Sirt3 confers protection against neuronal ischemia by inducing autophagy: Involvement of the AMPK-mTOR pathway

Dai, Shuhui; Chen, Tao; Li, Xia; Yue, Kangyi; Luo, Peng; Yang, Likun; Zhu, Jie; Wang, Yuhai; Zhou, Fei; Jiang, Xiaofan

doi:10.1016/j.freeradbiomed.2017.04.005

Cited by 132 publications

(90 citation statements)

References 52 publications

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“…The significant role of SIRT3 activity in ROS detoxification was shown in studies with oxygen and glucose deprivation‐induced neuronal damage (Dai et al, ), oxidative stress in type I diabetic model (Liu et al, ), heart ischemia‐induced damage (Parodi‐Rullan, Chapa‐Dubocq, Rullan, Jang, & Javadov, ), intracerebral hemorrhage in diabetic animals (Zheng et al, ), or protective mechanisms in adaptive responses of neurons to physiological challenges and resistance to degeneration (Cheng et al, ). Our data show that SIRT3KO mice exhibit increased ROS levels when compared to WT animals with no change after NMN administration.…”

Section: Discussionmentioning

confidence: 97%

Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3‐dependent mechanism in male mice

Klimova

Long

Kristián

2019

J of Neuroscience Research

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Nicotinamide adenine dinucleotide (NAD+) is a central signaling molecule and enzyme cofactor that is involved in a variety of fundamental biological processes. NAD+ levels decline with age, neurodegenerative conditions, acute brain injury, and in obesity or diabetes. Loss of NAD+ results in impaired mitochondrial and cellular functions. Administration of NAD+ precursor, nicotinamide mononucleotide (NMN), has shown to improve mitochondrial bioenergetics, reverse age‐associated physiological decline, and inhibit postischemic NAD+ degradation and cellular death. In this study, we identified a novel link between NAD+ metabolism and mitochondrial dynamics. A single dose (62.5 mg/kg) of NMN, administered to male mice, increases hippocampal mitochondria NAD+ pools for up to 24 hr posttreatment and drives a sirtuin 3 (SIRT3)‐mediated global decrease in mitochondrial protein acetylation. This results in a reduction of hippocampal reactive oxygen species levels via SIRT3‐driven deacetylation of mitochondrial manganese superoxide dismutase. Consequently, mitochondria in neurons become less fragmented due to lower interaction of phosphorylated fission protein, dynamin‐related protein 1 (pDrp1 [S616]), with mitochondria. In conclusion, manipulation of mitochondrial NAD+ levels by NMN results in metabolic changes that protect mitochondria against reactive oxygen species and excessive fragmentation, offering therapeutic approaches for pathophysiologic stress conditions.

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Section: Discussionmentioning

confidence: 97%

Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3‐dependent mechanism in male mice

Klimova

Long

Kristián

2019

J of Neuroscience Research

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“…The decrease of macroautophagy further exacerbated LDs accumulation, eventually leading to hepatotoxicity and severe steatosis [5,45,46]. Most previous studies have recognized SIRT3 as a positive regulator of macroautophagy [16,[47][48][49][50]. Recently, Li et al reported that SIRT3 acted as a negative regulator of macroautophagy [51].…”

Section: Discussionmentioning

confidence: 99%

SIRT3 promotes lipophagy and chaperon-mediated autophagy to protect hepatocytes against lipotoxicity

