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Lipopolysaccharide stimulates mitochondrial biogenesis via activation of nuclear respiratory factor-1

Hagir B Suliman1, Martha S Carraway, Karen E Welty-Wolf

  • 1Departments of Medicine, Anesthesiology, and Pharmacology, Duke University Medical Center, Durham, North Carolina 27710, USA.

The Journal of Biological Chemistry
|August 7, 2003
PubMed

Insights

Bacterial lipopolysaccharide (LPS) exposure damages mitochondrial DNA and impairs energy production. Nuclear respiratory factor-1 (NRF-1) activation drives mitochondrial repair and cell proliferation.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Background:

  • Bacterial lipopolysaccharide (LPS) exposure in vivo causes mitochondrial DNA (mtDNA) damage, affecting mitochondrial transcription and oxidative phosphorylation (OXPHOS).
  • This damage is linked to oxidative stress and is reversible, suggesting a role for reactive oxygen species (ROS)-responsive factors.
  • Nuclear respiratory factor-1 (NRF-1) and mitochondrial transcription factor-A are key regulators of mitochondrial biogenesis.

Purpose of the Study:

  • To investigate the role of NRF-1 in LPS-induced mitochondrial damage and repair.
  • To determine if LPS stimulates mitochondrial biogenesis via ROS-responsive factors like NRF-1.
  • To elucidate the mechanisms underlying mitochondrial recovery and hepatocyte proliferation after LPS exposure.

Main Methods:

  • In vivo studies using rat liver models exposed to LPS.
  • Analysis of gene and protein expression, including NRF-1, mitochondrial transcription factor-A, and OXPHOS components.
  • Generation and study of novel mtDNA-deficient (rho(0)) rat hepatoma cells overexpressing NRF-1.

Main Results:

  • LPS exposure increased NRF-1 protein expression and activity in rat liver.
  • LPS induced mRNA expression for key mitochondrial biogenesis factors, restoring mtDNA copy number and OXPHOS gene expression.
  • NRF-1 overexpression in mtDNA-depleted cells restored growth and oxidant production, indicating oxidative stress stimulates biogenesis via NRF-1.

Conclusions:

  • NRF-1 plays a crucial role in oxidant-mediated mitochondrial biogenesis and recovery from LPS-induced liver damage.
  • Oxidative stress stimulates mitochondrial biogenesis partly through NRF-1 activation.
  • NRF-1 is implicated in providing OXPHOS capacity necessary for hepatocyte proliferation.

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