Modulation of the mitochondrial permeability transition pore complex in GSK-3β-mediated myocardial protection

Nishihara, Masahiro; Miura, Tetsuji; Miki, Takayuki; Tanno, Masaya; Yano, Toshiyuki; Naitoh, Kazuyuki; Ohori, Katsuhiko; Hotta, Hiroyuki; Terashima, Yoshiaki; Shimamoto, Kazuaki

doi:10.1016/j.yjmcc.2007.08.010

Cited by 209 publications

(187 citation statements)

References 30 publications

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“…6 Accumulating evidence indicates that phospho-Ser9-GSK3β-mediated cytoprotection is achieved by an increased threshold for permeability transition pore (PTP) opening. [6][7][8][9] The mechanism by which GSK3β delays PTP opening still remains unclear. It has been reported that GSK3β could interact with ANT at the inner mitochondrial membrane in the heart 9 and/or to phosphorylate voltage-dependent anion channel (VDAC) and cyclophilin D (CypD) in cancer cells.…”

mentioning

confidence: 99%

“…[6][7][8][9] The mechanism by which GSK3β delays PTP opening still remains unclear. It has been reported that GSK3β could interact with ANT at the inner mitochondrial membrane in the heart 9 and/or to phosphorylate voltage-dependent anion channel (VDAC) and cyclophilin D (CypD) in cancer cells. 10,11 GSK3β also has other proposed mechanisms of action, including a poorly characterized role in calcium (Ca 2+ ) homeostasis regulation 12 and protein-protein interactions, 9 as well as functions in different subcellular fractions such as the nucleus, cytosol and mitochondria.…”

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confidence: 99%

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The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury

Gomez¹,

Thiebaut²,

Paillard³

et al. 2015

Cell Death Differ

108

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Glycogen synthase kinase-3β (GSK3β) is a multifunctional kinase whose inhibition is known to limit myocardial ischemiareperfusion injury. However, the mechanism mediating this beneficial effect still remains unclear. Mitochondria and sarco/ endoplasmic reticulum (SR/ER) are key players in cell death signaling. Their involvement in myocardial ischemia-reperfusion injury has gained recognition recently, but the underlying mechanisms are not yet well understood. We questioned here whether GSK3β might have a role in the Ca 2+ transfer from SR/ER to mitochondria at reperfusion. We showed that a fraction of GSK3β protein is localized to the SR/ER and mitochondria-associated ER membranes (MAMs) in the heart, and that GSK3β specifically interacted with the inositol 1,4,5-trisphosphate receptors (IP 3 Rs) Ca 2+ channeling complex in MAMs. We demonstrated that both pharmacological and genetic inhibition of GSK3β decreased protein interaction of IP 3 R with the Ca 2+ channeling complex, impaired SR/ER Ca 2+ release and reduced the histamine-stimulated Ca 2+ exchange between SR/ER and mitochondria in cardiomyocytes. During hypoxia reoxygenation, cell death is associated with an increase of GSK3β activity and IP 3 R phosphorylation, which leads to enhanced transfer of Ca 2+ from SR/ER to mitochondria. Inhibition of GSK3β at reperfusion reduced both IP 3 R phosphorylation and SR/ER Ca 2+ release, which consequently diminished both cytosolic and mitochondrial Ca 2+ concentrations, as well as sensitivity to apoptosis. We conclude that inhibition of GSK3β at reperfusion diminishes Ca 2+ leak from IP 3 R at MAMs in the heart, which limits both cytosolic and mitochondrial Ca 2+ overload and subsequent cell death. Glycogen synthase kinase-3 (GSK3) was originally identified as a phosphorylating kinase for glycogen synthase. 1,2 It has two isoforms, α and β, that possess strong homology in their kinase domains with, however, distinct functions. 3 GSK3 is constitutively active but it can be inhibited by phosphorylation on serine 21 (Ser21) for GSK3α and Ser9 for GSK3β. 4 In the heart, GSK3β has several important roles in cardiac hypertrophy 5 and ischemia-reperfusion (IR) injury. 6 Accumulating evidence indicates that phospho-Ser9-GSK3β-mediated cytoprotection is achieved by an increased threshold for permeability transition pore (PTP) opening. [6][7][8][9] The mechanism by which GSK3β delays PTP opening still remains unclear. It has been reported that GSK3β could interact with ANT at the inner mitochondrial membrane in the heart 9 and/or to phosphorylate voltage-dependent anion channel (VDAC) and cyclophilin D (CypD) in cancer cells. 10,11 GSK3β also has other proposed mechanisms of action, including a poorly characterized role in calcium (Ca 2+ ) homeostasis regulation 12 and protein-protein interactions, 9 as well as functions in different subcellular fractions such as the nucleus, cytosol and mitochondria. 13 Reperfusion is the most powerful intervention to salvage ischemic myocardium. However, it can also paradoxically lead to ca...

