Rapamycin attenuates mitochondrial dysfunction via activation of mitophagy in experimental ischemic stroke

Li, Qiang; Zhang, Ting; Wang, Jixian; Zhang, Zhijun; Yu, Zhengquan; Yang, Guo‐Yuan; Sun, Xiaojiang

doi:10.1016/j.bbrc.2014.01.032

Cited by 167 publications

(126 citation statements)

References 27 publications

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“…It was worth mentioning that in the present study we assessed autophagic flux via monitoring the fluorescence of mRFP-GFP-LC3 constructs. In addition, in our experiment little mitophagy were not founded by TEM, which seemed not consist with some previous researches [36, 37]. The results of TEM showed several mitochondrial were swelling and vacuolar.…”

Section: Discussionmentioning

confidence: 60%

Mitofusin 2 Exerts a Protective Role in Ischemia Reperfusion Injury Through Increasing Autophagy

Peng

Rao

Zhang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Autophagy is essential for maintaining cellular homeostasis and the survival of terminally differentiated cells as neurons. In this study, we aim to investigate whether mitofusin 2, a mitochondrial fusion protein, mediates autophagy in cerebral ischemia/reperfusion (I/R) injury. Methods: Primary cultured neurons were treated with oxygen-glucose deprivation/reperfusion to mimic cerebral I/R injury in vitro. Autophagosomes were visualized upon TEM. Autophagy-markers were then detected to monitor autophagy by western-blot and real-time PCR, and the autophagic flux was tracked with a mRFP-GFP-LC3 construct by fluorescence as well as autophagy inhibitors and agonists. The up- and downregulation of Mfn2 were through transfecting a lentivirusexpression vector respectively. And neuronal injury was detected by cell counting kit and TUNEL assay. Results: Results showed I/R increased autophagosome formation and inhibited autolysosome degradation. Furthermore, use of autophagy related agents demonstrated that I/R injury was caused by insufficient autophagy and aggravated by impaired autophagic degradation. The results also indicated that mitofusin 2 could ameliorate I/R injury through increasing autophagosome formation and promoting the fusion of autophagosomes and lysosomes. In contrast, downregulation of mitofusin 2 aggravated the I/R injury by inhibiting autophagosome formation and the fusion of autophagosomes and lysosomes. Additionly, mitofusin 2 overexpression did not lead to autolysosome accumulation induced by I/R. Conclusions: In summary, this study explicitly demonstrated that mitofusin 2 could ameliorate I/R injury mainly through promoting autophagy, which represented a potential novel strategy for neuroprotection against cerebral I/R damage.

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Section: Discussionmentioning

confidence: 60%

Mitofusin 2 Exerts a Protective Role in Ischemia Reperfusion Injury Through Increasing Autophagy

Peng

Rao

Zhang

et al. 2018

Cell Physiol Biochem

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“…Dysfunctional mitophagy has been implicated in several human CNS diseases, including Alzheimer's disease [24] and Parkinson's disease [25] . I ntriguingly, it has also been reported in ischemic brain injury by several independent groups [15,[26][27][28] .…”

Section: Introductionmentioning

confidence: 95%

“…However, in the reperfusion phase after ischemia, mitophagy plays beneficial roles [15] . Inhibition of autophagy either pharmacologically or genetically rescues the ischemic brain [15] and conversely, injection of rapamycin, an autophagy inducer, has the opposite effects in rats with transient MCAO [28] . More interestingly, inhibition of autophagy immediately after reperfusion aggravates ischemic brain injury by reducing mitochondriabased apoptosis [15] , while delayed inhibition of autophagy by 3-MA after reperfusion (3 h later) does not signifi cantly increase brain damage (unpublished data), indicating that the protective action of autophagy occurs only at the initial step.…”

mentioning

confidence: 99%

Regulation of mitophagy in ischemic brain injury

et al. 2015

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The selective degradation of damaged or excessive mitochondria by autophagy is termed mitophagy. Mitophagy is crucial for mitochondrial quality control and has been implicated in several neurodegenerative disorders as well as in ischemic brain injury. Emerging evidence suggested that the role of mitophagy in cerebral ischemia may depend on different pathological processes. In particular, a neuroprotective role of mitophagy has been proposed, and the regulation of mitophagy seems to be important in cell survival. For these reasons, extensive investigations aimed to profile the mitophagy process and its underlying molecular mechanisms have been executed in recent years. In this review, we summarize the current knowledge regarding the mitophagy process and its role in cerebral ischemia, and focus on the pathological events and molecules that regulate mitophagy in ischemic brain injury.

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“…To evaluate the impairment of neuronal function after tMCAO, a neurological deficit grading system with a scale of zero to five was performed on each animal as described previously (n = 16 in each group) [19]: grade 0: normal behavior; grade 1: rats exhibited contralateral forelimb consistently flexed during the suspension from the tail; grade 2: rats moved spontaneously in all directions but exhibited a monodirectional circling toward the paretic side; grade 3: rats exhibited a consistent spontaneous contralateral circling; grade 4: rats were very weak and walked only when stimulated; and grade 5: rats died by the day of assessment. Higher scores indicated more severe impairment of neuronal function.…”

Section: Neurological Deficit Evaluationmentioning

confidence: 99%

Neuroprotective Effects of (−)-Epigallocatechin-3-Gallate Against Focal Cerebral Ischemia/Reperfusion Injury in Rats Through Attenuation of Inflammation

Zhang

Lin-lan

et al. 2015

Neurochem Res

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Stroke is the second leading cause of death among adults worldwide. (-)-Epigallocatechin-3-gallate (EGCG) has been demonstrated to exhibit neuroprotective functions in cerebral ischemia/reperfusion injury. However, the underlying mechanisms in this process and its contribution to the protection function remain unknown. The current study examined the neuroprotective effects of EGCG after transient middle cerebral artery occlusion (tMCAO) in rats. tMCAO for 120 min was induced in male Sprague-Dawley rats treated with EGCG (50 mg/kg, i.p.) or Vehicle immediately after reperfusion. Neurological score, infarct ratio and inflammation-related molecules (assessed by 2,3,5-triphenyltetrazolium chloride, enzyme-linked immunosorbent assays, quantitative real-time PCR or western blotting) were estimated at 24 h after operation. EGCG prevented the impairment of neurological function and decreased the infarct volume, compared with the Vehicle group. The inflammation-related molecules TNF-α, IL-1β, IL-6 levels usually caused by ischemia/reperfusion were significantly ameliorated by EGCG. EGCG also inhibited the upregulation of nuclear factor-kappa B/p65 (NF-κB/p65), and induction of cyclooxygenase 2 and inducible nitric oxide synthase. The present study indicates that EGCG may be a promising therapeutic agent for cerebral ischemia/reperfusion injury through attenuation of inflammation.

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Rapamycin attenuates mitochondrial dysfunction via activation of mitophagy in experimental ischemic stroke

Cited by 167 publications

References 27 publications

Mitofusin 2 Exerts a Protective Role in Ischemia Reperfusion Injury Through Increasing Autophagy

Mitofusin 2 Exerts a Protective Role in Ischemia Reperfusion Injury Through Increasing Autophagy

Regulation of mitophagy in ischemic brain injury

Neuroprotective Effects of (−)-Epigallocatechin-3-Gallate Against Focal Cerebral Ischemia/Reperfusion Injury in Rats Through Attenuation of Inflammation

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