Mitochondrial c-Jun N-terminal Kinase (JNK) Signaling Initiates Physiological Changes Resulting in Amplification of Reactive Oxygen Species Generation

Chambers, Jeremy W.; LoGrasso, Philip V.

doi:10.1074/jbc.m111.223602

Cited by 162 publications

(169 citation statements)

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“…1A), which indicates that MLK3 plays a critical role in APAPinduced JNK activation in hepatocytes. It was demonstrated that oxidative stress causes JNK activation and translocation to the mitochondria (Chambers and LoGrasso, 2011). However, it is not known which cellular compartment MLK3 signals for JNK activation or whether activated MLK3 also is translocated to the mitochondria.…”

Section: Discussionmentioning

confidence: 99%

“…Once the intracellular pool of GSH is depleted, NAPQI covalently modifies cellular proteins, which results in mitochondrial dysfunction and oxidative stress (Hinson et al, 2004;Jaeschke and Bajt, 2006). Oxidative stress induces c-Jun NH 2 -terminal kinase (JNK) activation, which is thought to promote mitochondrial dysfunction and mitochondrial permeability transition and thereby to amplify oxidative stress and to lead to sustained JNK activation, which ultimately causes cell death (Saito et al, 2010;Chambers and LoGrasso, 2011). Genetic deletion and pharmacological inhibition studies suggested that JNK activation plays a major role in APAP-induced hepatotoxicity (Gunawan et al, 2006;Henderson et al, 2007;Latchoumycandane et al, 2007;Hanawa et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Critical Role for Mixed-Lineage Kinase 3 in Acetaminophen-Induced Hepatotoxicity

2012

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c-Jun NH 2 -terminal kinase (JNK) activation plays a major role in acetaminophen (APAP)-induced hepatotoxicity. However, the exact mechanism of APAP-induced JNK activation is incompletely understood. It has been established that apoptosis signal-regulating kinase 1 (ASK1) regulates the late phase of APAP-induced JNK activation, but the mitogen-activated protein kinase kinase kinase that mediates the initial phase of APAP-induced JNK activation has not been identified. Oxidative stress produced during APAP metabolism causes JNK activation, which promotes mitochondrial dysfunction and results in the amplification of oxidative stress. Therefore, inhibition of the initial phase of JNK activation may be key to protection against APAP-induced liver injury. The goal of this study was to determine whether mixed-lineage kinase 3 (MLK3) mediates the initial, ASK1-independent phase of APAP-induced JNK activation and thus promotes drug-induced hepatotoxicity. We found that MLK3 was activated by oxidative stress and was required for JNK activation in response to oxidative stress. Loss of MLK3 attenuated APAP-induced JNK activation and hepatocyte death in vitro, independent of receptor-interacting protein 1. Moreover, JNK and glycogen synthase kinase 3␤ activation was significantly attenuated, and Mcl-1 degradation was inhibited in APAP-treated MLK3-knockout mice. Furthermore, we showed that loss of MLK3 increased expression of glutamate cysteine ligase, accelerated hepatic GSH recovery, and decreased production of reactive oxygen species after APAP treatment. MLK3-deficient mice were significantly protected from APAP-induced liver injury, compared with wildtype mice. Together, these studies establish a novel role for MLK3 in APAP-induced JNK activation and hepatotoxicity, and they suggest MLK3 as a possible target in the treatment of APAP-induced liver injury.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Critical Role for Mixed-Lineage Kinase 3 in Acetaminophen-Induced Hepatotoxicity

2012

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“…Conversely, research demonstrated that JNK signaling contributes to the amplification of ROS generation. 43 Therefore, we speculated that the suppressive effect of NAC pretreatment on SiNPs-induced JNK activation may contribute to the decline of elevated ROS level in HUVECs exposed to SiNPs.…”

Section: Discussionmentioning

confidence: 99%

Amorphous silica nanoparticles trigger vascular endothelial cell injury through apoptosis and autophagy via reactive oxygen species-mediated MAPK/Bcl-2 and PI3K/Akt/mTOR signaling

Guo¹,

Yang²,

Li³

et al. 2016

IJN

188

111

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Environmental exposure to silica nanoparticles (SiNPs) is inevitable due to their widespread application in industrial, commercial, and biomedical fields. In recent years, most investigators focus on the evaluation of cardiovascular effects of SiNPs in vivo and in vitro. Endothelial injury and dysfunction is now hypothesized to be a dominant mechanism in the development of cardiovascular diseases. This study aimed to explore interaction of SiNPs with endothelial cells, and extensively investigate the exact effects of reactive oxygen species (ROS) on the signaling molecules and cytotoxicity involved in SiNPs-induced endothelial injury. Significant induction of cytotoxicity as well as oxidative stress, apoptosis, and autophagy was observed in human umbilical vein endothelial cells following the SiNPs exposure ( P <0.05). The oxidative stress was induced by ROS generation, leading to redox imbalance and lipid peroxidation. SiNPs induced mitochondrial dysfunction, characterized by membrane potential collapse, and elevated Bax and declined bcl-2 expression, ultimately leading to apoptosis, and also increased number of autophagosomes and autophagy marker proteins, such as LC3 and p62. Phosphorylated ERK, PI3K, Akt, and mTOR were significantly decreased, but phosphorylated JNK and p38 MAPK were increased in SiNPs-exposed endothelial cells. In contrast, all of these stimulation phenomena were effectively inhibited by N -acetylcysteine. The N -acetylcysteine supplement attenuated SiNPs-induced endothelial toxicity through inhibition of apoptosis and autophagy via MAPK/Bcl-2 and PI3K/Akt/mTOR signaling, as well as suppression of intracellular ROS property via activating antioxidant enzyme and Nrf2 signaling. In summary, the results demonstrated that SiNPs triggered autophagy and apoptosis via ROS-mediated MAPK/Bcl-2 and PI3K/Akt/mTOR signaling in endothelial cells, and subsequently disturbed the endothelial homeostasis and impaired endothelium. Our findings may provide experimental evidence and explanation for cardiovascular diseases triggered by SiNPs. Furthermore, results hint that the application of antioxidant may provide a novel way for safer use of nanomaterials.