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confidence: 99%

mentioning

confidence: 99%

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury

Gomez¹,

Thiebaut²,

Paillard³

et al. 2015

Cell Death Differ

108

View full text Add to dashboard Cite

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“…This may contribute to higher susceptibility to mPTP opening (Marzetti et al., 2008) and to the reduction in affinity of ANT for CypD. An increased phospho‐GSK‐3β binding to ANT was suggested to be responsible for the inhibition of mPTP opening (Miura & Tanno, 2010; Nishihara et al., 2007). This mechanism would contribute to the cardioprotective effect of several drugs such as formononetin or resveratrol and of ischemic preconditioning (Cheng, Xia, Han, & Rong, 2016; Xi, Wang, Mueller, Norfleet, & Xu, 2009; Zhu, Rebecchi, Glass, Brink, & Liu, 2013; Zhu, Rebecchi, Wang, et al., 2013).…”

Section: Putative Molecular Components Of Mptp and Agingmentioning

confidence: 99%

Mitochondria and aging: A role for the mitochondrial transition pore?

2018

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SummaryThe cellular mechanisms responsible for aging are poorly understood. Aging is considered as a degenerative process induced by the accumulation of cellular lesions leading progressively to organ dysfunction and death. The free radical theory of aging has long been considered the most relevant to explain the mechanisms of aging. As the mitochondrion is an important source of reactive oxygen species (ROS), this organelle is regarded as a key intracellular player in this process and a large amount of data supports the role of mitochondrial ROS production during aging. Thus, mitochondrial ROS, oxidative damage, aging, and aging‐dependent diseases are strongly connected. However, other features of mitochondrial physiology and dysfunction have been recently implicated in the development of the aging process. Here, we examine the potential role of the mitochondrial permeability transition pore (mPTP) in normal aging and in aging‐associated diseases.

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“…Mcl-1 has been shown to play a protective role in other types of liver injury (47,48), and thus its degradation may play an important role in APAP-induced liver injury. The translocation of GSK-3␤ to mitochondria, independent of Mcl-1 regulation, has also been shown to promote MPT in heart (17,18). Thus, GSK-3␤ translocation to mitochondria during APAP hepatotoxicity may also play an important role in mediating mitochondria dysfunction.…”

Section: Mcl-1mentioning

confidence: 99%

Silencing Glycogen Synthase Kinase-3β Inhibits Acetaminophen Hepatotoxicity and Attenuates JNK Activation and Loss of Glutamate Cysteine Ligase and Myeloid Cell Leukemia Sequence 1

Shinohara

Ybanez

Win

et al. 2010

Journal of Biological Chemistry

108

101

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Modulation of the mitochondrial permeability transition pore complex in GSK-3β-mediated myocardial protection

Cited by 209 publications

References 30 publications

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury

Mitochondria and aging: A role for the mitochondrial transition pore?

Silencing Glycogen Synthase Kinase-3β Inhibits Acetaminophen Hepatotoxicity and Attenuates JNK Activation and Loss of Glutamate Cysteine Ligase and Myeloid Cell Leukemia Sequence 1

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