Glycogen synthase kinase-3β opens mitochondrial permeability transition pore through mitochondrial hexokinase II dissociation

Tanaka, Takamitsu; Saotome, Masao; Katoh, Hideki; Satoh, Terumori; Hasan, Prottoy; Ohtani, Hayato; Satoh, Hiroshi; Hayashi, Hideharu; Maekawa, Yuichiro

doi:10.1007/s12576-018-0611-y

Cited by 21 publications

(10 citation statements)

References 22 publications

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“…However, under specific circumstances, such as hypoxia or I/R, a large number of free radicals promote MPTP opening, further causing mitochondrial damage and proapoptotic factor release (2). Numerous studies have confirmed that the mitochondrial dysfunction caused by MPTP opening serves an important role in cell necrosis and apoptosis during I/R (2,7,30,41). In the early reperfusion stage, I/R damage can be directly ameliorated if MPTP opening is effectively inhibited (4,30).…”

Section: Discussionmentioning

confidence: 99%

EP4 activation ameliorates liver ischemia/reperfusion injury via ERK1/2‑GSK3β‑dependent MPTP inhibition

Cai

Wang

et al. 2020

Int J Mol Med

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Prostaglandin E receptor subtype 4 (EP4) is widely distributed in the heart, but its role in hepatic ischemia/reperfusion (I/R), particularly in mitochondrial permeability transition pore (MPTP) modulation, is yet to be elucidated. In the present study, an EP4 agonist (cAY10598) was used in a rat model to evaluate the effects of EP4 activation on liver I/R and the mechanisms underlying this. I/R insult upregulated hepatic EP4 expression during early reperfusion. In addition, subcutaneous cAY10598 injection prior to the onset of reperfusion significantly increased hepatocyte cAMP concentrations and decreased serum ALT and AST levels and necrotic and apoptotic cell percentages, after 6 h of reperfusion. Moreover, cAY10598 protected mitochondrial morphology, markedly inhibited mitochondrial permeability transition pore (MPTP) opening and decreased liver reactive oxygen species levels. This occurred via activation of the ERK1/2-GSK3β pathway rather than the janus kinase (JAK)2-signal transducers and activators of transcription (STAT)3 pathway, and resulted in prevention of mitochondria-associated cell injury. The MPTP opener carboxyatractyloside (cATR) and the ERK1/2 inhibitor Pd98059 also partially reversed the protective effects of CAY10598 on the liver and mitochondria. The current findings indicate that EP4 activation induces ERK1/2-GSK3β signaling and subsequent MPTP inhibition to provide hepatoprotection, and these observations are informative for developing new molecular targets and preventative therapies for I/R in a clinical setting.

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Section: Discussionmentioning

confidence: 99%

EP4 activation ameliorates liver ischemia/reperfusion injury via ERK1/2‑GSK3β‑dependent MPTP inhibition

Cai

Wang

et al. 2020

Int J Mol Med

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“…Based on this study and that conducted by Tanaka, who demonstrated that GSK-3 and mainly the GSK-3β isoform plays a key role in opening the mitochondrial mega-channels (Tanaka et al, 2018), increased gene expression of this enzyme is expected to result in the induction of mitochondrial dysfunction. In the present study, however, we surprisingly observed that glucose given in high doses signi icantly decreased the expression of mRNA of GSK-3β isoform but increased the expression of GSK-3α, possibly demonstrating the implication of the later in hyperglycemia-induced mitochondrial impairment.…”

Section: Expression Of Glycogen Synthase Kinasementioning

confidence: 70%

Differential expression of glycogen synthase kinase 3α and 3β isomers in brain cortex of mice following high doses of glucose

Alaraj

Kosińska

Al‐Trad

et al. 2020

ijrps

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Glycogen synthase kinase 3 (GSK3) encodes a serine/threonine protein kinase. We investigated the effects of Subcutaneous (SC) glucose administration on the expression of glycogen synthase kinase 3 (GKS-3) isomers (α and β) genes in the cerebral cortex of mice with the aim of determining the possible mechanism(s) involved in mitochondrial dysfunction induced by hyperglycemia. Adult male BALB/c mice were treated with 12 gm/kg glucose solution SC once daily for 3 days. Ultrastructure study, histopathological analysis, and Real-time PCR investigations were carried out on the cerebral cortex from glucose treated mice and from vehicle-treated control animals. We observed significant ultrastructural damage of mitochondria in the cerebral cortex of mice received high doses of glucose. Histopathological alterations in the cortex of these animals were also detected. A significant increased of GSK-3α gene expression and decreased expressions of GKS-3β gene in high glucose treated animals were noticed. The hyperglycemia-induced ultrastructural changes may occur via modulation of gene expression of GSK-3 isomers, and we hypothesize this as an early etiopathological factor in hyperglycemia-related neurodegenerative diseases (NDD). It considered the first study describing "modulation of expression of GSK-3 isomer genes" as a possible mechanism of hyperglycemia-induced mitochondrial dysfunction.

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“…The GSK3β pathway is a primary upstream mPTP regulator (47)(48)(49). A recent study (50) indicated that a prostaglandin E receptor subtype 4 agonist inhibited mPTP opening following ischemia-reperfusion in hepatocytes through the GSK3β pathway.…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E1 attenuates post‑cardiac arrest myocardial dysfunction through inhibition of mitochondria‑mediated cardiomyocyte apoptosis

Fan

et al. 2020

Mol Med Rep

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Post-cardiac arrest myocardial dysfunction (PAMD) is a leading cause of death in patients undergoing resuscitation patients following cardiac arrest (CA). Although prostaglandin E1 (PGE1) is a clinical drug used to mitigate ischemia injury, its effect on PAMD remains unknown. In the present study, the protective effects of PGE1 on PAMD were evaluated in a rat model of CA and in a hypoxia-reoxygenation (H/R) in vitro model. Rats were randomly assigned to CA, CA+PGE1 or sham groups. Asphyxia for 8 min followed by cardiopulmonary resuscitation were performed in the CA and CA+PGE1 groups. PGE1 was intravenously administered at the onset of return of spontaneous circulation (ROSC). PGE1 treatment significantly increased the ejection fraction and cardiac output within 4 h following ROSC and improved the survival rate, compared with the CA group. Moreover, PGE1 inactivated GSK3β, prevented mitochondrial permeability transition pore (mPTP) opening, while reducing cytochrome c and cleaved caspase-3 expression, as well as cardiomyocyte apoptosis in the rat model. To examine the underlying mechanism, H/R H9c2 cells were treated with PGE1 at the start of reoxygenation. The changes in GSK3β activity, mPTP opening, cytochrome c and cleaved caspase-3 expression, and apoptosis of H9c2 cells were consistent with those noted in vivo. The results indicated that PGE1 attenuated PAMD by inhibiting mitochondria-mediated cardiomyocyte apoptosis.

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Glycogen synthase kinase-3β opens mitochondrial permeability transition pore through mitochondrial hexokinase II dissociation

Cited by 21 publications

References 22 publications

EP4 activation ameliorates liver ischemia/reperfusion injury via ERK1/2‑GSK3β‑dependent MPTP inhibition

EP4 activation ameliorates liver ischemia/reperfusion injury via ERK1/2‑GSK3β‑dependent MPTP inhibition

Differential expression of glycogen synthase kinase 3α and 3β isomers in brain cortex of mice following high doses of glucose

Prostaglandin E1 attenuates post‑cardiac arrest myocardial dysfunction through inhibition of mitochondria‑mediated cardiomyocyte apoptosis

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