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Oxygen–Glucose Deprivation/Reperfusion-Induced Sirt3 Reduction Facilitated Neuronal Injuries in an Apoptosis-Dependent Manner During Prolonged Reperfusion

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Abstract

Cerebral ischemia is a major cause of morbidity and permanent disability. To date, no treatments for cerebral ischemia/reperfusion injury can be effectively administered beyond 4–6 h after the ischemic insult. Our study aimed to clarify the significance of Sirt3 during acute cerebral ischemia and explore Sirt3-targeted therapy for ischemic injuries. Upon establishing the oxygen–glucose deprivation/reperfusion (OGD/R) cell model, changes of Sirt3 protein levels and the effects of Sirt3 overexpression on primary hippocampal neurons were detected at indicated time points. Moreover, mitochondrial damage was observed in neurons upon OGD/R injury. The results showed that compared with the normoxia group, Sirt3 protein was significantly decreased in hippocampal neurons exposed to 1 h of OGD followed by 12 h of reperfusion. In addition, the reduction of Sirt3 protein levels contributed to OGD/R-induced neuronal injuries, a higher ratio of neuronal apoptosis, and extensive production of reactive oxygen species (ROS). However, all neuronal injuries were partly rescued by Sirt3 overexpression induced by lentivirus transfection. Mitochondrial morphologies were significantly impaired after OGD/R, but partly salvaged by Sirt3 overexpression. We further explored whether pharmacologically activating Sirt3 is protective for neurons, and found that treatment with honokiol (a Sirt3 agonist) after OGD exposure activated Sirt3 during reperfusion and significantly alleviated OGD/R-induced neuronal injuries. Because mitochondrial functions are essential for neuronal survival, the current results indicate that Sirt3 may be an efficient target to suppress ischemic injuries via maintenance of mitochondrial homeostasis. Our current findings shed light on a novel therapeutic strategy against subacute ischemic injuries.

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Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Funding

The research leading to these results received funding from the National Natural Science Foundation of China under Grant Agreement No 31771292, 31571162 and from Natural Science Foundation of Beijing Municipality under Grant Agreement No 7202006.

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Authors and Affiliations

  1. Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, People’s Republic of China

    Rongqi Wan, Jiahui Fan, Huimeng Song & Yanling Yin

  2. Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China

    Wei Sun

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  1. Rongqi Wan
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  4. Wei Sun
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Contributions

Conceptualization: RW, JF, YY; Data curation: HS, JF; Formal analysis: WS; Funding acquisition: YY; Investigation: RW, JF; Project administration: YY; Resources: YY; Supervision: WS; Validation: HS; Visualization: HS, JF; Writing—original draft: RW, WS; Writing—review & editing: RW, YY. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Wei Sun or Yanling Yin.

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All procedures involving care and operations of animals were approved by the Ethics Committee of Institutional Animal Care and Use Committee (IACUC), and followed the Code of Practice for the Housing and Care of Animals Used in Scientific Procedures (Protocol Code AEEI-2018–024).

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Wan, R., Fan, J., Song, H. et al. Oxygen–Glucose Deprivation/Reperfusion-Induced Sirt3 Reduction Facilitated Neuronal Injuries in an Apoptosis-Dependent Manner During Prolonged Reperfusion. Neurochem Res 47, 1012–1024 (2022). https://doi.org/10.1007/s11064-021-03502-y

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