Nox4 as a novel therapeutic target for diabetic vascular complications

Wang, Dongxia; Luo, Gang; Zhou, Juan; Wang, Ning; Wang, Shanshan; Zhao, Rui; Cao, Xia; Ma, Yuxia; Liu, Gang; Hao, Liping

doi:10.1016/j.redox.2023.102781

Cited by 23 publications

(16 citation statements)

References 237 publications

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“…Understanding the regulatory mechanisms that control the expression of NOX enzymes, especially the negative mechanisms that inhibit their expression, can help uncover the development of diseases such as diabetes. The ability of NOX4 to constitutively produce H 2 O 2 makes it unique among NOX family members(Wang et al, 2023). Current research into the molecular mechanisms that control NOX4 expression is focused primarily at the transcriptional level(Hecker et al, 2023), and there are few studies on translation.…”

Section: Discussionmentioning

confidence: 99%

“…The major intracellular sources of H 2 O 2 include mitochondrial electron transport chain, peroxisome, and the membrane-bound nicotinamide adenine dinucleotide phosphate oxidase (NOX)(Shields et al, 2021). So far, the NOX family consists of seven isoforms, with NOX4 being the only member that does not require upstream activators and is constitutively active(Wang et al, 2023). Hence, precise regulation of the expression levels NOX4 is crucial for the production H 2 O 2 .…”

Section: Introductionmentioning

confidence: 99%

“…Hence, precise regulation of the expression levels NOX4 is crucial for the production H 2 O 2 . However, despite accumulating evidence that NOX4 may contribute to the occurrence and development of diseases and that its expression levels are dynamically regulated in response to a wide range of stimuli(Canugovi et al, 2019; Chen et al, 2012; Pejenaute et al, 2020; Peñuelas-Haro et al, 2023; Wang et al, 2023), the molecular mechanisms that govern NOX4 expression levels are not yet fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Translational repression ofNox4mRNA via the EI24-RTRAF interaction is crucial for hydrogen peroxide homeostasis and insulin synthesis

Pei,

Wang,

et al. 2024

Preprint

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As a double-edged sword, the content of reactive oxygen species (ROS) is precisely controlled. Disordered actions of ROS contribute to deleterious effects, such as cancer and metabolic dysregulation associated with aging and obesity. Although it is well established that cells have developed evolutionarily conserved programs to sense and adapt to redox fluctuations, it remains unclear how to control the expression of key ROS-producing enzymes to regulate continued ROS production at healthy levels for cells such as neurons and pancreatic beta cells. These cells have weaker antioxidant defense systems but strong secretion ability. Here, we found that the endoplasmic reticulum membrane-localized protein, EI24, controls the translation of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4), which constitutively produces hydrogen peroxide (H2O2), by recruiting an RNA transcription, translation, and transport factor (RTRAF) to the 3’-UTRs ofNox4. Depletion of EI24 causes RTRAF to relocate into the nucleus, releasing the brake onNox4mRNA translation, and thus, the uncontrolled translation ofNox4leads to a substantial generation of intracellular H2O2. This suppresses the translation of V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), inhibits its binding to theIns2gene promoter, and ultimately hinders insulin transcription. Treatment with a specific NOX4 inhibitor or the antioxidant N-acetyl-cysteine (NAC) restoredMafAtranslation and downstream insulin synthesis while alleviating the diabetic symptoms in pancreatic beta-cell specificEi24-KO mice. In summary, our study revealed a molecular mechanism that controls the expression of NOX4, a key enzyme responsible for continuous ROS generation. This mechanism ensures low levels of H2O2and normal biological functions under physiological conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Translational repression ofNox4mRNA via the EI24-RTRAF interaction is crucial for hydrogen peroxide homeostasis and insulin synthesis

Pei,

Wang,

et al. 2024

Preprint

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show abstract

“…Another source of H 2 O 2 in the ER stems from the ER membrane-bound nicotinamide adenine dinucleotide phosphate oxidase (NOX) [ 1 ]. So far, the NOX family consists of seven isoforms, with NOX4 being the only member that does not require upstream activators and is constitutively active [ 4 ]. Precisely regulating the expression and activity of NOX4, while maintaining the concentration of H 2 O 2 within a narrow physiological range, is crucial for cells with robust secretion.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, precise control of NOX4 expression levels is vital for the production of H 2 O 2 in beta cells to facilitate efficient synthesis and correct folding of insulin. However, despite accumulating evidence implicating NOX4 in the onset and progression of diabetes [ 4 , 8 , 9 ], the molecular mechanisms that govern NOX4 expression levels in pancreatic beta cells and its role in regulating insulin synthesis remain unknown.…”

Section: Introductionmentioning

confidence: 99%