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Reactive oxygen species (ROS) as pleiotropic physiological signalling agents
Abstract
'Reactive oxygen species' (ROS) is an umbrella term for an array of derivatives of molecular oxygen that occur as a normal attribute of aerobic life. Elevated formation of the different ROS leads to molecular damage, denoted as 'oxidative distress'. Here we focus on ROS at physiological levels and their central role in redox signalling via different post-translational modifications, denoted as 'oxidative eustress'. Two species, hydrogen peroxide (H 2 O 2) and the superoxide anion radical (O 2·-), are key redox signalling agents generated under the control of growth factors and cytokines by more than 40 enzymes, prominently including NADPH oxidases and the mitochondrial electron transport chain. At the low physiological levels in the nanomolar range, H 2 O 2 is the major agent signalling through specific protein targets, which engage in metabolic regulation and stress responses to support cellular adaptation to a changing environment and stress. In addition, several other reactive species are involved in redox signalling, for instance nitric oxide, hydrogen sulfide and oxidized lipids. Recent methodological advances permit the assessment of molecular interactions of specific ROS molecules with specific targets in redox signalling pathways. Accordingly, major advances have occurred in understanding the role of these oxidants in physiology and disease, including the nervous, cardiovascular and immune systems, skeletal muscle and metabolic regulation as well as ageing and cancer. In the past, unspecific elimination of ROS by use of low molecular mass antioxidant compounds was not successful in counteracting disease initiation and progression in clinical trials. However, controlling specific ROS-mediated signalling pathways by selective targeting offers a perspective for a future of more refined redox medicine. This includes enzymatic defence systems such as those controlled by the stress-response transcription factors NRF2 and nuclear factor-κB, the role of trace elements such as selenium, the use of redox drugs and the modulation of environmental factors collectively known as the exposome (for example, nutrition, lifestyle and irradiation).
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In the citing paper
“In glia, the main sources of ROS include peroxisomes and mitochondria that perform lipid β-oxidation52.”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [52]
In the citing paper
“However, many LDs in iMGs were also peroxidated (Extended Data Fig. 11b–e), suggesting that ROS may also occur first and the peroxidized lipids are sequestered in LDs16,42,52.”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [52]
In the citing paper
“oxidative muscle damage, as assessed by immunoblotting gastrocnemius muscle homogenates for 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation, and for protein carbonylation, a marker of protein oxidation and damage (18), was increased in 6-month-old Mck-Cre;Nox4fl/fl mice (Fig. 6, I and J)”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [18]
In the citing paper
“Obesity is associated with systemic oxidative stress (43, 44), which promotes insulin resistance (11–18).”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [18]
In the citing paper
“Given the well-established potential for oxidative stress and consequent oxidative damage to drive insulin resistance (11–18), we reasoned that the development of insulin resistance in the sedentary aged mice may be attributed to decreased NOX4 abundance or activity.”
From Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance (2021) · cites this paper as [18]
In the citing paper
“ROS levels that exceed the capacity of the cellular antioxidant defense system induce oxidative stress [29,75].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [29]
In the citing paper
“H2O2, as a diffusible and relatively stable molecule, is more suitable as a cellular signaling factor than O2●− [29,30,31,32,33].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [29]
In the citing paper
“Moreover, growing evidence suggests that a tightly controlled increase in cellular ROS levels can actually have beneficial consequences for the cell, a condition that has been termed oxidative eustress [29,75].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [29]
In the citing paper
“supporting the observation of other studies that ROS have to be produced in direct vicinity of the regulated target and do not excessively saturate the cell until they hit their target at random [29,30,37,61,125,273].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [29]
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Metadata
- Authors
- Sies, H., & Jones, D. P.
- Affiliations
- Leibniz Institute of Environmental Medicine (DE)
- Emory University (US)
- Corresponding author
- Sies, Helmut
- Jones, Dean P.
- Venue
- Nature Reviews Molecular Cell Biology
- Published
- 2020-03-30
- Volume
- 21
- Issue
- 7
- Pages
- 363-383
- ISSN
- 1471-0072 (ISSN-L)
- 1471-0080
- OpenAlex
- W3013352992
- Cited by
- 5,335
- References
- 312
- Citations by year
- 2026: 1007 · 2025: 1036 · 2024: 1002 · 2023: 848 · 2022: 755 · 2021: 526 · 2020: 159
- FWCI
- 54.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Reviews Molecular Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
- Keywords
- reactive oxygen species, redox signaling, hydrogen peroxide, superoxide, post-translational modification, NADPH oxidase, mitochondrial electron transport chain, nitric oxide, hydrogen sulfide, oxidized lipids, Nrf2, NF-κB, selenium, exposome, aging, cancer, metabolic regulation
- MeSH terms
- Aging, Animals, Antioxidants, Humans, Neoplasms, Oxidation-Reduction, Protein Processing, Post-Translational, Signal Transduction, Reactive Oxygen Species, Oxidative Stress
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