Emerging evidence for crosstalk between Nrf2 and mitochondria in physiological homeostasis and in heart disease

Tsushima, Megumi; Li, Jun; Hirao, Wataru; Yamazaki, Hiromi; Tomita, Hirofumi; Itoh, Ken

doi:10.1007/s12272-019-01188-z

Cited by 36 publications

(29 citation statements)

References 81 publications

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“…Consistent with the function of the Keap1-mediated "canonical" pathway, "canonical" Nrf2 target genes are those that detoxify environmental electrophiles in the cytosol, such as glutathione S-transferases or cytosolic antioxidant enzymes, as well as those involved in the synthesis of antioxidants such as glutathione and NADPH, in the cytosol [26]. However, as reviewed by us and others (we are not going to detail in this review), Nrf2 activation leads to mitochondrial biogenesis, mitophagy and an increase in the mitochondrial antioxidant response as well as the activation of OxPhos via the regulation of substrate availability [18,[27][28][29]. Although Nrf2 activation is often associated with the induction of mitochondrial localized antioxidant enzymes such as thioredoxin reductase-2 (Txnrd2), peroxiredoxin 3 (Prdx3) and 5 (Prdx5), and SOD2, its regulatory mechanisms are not fully understood [18].…”

Section: Nrf2 Contributes To the Homeostasis Of Mitochondrial Functionmentioning

confidence: 95%

“…Generally, various mitochondrial abnormalities can be signaled to the cytosol by non-ROS-related mechanisms, as seen in mitochondrial retrograde signaling, such as in the C. elegans ATFS-1 system, in which the drop in membrane potential inhibits peptide transport activity and proteolysis, leading to the nuclear translocation of ATFS-1 [34]. Regarding Nrf2, it has been reported that alterations in complex I activity may determine Nrf2 gene expression via the ERK5-myocyte enhancer factor 2 (MEF2) pathway in a ROS-independent manner [27,35]. However, several reports have shown that changes in mtROS generation through alterations of the level of SOD2 [36] or mitochondria-localized paraquat [37] actually change the cellular response, indicating that alterations in mtROS actually signals to the cytosol using unknown signaling mediators or cascades.…”

Section: Activation Of Nrf2 By Mtrosmentioning

confidence: 99%

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Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology

et al. 2020

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Reactive oxygen species (ROS) are byproducts of aerobic respiration and signaling molecules that control various cellular functions. Nrf2 governs the gene expression of endogenous antioxidant synthesis and ROS-eliminating enzymes in response to various electrophilic compounds that inactivate the negative regulator Keap1. Accumulating evidence has shown that mitochondrial ROS (mtROS) activate Nrf2, often mediated by certain protein kinases, and induce the expression of antioxidant genes and genes involved in mitochondrial quality/quantity control. Mild physiological stress, such as caloric restriction and exercise, elicits beneficial effects through a process known as “mitohormesis”. Exercise induces NOX4 expression in the heart, which activates Nrf2 and increases endurance capacity. Mice transiently depleted of SOD2 or overexpressing skeletal muscle-specific UCP1 exhibit Nrf2-mediated antioxidant gene expression and PGC1α-mediated mitochondrial biogenesis. ATF4 activation may induce a transcriptional program that enhances NADPH synthesis in the mitochondria and might cooperate with the Nrf2 antioxidant system. In response to severe oxidative stress, Nrf2 induces Klf9 expression, which represses mtROS-eliminating enzymes to enhance cell death. Nrf2 is inactivated in certain pathological conditions, such as diabetes, but Keap1 down-regulation or mtROS elimination rescues Nrf2 expression and improves the pathology. These reports aid us in understanding the roles of Nrf2 in pathophysiological alterations involving mtROS.

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Section: Nrf2 Contributes To the Homeostasis Of Mitochondrial Functionmentioning

confidence: 95%

Section: Activation Of Nrf2 By Mtrosmentioning

confidence: 99%

Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology

et al. 2020

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“…Activation of Nrf2 is also required for the induction of mitochondrial biogenesis and antioxidant response. Furthermore, there is a regulation of substrate supply to mitochondria by Nrf2 [43][44][45] (Figure 2).…”

Section: Phenolic Phytochemicals In Coffee May Account For Health Effmentioning

confidence: 99%

Health Effects of Coffee: Mechanism Unraveled?

