bims-noxint 2022-08-07 papers

Issue of 2022‒08‒07
four papers selected by
Laia Caja Puigsubira
Uppsala University

Front Cell Dev Biol. 2022 ;10 945749

Regulation of Neutrophil NADPH Oxidase, NOX2: A Crucial Effector in Neutrophil Phenotype and Function.

Marie-Hélène Paclet, Salomé Laurans, Sophie Dupré-Crochet.

Reactive oxygen species (ROS), produced by the phagocyte NADPH oxidase, NOX2, are involved in many leukocyte functions. An excessive or inappropriate ROS production can lead to oxidative stress and tissue damage. On the other hand, an absence of ROS production due to a lack of a functional NADPH oxidase is associated with recurrent infections as well as inflammation disorders. Thus, it is clear that the enzyme NADPH oxidase must be tightly regulated. The NOX2 complex bears both membrane and cytosolic subunits. The membrane subunits constitute the flavocytochrome b 558, consisting of gp91phox (Nox2) and p22phox subunits. The cytosolic subunits form a complex in resting cells and are made of three subunits (p47phox, p40phox, p67phox). Upon leukocyte stimulation, the cytosolic subunits and the small GTPase Rac assemble with the flavocytochrome b 558 in order to make a functional complex. Depending on the stimulus, the NADPH oxidase can assemble either at the phagosomal membrane or at the plasma membrane. Many studies have explored NOX2 activation; however, how this activation is sustained and regulated is still not completely clear. Here we review the multiple roles of NOX2 in neutrophil functions, with a focus on description of its components and their assembly mechanisms. We then explain the role of energy metabolism and phosphoinositides in regulating NADPH oxidase activity. In particular, we discuss: 1) the link between metabolic pathways and NOX2 activity regulation through neutrophil activation and the level of released ROS, and 2) the role of membrane phosphoinositides in controlling the duration of NOX2 activity.

Keywords: NADPH oxidase (NOX2); metabolism; neutrophil; phagocytose; phosphoinositides

DOI: https://doi.org/10.3389/fcell.2022.945749

Hepatology. 2022 Aug 03.

The NADPH oxidase NOX4 regulates redox and metabolic homeostasis preventing hepatocellular carcinoma progression.

Irene Peñuelas-Haro, Rut Espinosa-Sotelo, Eva Crosas-Molist, Macarena Herranz-Itúrbide, Daniel Caballero-Díaz, Ania Alay, Xavier Solé, Emilio Ramos, Teresa Serrano, María L Martínez-Chantar, Ulla G Knaus, José M Cuezva, Antonio Zorzano, Esther Bertran, Isabel Fabregat.

BACKGROUND & AIMS: The NADPH oxidase NOX4 plays a tumor suppressor function in hepatocellular carcinoma (HCC). Silencing NOX4 confers higher proliferative and migratory capacity to HCC cells and increases their in vivo tumorigenic potential in xenografts in mice. NOX4 gene deletions are frequent in HCC, correlating with higher tumor grade and worse recurrence-free and overall survival rates. However, despite of the accumulating evidence of a protective regulatory role in HCC, the cellular processes governed by NOX4 are not yet understood. Accordingly, the aim of this work was to better understand the molecular mechanisms regulated by NOX4 in HCC in order to explain its tumor suppressor action.APPROACH & RESULTS: Cell-based loss- or gain-of- NOX4 function experiments, in vivo hepatocarcinogenesis induced by diethylnitrosamine (DEN) in Nox4 deficient mice, and analyses in human HCC samples. Methods include cellular and molecular biology analyses, proteomics, transcriptomics, and metabolomics, as well as histological and immunohistochemical analyses in tissues. Results identified MYC as being negatively regulated by NOX4. MYC mediated mitochondrial dynamics and a transcriptional program leading to increased oxidative metabolism, enhanced use of both glucose and fatty acids and an overall higher energetic capacity and ATP level. NOX4 deletion induced a redox imbalance that augmented Nrf2 activity and was responsible for MYC up-regulation.
CONCLUSIONS: Loss of NOX4 in HCC tumor cells induces metabolic reprogramming in a Nrf2/MYC-dependent manner to promote HCC progression.

