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Cited by 983Genomics, phytochemicals, and oxidative stressMitochondrial Function and PathologyRedox biology and oxidative stress

The emerging role of Nrf2 in mitochondrial function

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Dinkova-Kostova, Albena T., Abramov, Andrey Y.·2015·Free Radical Biology and Medicine
DOI 10.1016/j.freeradbiomed.2015.04.036PMC PMC4726722
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Abstract

The transcription factor NF-E2 p45-related factor 2 (Nrf2; gene name NFE2L2) allows adaptation and survival under conditions of stress by regulating the gene expression of diverse networks of cytoprotective proteins, including antioxidant, anti-inflammatory, and detoxification enzymes as well as proteins that assist in the repair or removal of damaged macromolecules. Nrf2 has a crucial role in the maintenance of cellular redox homeostasis by regulating the biosynthesis, utilization, and regeneration of glutathione, thioredoxin, and NADPH and by controlling the production of reactive oxygen species by mitochondria and NADPH oxidase. Under homeostatic conditions, Nrf2 affects the mitochondrial membrane potential, fatty acid oxidation, availability of substrates (NADH and FADH2/succinate) for respiration, and ATP synthesis. Under conditions of stress or growth factor stimulation, activation of Nrf2 counteracts the increased reactive oxygen species production in mitochondria via transcriptional upregulation of uncoupling protein 3 and influences mitochondrial biogenesis by maintaining the levels of nuclear respiratory factor 1 and peroxisome proliferator-activated receptor γ coactivator 1α, as well as by promoting purine nucleotide biosynthesis. Pharmacological Nrf2 activators, such as the naturally occurring isothiocyanate sulforaphane, inhibit oxidant-mediated opening of the mitochondrial permeability transition pore and mitochondrial swelling. Curiously, a synthetic 1,4-diphenyl-1,2,3-triazole compound, originally designed as an Nrf2 activator, was found to promote mitophagy, thereby contributing to the overall mitochondrial homeostasis. Thus, Nrf2 is a prominent player in supporting the structural and functional integrity of the mitochondria, and this role is particularly crucial under conditions of stress.

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  • These factors, including nuclear respiratory factor 1, nuclear factor erythroid-2-like 2, GA binding protein (nuclear respiratory factor 2), and Sp4, directly and indirectly control the expression of respiratory chain subunits encoded by nuclear and mitochondrial DNA.

    “These factors, including nuclear respiratory factor 1, nuclear factor erythroid-2-like 2, GA binding protein (nuclear respiratory factor 2), and Sp4 [110–114] directly and indirectly control the expression of respiratory chain subunits encoded by nuclear and mitochondrial DNA [110, 115, 116].”

    From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [114]

    The “Nrf2 and mitochondrial biogenesis” section (page unavailable) says nuclear respiratory factors 1 and 2 control genes encoding respiratory-complex subunits, and that Nrf2 can promote mitochondrial biogenesis through nuclear respiratory factor 1. The copy also reports Nrf2-associated changes in respiratory-chain proteins. It does not establish the claimed role for Sp4 or show that these factors control expression of subunits encoded by mitochondrial DNA. (LLM, conf=0.84)

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Sorted by citations

Authors
Dinkova-Kostova, A. T., & Abramov, A. Y.
Affiliations
UCL Queen Square Institute of Neurology (GB)
Corresponding author
Abramov, Andrey Y.
ORCID
Abramov, Andrey Y.
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2015-11
Volume
88
Issue
Pt B
Pages
179-188
ISSN
0891-5849 (ISSN-L)
DOI
10.1016/j.freeradbiomed.2015.04.036
PMC
PMC4726722
OpenAlex
W344068791
Cited by
983
References
8
Citations by year
2026: 80 · 2025: 96 · 2024: 97 · 2023: 113 · 2022: 108 · 2021: 99 · 2020: 113 · 2019: 94 · 2018: 65 · 2017: 64 · 2016: 40 · 2015: 14
FWCI
5.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Free Radical Biology and Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (submittedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • Cancer Research UK (C20953/A10270, C20953/A18644)
  • BBSRC (BB/J007498/1, BB/L01923X/1)
  • Wellcome Trust/MRC
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
Nrf2, mitochondrial function, redox homeostasis, reactive oxygen species, mitochondrial permeability transition pore, UCP3, mitochondrial biogenesis, mitophagy, purine nucleotide biosynthesis, sulforaphane, Nrf2 activators, mitochondrial homeostasis, oxidative stress
MeSH terms
Animals, Energy Metabolism, Humans, Mitochondria, Oxidation-Reduction, NF-E2-Related Factor 2

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