scholarly journals The spatiotemporal regulation of the Keap1–Nrf2 pathway and its importance in cellular bioenergetics

2015 ◽  
Vol 43 (4) ◽  
pp. 602-610 ◽  
Author(s):  
Albena T. Dinkova-Kostova ◽  
Liam Baird ◽  
Kira M. Holmström ◽  
Colin J. Meyer ◽  
Andrey Y. Abramov
Keyword(s):  
Protein Complex ◽  
Reciprocal Relationship ◽  
Acid Oxidation ◽  
Mitochondrial Activity ◽  
Related Factor ◽  
Nrf2 Pathway ◽  
Spatiotemporal Regulation ◽  
Cellular Bioenergetics ◽  
Cellular Defence

The Kelch-like ECH associated protein 1 (Keap1)–NF-E2 p45-related factor 2 (Nrf2) pathway regulates networks of proteins that protect against the cumulative damage of oxidants, electrophiles and misfolded proteins. The interaction between transcription factor Nrf2 and its main negative cytoplasmic regulator Keap1 follows a cycle whereby the protein complex sequentially adopts two conformations: ‘open’, in which Nrf2 binds to one monomer of Keap1, followed by ‘closed’, in which Nrf2 interacts with both members of the Keap1 dimer. Electrophiles and oxidants (inducers) are recognized by cysteine sensors within Keap1, disrupting its ability to target Nrf2 for ubiquitination and degradation. Consequently, the protein complex accumulates in the ‘closed’ conformation, free Keap1 is not regenerated and newly synthesized Nrf2 is stabilized to activate target-gene transcription. The prevailing view of the Keap1–Nrf2 pathway, for which there exists a wealth of experimental evidence, is that it lies at the heart of cellular defence, playing crucial roles in adaptation and survival under conditions of stress. More recently, the significance of Nrf2 in intermediary metabolism and mitochondrial physiology has also been recognized, adding another layer of cytoprotection to the repertoire of functions of Nrf2. One way by which Nrf2 influences mitochondrial activity is through increasing the availability of substrates (NADH and FADH2) for respiration. Another way is through accelerating fatty acid oxidation (FAO). These findings reinforce the reciprocal relationship between oxidative phosphorylation and the cellular redox state, and highlight the key role of Nrf2 in regulating this balance.

scholarly journals Basic Concepts on the Role of Nuclear Factor Erythroid-Derived 2-Like 2 (Nrf2) in Age-Related Diseases

2019 ◽  
Vol 20 (13) ◽  
pp. 3208 ◽  
Author(s):  
Fabiane Valentini Francisqueti-Ferron ◽  
Artur Junio Togneri Ferron ◽  
Jéssica Leite Garcia ◽  
Carol Cristina Vágula de Almeida Silva ◽  
Mariane Róvero Costa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Transcriptional Factor ◽  
Future Research ◽  
Related Factor ◽  
Nuclear Factor ◽  
Nrf2 Pathway ◽  
Age Related ◽  
Basic Concepts

The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is one of the most important oxidative stress regulator in the human body. Once Nrf2 regulates the expression of a large number of cytoprotective genes, it plays a crucial role in the prevention of several diseases, including age-related disorders. However, the involvement of Nrf2 on these conditions is complex and needs to be clarified. Here, a brief compilation of the Nrf2 enrollment in the pathophysiology of the most common age-related diseases and bring insights for future research on the Nrf2 pathway is described. This review shows a controversial response of this transcriptional factor on the presented diseases. This reinforces the necessity of more studies to investigate modulation strategies for Nrf2, making it a possible therapeutic target in the treatment of age-related disorders.

scholarly journals The Role of the Keap1/Nrf2 Pathway in the Cellular Response to Methylmercury

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Yoshito Kumagai ◽  
Hironori Kanda ◽  
Yasuhiro Shinkai ◽  
Takashi Toyama
Keyword(s):  
Cellular Response ◽  
Cultured Cells ◽  
Protein Adducts ◽  
Negative Regulator ◽  
Cellular Damage ◽  
Cellular Proteins ◽  
Related Factor ◽  
Mehg Exposure ◽  
Nrf2 Pathway

Methylmercury (MeHg) is an environmental electrophile that covalently modifies cellular proteins with reactive thiols, resulting in the formation of protein adducts. While such protein modifications, referred to asS-mercuration, are thought to be associated with the enzyme dysfunction and cellular damage caused by MeHg exposure, the current consensus is that (1) there is a cellular response to MeHg through the activation of NF-E2-related factor 2 (Nrf2) coupled toS-mercuration of its negative regulator, Kelch-like ECH-associated protein 1 (Keap1), and (2) the Keap1/Nrf2 pathway protects against MeHg toxicity. In this review, we introduce our findings and discuss the observations of other workers concerning theS-mercuration of cellular proteins by MeHg and the importance of the Keap1/Nrf2 pathway in protection against MeHg toxicity in cultured cells and mice.

