ArticleAntioxidants & redox signaling2014
Membrane-bound CYB5R3 is a common effector of nutritional and oxidative stress response through FOXO3a and Nrf2.
Article in Antioxidants & redox signaling, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 54 citations in OpenAlex.
- The CYB5R3-mARC1 Redox Axis in Metabolic Dysfunction-associated Steatotic Liver Disease: Mechanistic Basis and Therapeutic Prospects across the Steatosis-Cirrhosis-Hepatocellular Carcinoma Spectrum.Journal of clinical and translational hepatology · 2026Review
- Cytochrome bBiomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2026Article
- Breath-by-breath quantification of inhaled nitric oxide absorption and modeling of methemoglobin kinetics.Redox biology · 2026Article
- Modulation of PKCα/ETS1 by klotho restores CYB5R4-dependent mitochondrial function in proximal tubular epithelial cells to attenuate the progression of diabetic kidney disease.Cardiovascular diabetology · 2026Article
- Article
- Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues.Science (New York, N.Y.) · 2025Article
- Electronic cigarette vape decreases nitric oxide bioavailability in vascular smooth muscle cells via increased cytoglobin-mediated metabolism.Free radical biology & medicine · 2025Article
- Apolipoprotein O modulates cholesterol metabolism via NRF2/CYB5R3 independent of LDL receptor.Cell death & disease · 2024Article
- Mechanosensitive super-enhancers regulate genes linked to atherosclerosis in endothelial cells.The Journal of cell biology · 2024Article
- Vitamin E/Coenzyme Q-Dependent "Free Radical Reductases": Redox Regulators in Ferroptosis.Antioxidants & redox signaling · 2024Review
- CYB5R3 functions as a tumor suppressor by inducing ER stress-mediated apoptosis in lung cancer cells via the PERK-ATF4 and IRE1α-JNK pathways.Experimental & molecular medicine · 2024Article
- A New Landscape of Human Dental Aging: Causes, Consequences, and Intervention Avenues.Aging and disease · 2023Review
- CYB5R3 in type II alveolar epithelial cells protects against lung fibrosis by suppressing TGF-β1 signaling.JCI insight · 2023Article
- Loss of cardiomyocyte CYB5R3 impairs redox equilibrium and causes sudden cardiac death.The Journal of clinical investigation · 2022Article
- Proteomics-based investigation of cerebrovascular molecular mechanisms in cerebral amyloid angiopathy by the FFPE-LMD-PCT-SWATH method.Fluids and barriers of the CNS · 2022Article
- Three novel mutations in CYB5R3 gene causing NADH-cytochrome b5 reductase enzyme deficiency leads to recessive congenital methaemoglobinemia.Molecular biology reports · 2022Article
- Role of cytoglobin in cigarette smoke constituent-induced loss of nitric oxide bioavailability in vascular smooth muscle cells.Nitric oxide : biology and chemistry · 2022Article
- Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance.Molecules (Basel, Switzerland) · 2022Review
- Cooperation between CYB5R3 and NOX4 via coenzyme Q mitigates endothelial inflammation.Redox biology · 2021Article
- Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders.Antioxidants (Basel, Switzerland) · 2021Review
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 3 countries.
Funding
Abstract
aimsMembrane-bound CYB5R3 deficiency in humans causes recessive hereditary methaemoglobinaemia (RHM), an incurable disease that is characterized by severe neurological disorders. CYB5R3 encodes for NADH-dependent redox enzyme that contributes to metabolic homeostasis and stress protection; however, how it is involved in the neurological pathology of RHM remains unknown. Here, the role and transcriptional regulation of CYB5R3 was studied under nutritional and oxidative stress.
resultsCYB5R3-deficient cells exhibited a decrease of the NAD(+)/NADH ratio, mitochondrial respiration rate, ATP production, and mitochondrial electron transport chain activities, which were associated with higher sensitivity to oxidative stress, and an increase in senescence-associated β-galactosidase activity. Overexpression of either forkhead box class O 3a (FOXO3a) or nuclear factor (erythroid-derived 2)-like2 (Nrf2) was associated with increased CYB5R3 levels, and genetic ablation of Nrf2 resulted in lower CYB5R3 expression. The presence of two antioxidant response element sequences in the CYB5R3 promoter led to chromatin immunoprecipitation studies, which showed that cellular stressors enhanced the binding of Nrf2 and FOXO3a to the CYB5R3 promoter. INNOVATION: Our findings demonstrate that CYB5R3 contributes to regulate redox homeostasis, aerobic metabolism, and cellular senescence, suggesting that CYB5R3 might be a key effector of oxidative and nutritional stress pathways. The expression of CYB5R3 is regulated by the cooperation of Nrf2 and FOXO3a.
conclusionCYB5R3 is an essential gene that appears as a final effector for both nutritional and oxidative stress responses through FOXO3a and Nrf2, respectively, and their interaction promotes CYB5R3 expression. These results unveil a potential mechanism of action by which CYB5R3 deficiency contributes to the pathophysiological underpinnings of neurological disorders in RHM patients.
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