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“…Furthermore, JNK1, but not JNK2, was found to mediate starvation-induced Bcl-2 phosphorylation (34). Recently, JNK signaling was shown to mediate amplification of ROS production during multiple stresses, including infection (35). Cellular stress altered mitochondria, causing JNK to translocate to the mitochondria and to amplify up to 80% of the ROS generated largely by complex I. ROS activates JNK via a sequence of events for JNK mitochondrial signaling (35).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, JNK signaling was shown to mediate amplification of ROS production during multiple stresses, including infection (35). Cellular stress altered mitochondria, causing JNK to translocate to the mitochondria and to amplify up to 80% of the ROS generated largely by complex I. ROS activates JNK via a sequence of events for JNK mitochondrial signaling (35). There exists a molecular cross-talk between autophagy and apoptosis, because Beclin 1 can be cleaved by caspases, and its proautophagic activity is lost (36).…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7

Kim¹,

Song³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

165

152

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The intracellular pathogen Mycobacterium tuberculosis (Mtb) causes tuberculosis. Enhanced intracellular survival (Eis) protein, secreted by Mtb, enhances survival of Mycobacterium smegmatis (Msm) in macrophages. Mtb Eis was shown to suppress host immune defenses by negatively modulating autophagy, inflammation, and cell death through JNK-dependent inhibition of reactive oxygen species (ROS) generation. Mtb Eis was recently demonstrated to contribute to drug resistance by acetylating multiple amines of aminoglycosides. However, the mechanism of enhanced intracellular survival by Mtb Eis remains unanswered. Therefore, we have characterized both Mtb and Msm Eis proteins biochemically and structurally. We have discovered that Mtb Eis is an efficient N ɛ -acetyltransferase, rapidly acetylating Lys55 of dualspecificity protein phosphatase 16 (DUSP16)/mitogen-activated protein kinase phosphatase-7 (MKP-7), a JNK-specific phosphatase. In contrast, Msm Eis is more efficient as an N α -acetyltransferase. We also show that Msm Eis acetylates aminoglycosides as readily as Mtb Eis. Furthermore, Mtb Eis, but not Msm Eis, inhibits LPSinduced JNK phosphorylation. This functional difference against DUSP16/MKP-7 can be understood by comparing the structures of two Eis proteins. The active site of Mtb Eis with a narrow channel seems more suitable for sequence-specific recognition of the protein substrate than the pocket-shaped active site of Msm Eis. We propose that Mtb Eis initiates the inhibition of JNK-dependent autophagy, phagosome maturation, and ROS generation by acetylating DUSP16/MKP-7. Our work thus provides insight into the mechanism of suppressing host immune responses and enhancing mycobacterial survival within macrophages by Mtb Eis.Rv2416c | lysine acetylation | antituberculosis drug N early one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb). This pathogenic bacterium causes tuberculosis, which claims the lives of millions of people every year (1). Tuberculosis has also become a global health issue owing to the increased incidences of multidrug-resistant and extensively drug-resistant strains of Mtb (2). This makes a search for targets of new antituberculosis drugs urgent. Mtb is a highly successful human pathogen, surviving and multiplying within the human macrophage cells of the infected people (3). Therefore, treatment of tuberculosis is difficult, requiring many months of taking a combination of antibiotics. Mtb has the ability to persist in the form of a long-term asymptomatic infection, referred to as latent tuberculosis (4). Latent tuberculosis becomes activated when the body's immune system is weakened. As a result, tuberculosis is the major cause of death among immuno-compromised AIDS patients (5).In mycobacterial infection, host innate immune responses may play a crucial role in early protection against Mtb infection, leading to establishment of effective adaptive immunity to tuberculosis (6). Additionally, MAPK pathways are activated by Mtb or its components and play an e...

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Mitochondrial c-Jun N-terminal Kinase (JNK) Signaling Initiates Physiological Changes Resulting in Amplification of Reactive Oxygen Species Generation

Cited by 162 publications

References 48 publications

Critical Role for Mixed-Lineage Kinase 3 in Acetaminophen-Induced Hepatotoxicity

Critical Role for Mixed-Lineage Kinase 3 in Acetaminophen-Induced Hepatotoxicity

Amorphous silica nanoparticles trigger vascular endothelial cell injury through apoptosis and autophagy via reactive oxygen species-mediated MAPK/Bcl-2 and PI3K/Akt/mTOR signaling

Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7

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