Mechanisms and Implications of Reactive Oxygen Species Generation During the Unfolded Protein Response: Roles of Endoplasmic Reticulum Oxidoreductases, Mitochondrial Electron Transport, and NADPH Oxidase
Abstract
Cellular mechanisms governing redox homeostasis likely involve their integration with other stresses. Endoplasmic reticulum (ER) stress triggers complex adaptive or proapoptotic signaling defined as the unfolded protein response (UPR), involved in several pathophysiological processes. Since protein folding is highly redox-dependent, convergence between ER stress and oxidative stress has attracted interest. Evidence suggests that ROS production and oxidative stress are not only coincidental to ER stress, but are integral UPR components, being triggered by distinct types of ER stressors and contributing to support proapoptotic, as well as proadaptive UPR signaling. Thus, ROS generation can be upstream or downstream UPR targets and may display a UPR-specific plus a nonspecific component. Enzymatic mechanisms of ROS generation during UPR include: (a) Multiple thiol-disulfide exchanges involving ER oxidoreductases including flavooxidase Ero1 and protein disulfide isomerase (PDI); (b) Mitochondrial electron transport; (c) Nox4 NADPH oxidase complex, particularly Nox4. Understanding the roles of such mechanisms and how they interconnect with the UPR requires more investigation. Integration among such ROS sources may depend on Ca(2+) levels, ROS themselves, and PDI, which associates with NADPH oxidase and regulates its function. Oxidative stress may frequently integrate with a background of ER stress/UPR in several diseases; here we discuss a focus in the vascular system.
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- Authors
- Santos, C. X. C., Tanaka, L. Y., Wosniak, J., & Laurindo, F. R. M.
- Affiliations
- Universidade de São Paulo (BR)
- Venue
- Antioxidants & Redox Signaling
- Publisher
- SAGE Publications
- Published
- 2009-10
- Volume
- 11
- Issue
- 10
- Pages
- 2409-2427
- ISSN
- 1523-0864 (ISSN-L)
- 1557-7716
- OpenAlex
- W2064194224
- Cited by
- 572
- References
- 135
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 22 · 2023: 25 · 2022: 27 · 2021: 31 · 2020: 43 · 2019: 36 · 2018: 40 · 2017: 37 · 2016: 36 · 2015: 44 · 2014: 46 · 2013: 40 · 2012: 41
- FWCI
- 2.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Antioxidants and Redox Signaling (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- unfolded protein response, endoplasmic reticulum stress, reactive oxygen species, oxidative stress, redox homeostasis, Ero1, protein disulfide isomerase, mitochondrial electron transport chain, NADPH oxidase, NOX4, thiol-disulfide exchange, calcium signaling, vascular disease
- MeSH terms
- Electron Transport, Endoplasmic Reticulum, Enzyme Activation, Homeostasis, Isoenzymes, Mitochondria, Oxidation-Reduction, Oxidoreductases, Stress, Physiological, Vascular Diseases, Signal Transduction, Apoptosis, Reactive Oxygen Species, NADPH Oxidases, Protein Disulfide-Isomerases
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