Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration

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.