Inhibition of JNK Mitochondrial Localization and Signaling Is Protective against Ischemia/Reperfusion Injury in Rats

Chambers, Jeremy W.; Pachori, Alok S.; Howard, Shannon; Iqbal, Saba; LoGrasso, Philip V.

doi:10.1074/jbc.m112.406777

Cited by 70 publications

(97 citation statements)

References 31 publications

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“…It is reported that JNK controlled the rapid depolarization of mitochondrial membranes in rotenone-induced H9c2 cells necrosis [43]. In other context, JNK mitochondrial translocation is responsible for mitochondrial dysfunction and eventually the necrotic cell death [44]. In our study, JNK might acts as a crosstalk between ROS production and mitochondrial dysfunction or as a direct death inducer targeting mitochondria.…”

Section: Discussionmentioning

confidence: 76%

Protoporphyrin IX Induces a Necrotic Cell Death in Human THP-1 Macrophages through Activation of Reactive Oxygen Species/c-Jun N-Terminal Protein Kinase Pathway and Opening of Mitochondrial Permeability Transition Pore

Sun

Zhang

et al. 2014

Cell Physiol Biochem

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Background: Protoporphyrin IX (PpIX) and its derivatives are widely used in photodynamic therapy (PDT) to kill cancer cells. Studies showed that the application of these drugs could cause systemic toxic effects in human. However, the molecular pathways involved in PpIX-induced cytotoxicity are not well-defined. Macrophages represent the primary system for protecting tissues from toxicants and initiating the resolution of inflammation. Thus, this study aims to investigate the toxicity of PpIX on macrophages and provide strategies to prevent the toxic effects. Methods: THP-1 macrophages were incubated with PpIX and cell death was measured by MTT assay and Annexin V-PI staining. Intracellular reactive oxygen species (ROS) were evaluated by 2', 7'-Dichlorodihydrofluorescin diacetate (DCFH-DA) and MitoSOX® Red staining and mitochondrial membrane potential (ΔΨm) was detected by tetramethylrhodamine methyl ester (TMRM) staining. Mitogen-activated protein (MAP) kinase activation was assayed by western blotting. Mitochondrial permeability transition pore (mPTP) opening was measured by calcein loading/Co²⁺ quenching technique and evaluating the release of mitochondrial content. Results: PpIX reduced cell viability in a dose- and time-dependent manner. The cell death was characterized by increasing PI-positive cells, ATP depletion, LDH releasing and rapid ΔΨm loss favoring necrotic features. In addition, PpIX successively induced ROS production, c-Jun N-terminal protein kinase (JNK) activation and mPTP opening. ROS scavengers, N-acetylcysteine (NAC) and deferoxamine (DFX), JNK inhibitor, SP600125, and mPTP inhibitor, cyclosporin A (CsA), all significantly rescued this cell death. Furthermore, mPTP opening was directly regulated by ROS/JNK pathway. Conclusion: PpIX induces a necrotic cell death in THP-1 macrophages through ROS production, JNK activation, and mPTP opening. It is tempting to speculate that blocking the pathways involved in the cytotoxic effects of PpIX will alleviate its side effects.

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Section: Discussionmentioning

confidence: 76%

Protoporphyrin IX Induces a Necrotic Cell Death in Human THP-1 Macrophages through Activation of Reactive Oxygen Species/c-Jun N-Terminal Protein Kinase Pathway and Opening of Mitochondrial Permeability Transition Pore

Sun

Zhang

et al. 2014

Cell Physiol Biochem

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“…The JNK signaling pathway, on the other hand, has been well investigated in neurodegeneration and underscores the importance of JNK in the brain (15,16,18,39,40). The work presented here for the first time links the neuroprotective molecular components of SGK1 with the JNK signaling cascade in a PD neurotoxin cell and animal model.…”

Section: Discussionmentioning

confidence: 89%

Serum- and Glucocorticoid-Inducible Kinase 1 Confers Protection in Cell-Based and in In Vivo Neurotoxin Models via the c-Jun N-Terminal Kinase Signaling Pathway

