Sirt3 inhibits cerebral ischemia-reperfusion injury through normalizing Wnt/β-catenin pathway and blocking mitochondrial fission

Abstract

Cerebral ischemia-reperfusion injury (IRI) potentiates existing brain damage and increases mortality and morbidity via poorly understood mechanisms. The aim of our study is to investigate the role of Sirtuin 3 (Sirt3) in the development and progression of cerebral ischemia-reperfusion injury with a focus on mitochondrial fission and the Wnt/β-catenin pathway. Our data indicated that Sirt3 was downregulated in response to cerebral IRI. However, the overexpression of Sirt3 reduced the brain infarction area and repressed IRI-mediated neuron apoptosis. Functional assays demonstrated that IRI augmented mitochondrial fission, which induced ROS overproduction, redox imbalance, mitochondrial pro-apoptotic protein leakage, and caspase-9-dependent cell death pathway activation. However, the overexpression of Sirt3 blocked mitochondrial fission and induced pro-survival signals in neurons subjected to IRI. At the molecular level, our data further illustrated that the Wnt/β-catenin pathway is required for the neuroprotection exerted by Sirt3 overexpression. Wnt/β-catenin pathway activation via inhibiting β-catenin phosphorylation attenuates mitochondrial fission and mitochondrial apoptosis. Collectively, our data show that cerebral IRI is associated with Sirt3 downregulation, Wnt/β-catenin pathway phosphorylated inactivation, and mitochondrial fission initiation, causing neurons to undergo caspase-9-dependent cell death. Based on this, strategies for enhancing Sirt3 activity and activating the Wnt/β-catenin pathway could be therapeutic targets for treating cerebral ischemia-reperfusion injury.

Cannabinoid CB1 receptor agonist ACEA alleviates brain ischemia/reperfusion injury via CB1–Drp1 pathway

“…However, excessive mitochondrial fission produces a large amount of mitochondrial fragments, which are harmful to the homeostasis and functions of cells. Excessive mitochondrial fission has been reported to be involved in brain IRI, serving as a primary contributor to cerebral IRI-induced neuronal death 28 . In this study, by observing mitochondrial length and measuring the expression of mitochondrial fission-associated proteins 29 , we found that activation of the cannabinoid CB1 receptor using ACEA reduced OGD/R-or brain ischemia-induced mitochondrial fission and dysfunction.…”

“…Focal cerebral ischemia/reperfusion injury was performed as described previously 28 . The treatment of the animals conformed to the Committee on Publication Ethics guidelines.…”

Will Sirtuins Be Promising Therapeutic Targets for TBI and Associated Neurodegenerative Diseases?

“…Findings from rat models of TBI have revealed that ceramide is the first lipid to accumulate in the mitochondria after TBI (Roux et al, 2016), suggesting it may serve as a therapeutic indicator (Barbacci et al, 2017). Ceramide accumulation causes mitochondrial dysfunction (Novgorodov et al, 2016), which is associated with increased mitochondrial fission and excessive ROS production (Zhao et al, 2018). According to existing research, SIRT1 and SIRT3 have been detected to alleviate oxidative stress in TBI models (Rangarajan et al, 2015;Zou et al, 2018).…”

Overexpression of Mst1 reduces gastric cancer cell viability by repressing the AMPK-Sirt3 pathway and activating mitochondrial fission

“… 22 Elevated Sirt3 blocks mitochondrial fission in cerebral ischemia–reperfusion via suppressing the Wnt/β-catenin pathway. 23 In contrast, Sirt3 deficiency exacerbates p53-related mitochondrial dysfunction in aged hearts. 24 However, whether Mst1 has a role in regulating mitochondrial fission via the AMPK-Sirt3 pathway is not clear.…”