2020

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The association of habitual coffee consumption with a lower risk of diseases, like type 2 diabetes mellitus, chronic liver disease, certain cancer types, or with reduced all-cause mortality, has been confirmed in prospective cohort studies in many regions of the world. The molecular mechanism is still unresolved. The radical-scavenging and anti-inflammatory activity of coffee constituents is too weak to account for such effects. We argue here that coffee as a plant food has similar beneficial properties to many vegetables and fruits. Recent studies have identified a health promoting mechanism common to coffee, vegetables and fruits, i.e., the activation of an adaptive cellular response characterized by the upregulation of proteins involved in cell protection, notably antioxidant, detoxifying and repair enzymes. Key to this response is the activation of the Nrf2 (Nuclear factor erythroid 2-related factor-2) system by phenolic phytochemicals, which induces the expression of cell defense genes. Coffee plays a dominant role in that regard because it is the major dietary source of phenolic acids and polyphenols in the developed world. A possible supportive action may be the modulation of the gut microbiota by non-digested prebiotic constituents of coffee, but the available data are still scarce. We conclude that coffee employs similar pathways of promoting health as assumed for other vegetables and fruits. Coffee beans may be viewed as healthy vegetable food and a main supplier of dietary phenolic phytochemicals.

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“…Recently, emerging evidence showed that the regulatory cross-talks of between Nfe2l2 (but not Nfe2l1) with either -Pal NRF1 or GABP NRF2 are involved in the nuclear control of mitochondrial biogenesis and relevant biological functions (51,52,70). In this study, we unravel that knockout of Nfe2l1 causes significant decreases in mRNA and/or protein levels of -Pal NRF1 and its target genes TFAM, Ndufv1, Ndub6, COX5a and SOD1 in Nfe2l1 / MEFs, whereas knockout of to the nuclear-to-mitochondrial respiratory and antioxidant transcription networks (as modeled in Figure 8A).…”

Section: Synergism Of Mouse Nfe2l1 Nrf1 Nfe2l2mentioning

confidence: 99%

Synergism and antagonism of two distinct, but confused, Nrf1 factors in integral regulation of the nuclear-to-mitochondrial respiratory and antioxidant transcription networks

Zhang

Deng

Xiang

et al. 2020

Preprint

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There is hitherto no literature available for explaining two distinct, but confused Nrf1 transcription factors, because they shared the same abbreviations from nuclear factor erythroid 2-related factor 1 (also called Nfe2l1) and nuclear respiratory factor (originally designated -Pal). Thus, we have here identified that Nfe2l1 Nrf1 and -Pal NRF1 exert synergistic and antagonistic roles in integrative regulation of the nuclear-to-mitochondrial respiratory and antioxidant transcription profiles. In mouse embryonic fibroblasts (MEFs), knockout of Nfe2l1 / leads to substantial decreases in expression levels of -Pal NRF1 and Nfe2l2, together with TFAM (mitochondrial transcription factor A) and other target genes. Similar inhibitory results were determined in Nfe2l2 / MEFs, with an exception that GSTa1 and Aldh1a1 were distinguishably up-regulated in Nfe2l1 / MEFs. Such synergistic contributions of Nfe2l1 and Nfe2l2 to the positive regulation of -Pal NRF1 and TFAM were validated in Keap1 / MEFs. However, human -Pal NRF1 expression was unaltered by hNfe2l1 / , hNfe2l2 /TA or even hNfe2l1 / +siNrf2, albeit TFAM was activated by Nfe2l1 but inhibited by Nfe2l2; such an antagonism occured in HepG2 cells. Conversely, almost all of mouse Nfe2l1, Nfe2l2 and co-target genes were down-expressed in -Pal NRF1/ MEFs. On the contrary, up-regulation of human Nfe2l1, Nfe2l2 and relevant reporter genes took place after silencing of -Pal NRF1 , but their down-regulation occurred upon ectopic expression of -Pal NRF1 .Furtherly, Pitx2 (pituitary homeobox 2) was also identified as a direct upstream regulator of Nfe2l1 and TFAM, besides -Pal NRF1 . Overall, these across-talks amongst Nfe2l1, Nfe2l2 and -Pal NRF1 , along with Pitx2, are integrated from the endoplasmic reticulum to the nuclear-to-mitochondrial communication for targeting TFAM, in order to finely tune the cellular respiratory and antioxidant gene transcription networks, albeit they differ between the mouse and the human. Keywords: Nfe2l1/Nrf1, Nfe2l2/Nrf2, -Pal NRF1 , TFAM, Pitx2, cap'n'collar (CNC), antioxidant response element (ARE), nuclear-to-mitochondrial respiratory system, and ER-nuclear-mitochondrial (ENUM) communication Running title: Two distinct Nrf1 factors responsible for cellular antioxidant and respiration.

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Emerging evidence for crosstalk between Nrf2 and mitochondria in physiological homeostasis and in heart disease

Cited by 36 publications

References 81 publications

Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology

Regulation of Nrf2 by Mitochondrial Reactive Oxygen Species in Physiology and Pathology

Health Effects of Coffee: Mechanism Unraveled?

Synergism and antagonism of two distinct, but confused, Nrf1 factors in integral regulation of the nuclear-to-mitochondrial respiratory and antioxidant transcription networks

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