Sengupta 2016 Free Radic Biol Med

Sengupta S, Yang G, O'Donnell JC, Hinson MD, McCormack SE, Falk MJ, La P, Robinson MB, Williams ML, Yohannes MT, Polyak E, Nakamaru-Ogiso E, Dennery PA (2016) The circadian gene Rev-erbα improves cellular bioenergetics and provides preconditioning for protection against oxidative stress. Free Radic Biol Med 93:177-89.

» PMID: 26855417

Sengupta S, Yang G, O'Donnell JC, Hinson MD, McCormack SE, Falk MJ, La P, Robinson MB, Williams ML, Yohannes MT, Polyak E, Nakamaru-Ogiso E, Dennery PA (2016) Free Radic Biol Med

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.

Copyright © 2016 Elsevier Inc. All rights reserved. • Keywords: Bioenergetics, Circadian, Energy metabolism, Mitochondria, NR1D1, Oxidative stress, Peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α), (PPARGC1A), Preconditioning, Mouse lung fibroblasts

• O2k-Network Lab: US PA Philadelphia Falk MJ

Labels: MiParea: Respiration, mt-Biogenesis;mt-density, nDNA;cell genetics, Genetic knockout;overexpression, Exercise physiology;nutrition;life style 

Stress:Oxidative stress;RONS  Organism: Mouse  Tissue;cell: Lung;gill, Fibroblast  Preparation: Intact cells 

Coupling state: LEAK, ROUTINE, ET  Pathway: ROX  HRR: Oxygraph-2k 

2016-09