Iqbal

Howard

LoGrasso

2015

Molecular and Cellular Biology

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Serum glucocorticoid kinase 1 (SGK1) has been shown to be protective in models of Parkinson's disease, but the details by which it confers benefit is unknown. The current study was designed to investigate the details by which SGK1 confers neuroprotection. To do this we employed a cellular neurodegeneration model to investigate c-Jun N-terminal kinase (JNK) signaling and endoplasmic reticulum (ER) stress induced by 6-hydroxydopamine. SGK1-expressing adenovirus was created and used to overexpress SGK1 in SH-SY5Y cells, and dexamethasone was used to increase endogenous expression of SGK1. Oxidative stress, mitochondrial dysfunction, and cell death were monitored to test the protective effect of SGK1. To investigate the effect of SGK1 overexpression in vivo, SGK1-expressing adenovirus was injected into the striatum of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and protection of dopaminergic neurons was quantitatively assessed by tyrosine hydroxylase immunohistochemistry. SGK1 overexpression was found to decrease reactive oxygen species generation, alleviate mitochondrial dysfunction, and rescue cell death in vitro and in vivo by inactivating mitogen-activated protein kinase kinase 4 (MKK4), JNK, and glycogen synthase kinase 3␤ (GSK3␤) and thereby decreasing ER and oxidative stress. These results suggest that therapeutic strategies for activation of SGK1 may have the potential to be neuroprotective by deactivating the JNK and GSK3␤ pathways.S erum-and glucocorticoid-inducible kinase 1 (SGK1) belongs to the AGC family of kinases and has been shown to have various cellular functions, including the promotion of cell survival (1-3). SGK1 is activated by insulin and growth factors via phosphoinositide 3-kinase (PI3K), 3-phosphoinositide-dependent kinase 1 (PDK1), and mammalian target of rapamycin complex 2 (mTORC2) (4, 5). SGK1 shares its functions and some substrates with another kinase from the AGC family, protein kinase B (PKB/ Akt). Akt, like SGK1, has been shown to mediate cell survival through various signaling cascades and gets activated by a wide range of extracellular stimuli (6). SGK1 lacks the pleckstrin homology (PH) domain that tethers Akt to the plasma membrane, making SGK1 more accessible to cytosolic and nuclear sites and thereby providing it with cellular functions and substrates that do not overlap those of Akt (1, 6). SGK1 plays a protective role in oxidative stress conditions as small interfering RNA (siRNA) knockdown of SGK1 has shown an increase in oxidative stressinduced cell death in HEK293 cells (7). Oxidative stress is a hallmark of neurodegenerative disorders, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) (8). In a study published in 2005 by Schoenebeck et al., upregulation of SGK1 was seen in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model and in a transgenic model of ALS (SOD1-G93A), and protection from cell death was observed for animals treated with dexamethasone (De...

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“…Previous studies showed ischemic postC inhibits the phosphorylation of p38 MAPK, through which it can attenuate Cyt-c release from mitochondria in rat hearts [30]. In addition, studies also demonstrated that I/R induces JNK translocation to the mitochondria by binding to the mitochondrial membrane protein Sab (SH3BP5), and blocking JNK mitochondrial translocation or JNK inhibition prevents mitochondrial dysfunction and cardiomyocyte death [31,32]. The present study also showed that JNK/ p38MAPK activation facilitates mPTP opening during reperfusion, and MpostC inhibits JNK/ p38MAPK activation and results in a decrease in mPTP opening, Cyt-c release and IS/AAR.…”

Section: Discussionmentioning

confidence: 99%

Morphine Postconditioning Protects against Reperfusion Injury via Inhibiting JNK/p38 MAPK and Mitochondrial Permeability Transition Pores Signaling Pathways

Chen

Zhang²,

Liu³

et al. 2016

Cell Physiol Biochem

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Background: The purpose of this study was to determine whether c-jun NH₂ amino-terminal kinases (JNK) and p38 mitogen-activated protein kinases (MAPK) were involved in morphine postconditioning (MpostC). Methods: The isolated rat hearts were randomly assigned into one of the following groups. Hearts in the time control (TC) group were constantly perfused for 105min. Hearts in the ischemia-reperfusion (I/R) group were subjected to 45 min of ischemia followed by 1 h of reperfusion. MpostC was induced by 10 min of morphine administration at the onset of reperfusion. Anisomycin (an activator of JNK/p38 kinases) was administered with or without morphine during the first 10 min of reperfusion following the 45 min of ischemia. Mitochondria and cytosolic proteins were prepared to detect mitochondrial permeability transition (MPT) and cytochrome C (Cyt-c) respectively. Results: MpostC markedly reduced infarct size (IS/AAR), CK-MB release, and improved cardiac function recovery. However, these protective effects were partly abolished in the presence of anisomycin. I/R significantly increased the phosphorylation of JNK and p38 kinases, mitochondrial permeability transition (MPT) opening and Cyt-c release, while these effects were partly abolished by MpostC. The inhibitory effects of MpostC on the phosphorylation of JNK/p38 kinases, MPT opening and Cyt-c release were totally reversed by Anisocycin, which, used individually, did not show any influence on perfusion injury. Conclusions: These findings suggest that MpostC protects isolated rat hearts against reperfusion injury via inhibiting JNK/p38 MAPKs and mitochondrial permeability transition pores signaling pathways.

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Inhibition of JNK Mitochondrial Localization and Signaling Is Protective against Ischemia/Reperfusion Injury in Rats

Cited by 70 publications

References 31 publications

Protoporphyrin IX Induces a Necrotic Cell Death in Human THP-1 Macrophages through Activation of Reactive Oxygen Species/c-Jun N-Terminal Protein Kinase Pathway and Opening of Mitochondrial Permeability Transition Pore

Protoporphyrin IX Induces a Necrotic Cell Death in Human THP-1 Macrophages through Activation of Reactive Oxygen Species/c-Jun N-Terminal Protein Kinase Pathway and Opening of Mitochondrial Permeability Transition Pore

Serum- and Glucocorticoid-Inducible Kinase 1 Confers Protection in Cell-Based and in In Vivo Neurotoxin Models via the c-Jun N-Terminal Kinase Signaling Pathway

Morphine Postconditioning Protects against Reperfusion Injury via Inhibiting JNK/p38 MAPK and Mitochondrial Permeability Transition Pores Signaling Pathways

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