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The circadian gene Rev-erbα improves cellular bioenergetics and provides preconditioning for protection against oxidative stress
- Source :
- Free radical biologymedicine. 93
- Publication Year :
- 2015
-
Abstract
- Diurnal oscillations in the expression of antioxidant genes imply that protection against oxidative stress is circadian-gated. We hypothesized that stabilization of the core circadian gene Rev-erbα (Nr1d1) improves cellular bioenergetics and protects against nutrient deprivation and oxidative stress. Compared to WT, mouse lung fibroblasts (MLG) stably transfected with a degradation resistant Rev-erbα (Ser(55/59) to Asp; hence referred to as SD) had 40% higher protein content, 1.5-fold higher mitochondrial area (confocal microscopy), doubled oxidative phosphorylation by high-resolution respirometry (Oroboros) and were resistant to glucose deprivation for 24h. This resulted from a 4-fold reduction in mitophagy (L3CB co-localized with MitoTracker Red) versus WT. Although PGC1α protein expression was comparable between SD and WT MLG cells, the role of mitochondrial biogenesis in explaining increased mitochondrial mass in SD cells was less clear. Embryonic fibroblasts (MEF) from C57Bl/6-SD transgenic mice, had a 9-fold induction of FoxO1 mRNA and increased mRNA of downstream antioxidant targets heme oxygenase-1 (HO-1), Mn superoxide dismutase and catalase (1.5, 2 fold and 2 fold respectively) versus WT. This allowed the SD cells to survive 1h incubation with 500 µM H2O2 as well as 24h of exposure to 95% O2 and remain attached whereas most WT cells did not. These observations establish a mechanistic link between the metabolic functions of Rev-erbα with mitochondrial homeostasis and protection against oxidative stress.
- Subjects :
- 0301 basic medicine
Bioenergetics
FOXO1
Mice, Transgenic
Oxidative phosphorylation
Biology
Mitochondrion
medicine.disease_cause
Biochemistry
Antioxidants
Article
03 medical and health sciences
Mice
Physiology (medical)
Mitophagy
medicine
Animals
Superoxide Dismutase
Hydrogen Peroxide
Fibroblasts
Catalase
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Cell biology
Mitochondria
Oxidative Stress
030104 developmental biology
Mitochondrial biogenesis
Nuclear Receptor Subfamily 1, Group D, Member 1
biology.protein
Energy Metabolism
Oxidative stress
Heme Oxygenase-1
Subjects
Details
- ISSN :
- 18734596
- Volume :
- 93
- Database :
- OpenAIRE
- Journal :
- Free radical biologymedicine
- Accession number :
- edsair.doi.dedup.....710ac72824a2c7bcaa917d84d9749863