Lipopolysaccharide stimulates mitochondrial biogenesis via activation of nuclear respiratory factor-1.
Exposure to bacterial lipopolysaccharide (LPS) in vivo damages mitochondrial DNA (mtDNA) and interferes with mitochondrial transcription and oxidative phosphorylation (OXPHOS). Because this damage accompanies oxidative stress and is reversible, we postulated that LPS stimulates mtDNA replication and mitochondrial biogenesis via expression of factors responsive to reactive oxygen species, i.e. nuclear respiratory factor-1 (NRF-1) and mitochondrial transcription factor-A. In testing this hypothesis in rat liver, we found that LPS induces NRF-1 protein expression and activity accompanied by mRNA expression for mitochondrial transcription factor-A, mtDNA polymerase gamma, NRF-2, and single-stranded DNA-binding protein. These events restored the loss in mtDNA copy number and OXPHOS gene expression caused by LPS and increased hepatocyte mitotic index, nuclear cyclin D1 translocation, and phosphorylation of pro-survival kinase, Akt. Thus, NRF-1 was implicated in oxidant-mediated mitochondrial biogenesis to provide OXPHOS for proliferation. This implication was tested in novel mtDNA-deficient cells generated from rat hepatoma cells that overexpress NRF-1. Depletion of mtDNA (rhoo clones) diminished oxidant production and caused loss of NRF-1 expression and growth delay. NRF-1 expression and growth were restored by exogenous oxidant exposure indicating that oxidative stress stimulates biogenesis in part via NRF-1 activation and corresponding to recovery events after LPS-induced liver damage.
Suliman
Hagir B
HB
Departments of Medicine, Anesthesiology, and Pharmacology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Carraway
Martha S
MS
Welty-Wolf
Karen E
KE
Whorton
A Richard
AR
Piantadosi
Claude A
CA
D021581:Active Transport, Cell Nucleus; D000818:Animals; D015139:Blotting, Southern; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D051265:NF-E2-Related Factor 1; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*
D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D051265:NF-E2-Related Factor 1; C495632:Nfe2l1 protein, rat; D051266:Nuclear Respiratory Factor 1; D051264:Nuclear Respiratory Factors; D016877:Oxidants; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D015534:Trans-Activators; D019938:Cyclin D1; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010100:Oxygen