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Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration

Kira M Holmström1, Liam Baird, Ying Zhang

  • 1Department of Molecular Neuroscience, UCL Institute of Neurology , London WC1N 3BG , UK.

Biology Open
|August 17, 2013
PubMed

Insights

The Nrf2-Keap1 pathway, known for antioxidant gene regulation, directly controls cellular energy metabolism. This pathway is crucial for maintaining mitochondrial function and ATP production, impacting overall cellular health.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Genetics

Background:

  • The Nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) pathway regulates cytoprotective genes.
  • This pathway is primarily known for controlling drug-metabolizing and antioxidant genes.

Purpose of the Study:

  • To investigate the role of the Nrf2-Keap1 pathway in regulating mitochondrial bioenergetics.
  • To elucidate the direct impact of Nrf2 on cellular energy metabolism.

Main Methods:

  • Utilized murine neurons and embryonic fibroblasts with genetic alterations in Nrf2.
  • Assessed mitochondrial membrane potential, ATP levels, respiration rates, and oxidative phosphorylation efficiency.
  • Analyzed NADH regeneration rates and F1Fo-ATPase activity.

Main Results:

  • Nrf2 deficiency caused mitochondrial depolarization, reduced ATP, and impaired respiration.
  • Nrf2 activation enhanced mitochondrial membrane potential, ATP levels, and respiration efficiency.
  • Nrf2-deficient cells showed increased glycolysis-derived ATP supporting mitochondrial membrane potential maintenance.
  • Respiratory complex activities were unaffected in vitro but impaired in isolated mitochondria and live cells.

Conclusions:

  • Nrf2 directly regulates cellular energy metabolism by modulating substrate availability for mitochondrial respiration.
  • Efficient energy metabolism is vital for Nrf2-mediated cytoprotection.
  • The Nrf2 pathway plays a novel, direct role in mitochondrial function.
Keywords:
Energy metabolismKeap1MitochondriaNrf2Oxidative phosphorylation

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