scholarly journals The Role of Mitochondrial Calcium Homeostasis in Alzheimer’s and Related Diseases

2020 ◽  
Vol 21 (23) ◽  
pp. 9153
Author(s):  
Kerry C. Ryan ◽  
Zahra Ashkavand ◽  
Kenneth R. Norman
Keyword(s):  
Neurodegenerative Diseases ◽  
Calcium Signaling ◽  
Mitochondrial Function ◽  
Reciprocal Relationship ◽  
Mitochondrial Activity ◽  
Mitochondrial Calcium ◽  
Protein Homeostasis ◽  
Neuronal Function ◽  
The Impact

Calcium signaling is essential for neuronal function, and its dysregulation has been implicated across neurodegenerative diseases, including Alzheimer’s disease (AD). A close reciprocal relationship exists between calcium signaling and mitochondrial function. Growing evidence in a variety of AD models indicates that calcium dyshomeostasis drastically alters mitochondrial activity which, in turn, drives neurodegeneration. This review discusses the potential pathogenic mechanisms by which calcium impairs mitochondrial function in AD, focusing on the impact of calcium in endoplasmic reticulum (ER)–mitochondrial communication, mitochondrial transport, oxidative stress, and protein homeostasis. This review also summarizes recent data that highlight the need for exploring the mechanisms underlying calcium-mediated mitochondrial dysfunction while suggesting potential targets for modulating mitochondrial calcium levels to treat neurodegenerative diseases such as AD.

scholarly journals Targeting Glycogen Synthase Kinase-3βfor Therapeutic Benefit against Oxidative Stress in Alzheimer's Disease: Involvement of the Nrf2-ARE Pathway

2011 ◽  
Vol 2011 ◽  
pp. 1-9 ◽  
Author(s):  
Katja Kanninen ◽  
Anthony R. White ◽  
Jari Koistinaho ◽  
Tarja Malm
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Therapeutic Effects ◽  
Related Factor ◽  
Nrf2 Pathway ◽  
Gsk 3Β

Specific regions of the Alzheimer's disease (AD) brain are burdened with extracellular protein deposits, the accumulation of which is concomitant with a complex cascade of overlapping events. Many of these pathological processes produce oxidative stress. Under normal conditions, oxidative stress leads to the activation of defensive gene expression that promotes cell survival. At the forefront of defence is the nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates a broad spectrum of protective genes. Glycogen synthase kinase-3β (GSK-3β) regulates Nrf2, thus making this kinase a potential target for therapeutic intervention aiming to boost the protective activation of Nrf2. This paper aims to review the neuroprotective role of Nrf2 in AD, with special emphasis on the role of GSK-3β in the regulation of the Nrf2 pathway. We also examine the potential of inducing GSK-3β by small-molecule activators, dithiocarbamates, which potentially exert their beneficial therapeutic effects via the activation of the Nrf2 pathway.

Interpreting and Rendering of Qur’anic Verses in Conformity with Convention and Tradition

2020 ◽  
Vol 28 (2) ◽  
Author(s):  
MAE (Ashraf) Dockrat
Keyword(s):  
Reciprocal Relationship

In this article, the role of convention and tradition in the interpretation and rendering of Qur’anic verses are discussed. An overview is given of the reciprocal relationship between Muslim theology and that which is usually referred to as the “Sciences of the Qur’an”. Selected examples of the rendering of specific Qur’anic verses are  analysed, illustrating the influence (or presumed influence) of classical interpretative sources and convention on the translation of the meanings of the Qur’an.

Healing Touch: Clothed Images of the Virgin in Early Modern Portugal

2020 ◽  
pp. 51-78
Author(s):  
Diana Pereira
Keyword(s):  
Early Modern ◽  
Reciprocal Relationship ◽  
Physical Contact ◽  
Religious Art ◽  
Healing Touch ◽  
Devotional Art ◽  
Healing Power ◽  
The Many ◽  
Santa Maria

Over the last decades there was a growing interest in religious materiality, miraculous images, votive practices, and how the faithful engaged with devotional art, as well as a renewed impetus to discuss the long-recognized association between sculpture and touch, after the predominance of the visuality approach. Additionally, the neglected phenomenon of clothing statues has also been increasingly explored. Based on the reading of Santuario Mariano (1707–1723), written by Friar Agostinho de Santa Maria (1642–1728), this paper will closely examine those topics. Besides producing a monumental catalogue of Marian shrines and pilgrimage sites, this source offers a unique insight into the religious experience and the reciprocal relationship between image and devotee in Early Modern Portugal, and is a particularly rich source when describing the believers’ pursuit of physical contact with sculptures. This yearning for proximity is partly explained by the belief in the healing power of Marian sculptures, which in turn seemed to be conveniently transferred to a myriad of objects. When contact with the images themselves was not possible, devotees sought out their clothes, crowns, rosary beads, metric relics, and so forth. Items of clothing such as mantles and veils were particularly used and so it seems obvious they were not mere adornments or donations, but also mediums and extensions of the sculptures’ presence and power. By focusing on the thaumaturgic role of the statues’ clothes and jewels, I will argue how the practice of dressing sculptures was due to much more than stylistic desires or processional needs and draw attention to the many ways believers engaged with religious art in Early Modern Portugal.