DOI: https://doi.org/10.1002/hep.32702

Oxid Med Cell Longev. 2022 ;2022 8230214

Adropin Improves Radiation-Induced Myocardial Injury via VEGFR2/PI3K/Akt Pathway.

Bingda Li, Zhenhua Wang, Yuanqiao He, Tianpeng Chen, Yun Zhang, Xingxing Yuan, Ping Li.

Mediastinal cancer radiotherapy exposes the heart and causes myocardial injury. It is of utmost importance to identify effective prevention and treatment targets. In this study, the regulatory role of adropin (Ad) in radiation-induced myocardial injury (RIMI) was explored in mice. After C57BL/6 mice were administered E0771 cells and received radiotherapy, the effects of exogenous Ad intervention on myocardial fibrosis, apoptosis, microvessel density, oxidative stress, and protein expression levels were observed. The results showed that exogenous Ad effectively improved cardiac function, suppressed oxidative stress, inhibited myocardial fibrosis, reduced myocardial apoptosis, and promoted microangiogenesis in RIMI mice. Ad also downregulated the expression levels of transforming growth factor β1 (TGF-β1), NADPH oxidase 4 (NOX4), and cleaved caspase 3 and upregulated the expression of phosphor-endothelial nitric oxide synthase (p-eNOS). However, the above-mentioned effects of Ad were significantly reversed in Ad-/- mice. Radiotherapy resulted in the downregulation of phosphor-vascular endothelial growth factor receptor (p-VEGFR2) and p-Akt in myocardial tissue, which were upregulated by Ad. However, after targeted inhibition of VEGFR2 with apatinib, the effect of Ad on improving RIMI was significantly reversed. Taken together, exogenous Ad significantly ameliorated RIMI by reducing oxidative stress, promoting microangiogenesis, and inhibiting myocardial fibrosis and apoptosis. The underlying molecular mechanism involved may be elucidated by activation of the VEGFR2/PI3K/Akt pathway.

DOI: https://doi.org/10.1155/2022/8230214

Redox Biol. 2022 Jul 19. pii: S2213-2317(22)00183-5. [Epub ahead of print]55 102411

TRPM7 channel inhibition attenuates rheumatoid arthritis articular chondrocyte ferroptosis by suppression of the PKCα-NOX4 axis.

A role for ferroptosis in articular cartilage destruction associated with rheumatoid arthritis (RA) has not been identified. We previously reported transient receptor potential melastatin 7 (TRPM7) expression was correlated with RA cartilage destruction. Herein, we further characterized a role for TRPM7 in chondrocyte ferroptosis. The expression of TRPM7 was found to be elevated in articular chondrocytes derived from adjuvant arthritis (AA) rats, human RA patients, and cultured chondrocytes treated with the ferroptosis inducer, erastin. TRPM7 knockdown or pharmacological inhibition protected primary rat articular chondrocytes and human chondrocytes (C28/I2 cells) from ferroptosis. Moreover, TRPM7 channel activity was demonstrated to contribute to chondrocyte ferroptosis by elevation of intracellular Ca2+. Mechanistically, the PKCα-NOX4 axis was found to respond to stimulation with erastin, which resulted in TRPM7-mediated chondrocyte ferroptosis. Meanwhile, PKCα was shown to directly bind to NOX4, which could be reduced by TRPM7 channel inhibition. Adeno-associated virus 9-mediated TRPM7 silencing or TRPM7 blockade with 2-APB alleviated articular cartilage destruction in AA rats and inhibited chondrocyte ferroptosis. Collectively, both genetic and pharmacological inhibitions of TRPM7 attenuated articular cartilage damage and chondrocyte ferroptosis via the PKCα-NOX4 axis, suggesting that TRPM7-mediated chondrocyte ferroptosis is a promising target for the prevention and treatment of RA.

Keywords: Ferroptosis; NOX4; PKCα; Rheumatoid arthritis; TRPM7

DOI: https://doi.org/10.1016/j.redox.2022.102411