et al. 2019

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Lipophagy is a lysosomal lipolytic pathway that complements the actions of cytosolic neutral lipases. Chaperon-mediated autophagy (CMA) triggers lipid droplets (LDs) breakdown, to initiate lipolysis via either cytosolic lipases or macroautophagy. SIRT3, a mitochondrial NAD + -dependent deacetylase, regulates the acetylation status and activity of many substrates involving in energy metabolism. However, the role of SIRT3 in regulating lipophagy is controversial. The current study showed that SIRT3 expression was decreased and the macroautophagy flux was blocked in the primary hepatocytes from high-fat diet fed mice and P/O (palmitic acid and oleic acid mixture) treated AML12 mouse hepatocytes, compared with the corresponding controls. SIRT3 overexpression promoted macroautophagy in LDs from P/O-treated hepatocytes through activating AMP-activated protein kinase (AMPK) and unc-51-like kinase 1, to boost LDs digestion. Gain of SIRT3 expression stimulated the formation of lysosome-associated membrane protein 2A (LAMP-2A)-heat shock cognate 71 kDa protein (HSC70)-perilipin-2 (PLN2) complex, to promote CMA process and reduce the stability of LDs in hepatocytes. Moreover, SIRT3 reduced the expression of stearoyl-CoA desaturase 1, to suppress lipogenesis. In addition, SIRT3 overexpression promoted LDs dispersion on detyrosinated microtubules, and directly deacetylated long-chain acyl-CoA dehydrogenase to enhance mitochondrial energetics. Taken together, SIRT3 ameliorates lipotoxicity in hepatocytes, which might be a potential target for the treatment of nonalcoholic fatty liver disease.

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“…However, most of the neurons and their organelles appeared to be normal in the icariside II -treated group, with less neuronal damage (Figure 2a). Furthermore, we examined the extent of conversion of LC3-I to LC3-II, an important marker of autophagy that is responsible for the formation of autophagosome (Dai et al, 2017), as well as…”

Section: Icariside II Attenuates Cerebral I/r-induced Injury In Ratsmentioning

confidence: 99%

Icariside II, a phosphodiesterase 5 inhibitor, attenuates cerebral ischaemia/reperfusion injury by inhibiting glycogen synthase kinase‐3β‐mediated activation of autophagy

Gao

Long

et al. 2020

British J Pharmacology

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Background and Purpose Cerebral ischaemia/reperfusion causes exacerbated neuronal damage involving excessive autophagy and neuronal loss. The present study was designed to investigate the effect of icariside II, one of main active ingredients of Herba Epimedii on this loss and whether this is related to its PDE 5 inhibitory action. Experimental Approach Focal cerebral ischaemia was induced in the rat by transient middle cerebral artery occlusion over 2 hr, followed by reperfusion with icariside II, 3‐methylamphetamine or rapamycin. The effect of icariside II was determined measuring behaviour changes and the size of the infarction. The expressions of PDE 5, autophagy‐related proteins and the level of phosphorylation of glycogen synthase kinase‐3β (GSK‐3β) were determined. Cultured primary cortical neurons were subjected to oxygen and glucose deprivation followed by reoxygenation in the presence and absence of icariside II. A surface plasmon resonance assay and molecular docking were used to explore the interactions of icariside II with PDE 5 or GSK‐3β. Key Results Icariside II not only protected against induced ischaemic reperfusion injury in rats but also attenuated such injury in primary cortical neurons. The neuroprotective effects of icariside II on such injury were attributed to interfering with the PKG/GSK‐3β/autophagy axis by directly bounding to PDE 5 and GSK‐3β. Conclusions and Implications These findings indicate that icariside II attenuates cerebral I/R‐induced injury via interfering with PKG/GSK‐3β/autophagy axis. This study raises the possibility that icariside II and other PDE 5 inhibitors maybe effective in the treatment ischaemia stroke.

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Sirt3 confers protection against neuronal ischemia by inducing autophagy: Involvement of the AMPK-mTOR pathway

Cited by 132 publications

References 52 publications

Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3‐dependent mechanism in male mice

Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3‐dependent mechanism in male mice

SIRT3 promotes lipophagy and chaperon-mediated autophagy to protect hepatocytes against lipotoxicity

Icariside II, a phosphodiesterase 5 inhibitor, attenuates cerebral ischaemia/reperfusion injury by inhibiting glycogen synthase kinase‐3β‐mediated activation of autophagy

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