Partial involvement of Nrf2 in skeletal muscle mitohormesis as an adaptive response to mitochondrial uncoupling

Sci Rep. 2018 Feb 5;8(1):2446. doi: 10.1038/s41598-018-20901-4.


Mitochondrial dysfunction is usually associated with various metabolic disorders and ageing. However, salutary effects in response to mild mitochondrial perturbations have been reported in multiple organisms, whereas molecular regulators of cell-autonomous stress responses remain elusive. We addressed this question by asking whether the nuclear factor erythroid-derived-like 2 (Nrf2), a transcription factor and master regulator of cellular redox status is involved in adaptive physiological responses including muscle mitohormesis. Using a transgenic mouse model with skeletal muscle-specific mitochondrial uncoupling and oxidative phosphorylation (OXPHOS) inefficiency (UCP1-transgenic, TG) we show that additional genetic ablation of Nrf2 abolishes an adaptive muscle NAD(P)H quinone dehydrogenase 1 (NQO1) and catalase induction. Deficiency of Nrf2 also leads to decreased mitochondrial respiratory performance although muscle functional integrity, fiber-type profile and mitochondrial biogenesis were not significantly altered. Importantly, Nrf2 ablation did not abolish the induction of key genes and proteins of muscle integrated stress response including the serine, one-carbon cycle, and glycine synthesis (SOG) pathway in TG mice while further increasing glutathione peroxidase (GPX) activity linked to increased GPX1 protein levels. Conclusively, our results tune down the functions controlled by Nrf2 in muscle mitohormesis and oxidative stress defense during mitochondrial OXPHOS inefficiency.

MeSH terms

  • Animals
  • Catalase / genetics*
  • Catalase / metabolism
  • Citrate (si)-Synthase / genetics
  • Citrate (si)-Synthase / metabolism
  • Electron Transport / genetics
  • Female
  • Gene Expression Regulation
  • Glutathione Peroxidase / genetics
  • Glutathione Peroxidase / metabolism
  • Glutathione Reductase / genetics
  • Glutathione Reductase / metabolism
  • Hormesis / genetics*
  • Male
  • Mice
  • Mice, Transgenic
  • Mitochondria, Muscle / genetics
  • Mitochondria, Muscle / metabolism*
  • Mitochondria, Muscle / pathology
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • NAD(P)H Dehydrogenase (Quinone) / genetics*
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • NF-E2-Related Factor 2 / deficiency
  • NF-E2-Related Factor 2 / genetics*
  • Organelle Biogenesis
  • Oxidative Phosphorylation
  • Oxidative Stress
  • Signal Transduction
  • Uncoupling Protein 1 / genetics
  • Uncoupling Protein 1 / metabolism


  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • Catalase
  • Glutathione Peroxidase
  • NAD(P)H Dehydrogenase (Quinone)
  • Nqo1 protein, mouse
  • Glutathione Reductase
  • Citrate (si)-Synthase