scholarly journals Ndufs4 ablation decreases synaptophysin expression in hippocampus

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Subrata Kumar Shil ◽  
Yoshiteru Kagawa ◽  
Banlanjo Abdulaziz Umaru ◽  
Fumika Nanto-Hara ◽  
Hirofumi Miyazaki ◽  
...  
Keyword(s):  
Nadh Dehydrogenase ◽  
Leigh Syndrome ◽  
Mitochondrial Respiratory Chain ◽  
Mitochondrial Activity ◽  
Mitochondrial Complex ◽  
Neuronal Function ◽  
Mouse Hippocampus ◽  
Extracellular Regulated Kinase ◽  
Presynaptic Protein

AbstractAltered function of mitochondrial respiratory chain in brain cells is related to many neurodegenerative diseases. NADH Dehydrogenase (Ubiquinone) Fe-S protein 4 (Ndufs4) is one of the subunits of mitochondrial complex I and its mutation in human is associated with Leigh syndrome. However, the molecular biological role of Ndufs4 in neuronal function is poorly understood. In this study, upon Ndufs4 expression confirmation in NeuN-positive neurons, and GFAP-positive astrocytes in WT mouse hippocampus, we found significant decrease of mitochondrial respiration in Ndufs4-KO mouse hippocampus. Although there was no change in the number of NeuN positive neurons in Ndufs4-KO hippocampus, the expression of synaptophysin, a presynaptic protein, was significantly decreased. To investigate the detailed mechanism, we silenced Ndufs4 in Neuro-2a cells and we observed shorter neurite lengths with decreased expression of synaptophysin. Furthermore, western blot analysis for phosphorylated extracellular regulated kinase (pERK) revealed that Ndufs4 silencing decreases the activity of ERK signalling. These results suggest that Ndufs4-modulated mitochondrial activity may be involved in neuroplasticity via regulating synaptophysin expression.

scholarly journals Role of cysteine in regulating morphogenesis and mitochondrial activity in the dimorphic fungus Histoplasma capsulatum.

1981 ◽  
Vol 78 (7) ◽  
pp. 4596-4600 ◽  
Author(s):  
B. Maresca ◽  
A. M. Lambowitz ◽  
V. B. Kumar ◽  
G. A. Grant ◽  
G. S. Kobayashi ◽  
...  
Keyword(s):  
Histoplasma Capsulatum ◽  
Mitochondrial Activity ◽  
Dimorphic Fungus

scholarly journals Depdc5 deficiency exacerbates alcohol-induced hepatic steatosis via suppression of PPARα pathway

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Lin Xu ◽  
Xinge Zhang ◽  
Yue Xin ◽  
Jie Ma ◽  
Chenyan Yang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Hepatic Steatosis ◽  
Liver Steatosis ◽  
Pharmacological Intervention ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Pathological Effect ◽  
Mtorc1 Pathway

AbstractAlcohol-related liver disease (ALD), a condition caused by alcohol overconsumption, occurs in three stages of liver injury including steatosis, hepatitis, and cirrhosis. DEP domain-containing protein 5 (DEPDC5), a component of GAP activities towards Rags 1 (GATOR1) complex, is a repressor of amino acid-sensing branch of the mammalian target of rapamycin complex 1 (mTORC1) pathway. In the current study, we found that aberrant activation of mTORC1 was likely attributed to the reduction of DEPDC5 in the livers of ethanol-fed mice or ALD patients. To further define the in vivo role of DEPDC5 in ALD development, we generated Depdc5 hepatocyte-specific knockout mouse model (Depdc5-LKO) in which mTORC1 pathway was constitutively activated through loss of the inhibitory effect of GATOR1. Hepatic Depdc5 ablation leads to mild hepatomegaly and liver injury and protects against diet-induced liver steatosis. In contrast, ethanol-fed Depdc5-LKO mice developed severe hepatic steatosis and inflammation. Pharmacological intervention with Torin 1 suppressed mTORC1 activity and remarkably ameliorated ethanol-induced hepatic steatosis and inflammation in both control and Depdc5-LKO mice. The pathological effect of sustained mTORC1 activity in ALD may be attributed to the suppression of peroxisome proliferator activated receptor α (PPARα), the master regulator of fatty acid oxidation in hepatocytes, because fenofibrate (PPARα agonist) treatment reverses ethanol-induced liver steatosis and inflammation in Depdc5-LKO mice. These findings provide novel insights into the in vivo role of hepatic DEPDC5 in the development of ALD.

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