Xinhua Hospital of Dalian University, Dalian, 116021, China

    Shi-xing Xue

  4. Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA

    Pei-dong Liu

  5. Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China

    Pei-dong Liu

Authors
  1. Long-xing Xue
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  2. Song-feng Chen
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  3. Shi-xing Xue
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Contributions

LX & SC conceived and designed the study and drafted the manuscript. SX collected the data and PL contributed to the statistical analysis. HL interpreted the data and put forward the concept of the study and reviewed the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Hong-bo Liu.

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Ethics approval and consent to participate

All animal experiments were carried out with the approval of the ethics committee of The First Affiliated Hospital of Zhengzhou University.

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The study was undertaken with the patient’s consent.

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The authors declare no competing interests.

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Supplementary information

Supplementary Figure 1

The effect of TUG1 knockdown on cell apoptosis in OGD/R-treated SH-SY5Y cells. SH-SY5Y cells were grouped into control, OGD/R, OGD/R + si-TUG1, OGD/R + si-NC, OGD/R + si-TUG1 + mdivi-1 (a mitophagy inhibitor). The reoxygenation duration of OGD/R was set at 12 h and cells were incubated with 25 μmol/L mdivi-1 during reoxygenation. TUNEL assay was performed to evaluate cell apoptosis in SH-SY5Y cells. Scale bar=50 μm. (PNG 407 kb)

High resolution image (TIF 1.21 mb)

Supplementary Figure 2

The effect of FBXW7/SIRT1 axis on cell apoptosis in OGD/R-treated SH-SY5Y cells. SH-SY5Y cells were grouped into OGD/R + si-NC, OGD/R + si-TUG1, OGD/R + si-TUG1 + pcDNA, OGD/R + si-TUG1 + pcDNA-FBXW7, OGD/R + si-TUG1 + pcDNA-FBXW7 + pcDNA-SIRT1. The reoxygenation duration of OGD/R was performed for 12 h. TUNEL assay was carried out to assess the apoptosis of SH-SY5Y cells. Scale bar=50 μm. (PNG 904 kb)

High resolution image (TIF 928 kb)

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Xue, Lx., Chen, Sf., Xue, Sx. et al. LncRNA TUG1 compromised neuronal mitophagy in cerebral ischemia/reperfusion injury by targeting sirtuin 1. Cell Biol Toxicol 38, 1121–1136 (2022). https://doi.org/10.1007/s10565-022-09700-w

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