title: Lipopolysaccharide-induced mitochondrial DNA depletion.
abstract: Hepatic energy depletion has been described in severe sepsis, and lipopolysaccharide (LPS) has been shown to cause mitochondrial DNA (mtDNA) damage. To clarify the mechanisms of LPS-induced mtDNA damage and mitochondrial alterations, we treated wild-type (WT) or transgenic manganese superoxide dismutase-overerexpressing (MnSOD(+++)) mice with a single dose of LPS (5 mg/kg). In WT mice, LPS increased mitochondrial reactive oxygen species formation, hepatic inducible nitric oxide synthase (NOS) mRNA and protein, tumor necrosis factor-alpha, interleukin-1 beta, and high-mobility group protein B1 concentrations. Six to 48 h after LPS administration (5 mg/kg), liver mtDNA levels, respiratory complex I activity, and adenosine triphosphate (ATP) contents were decreased. In addition, LPS increased interferon-β concentration and decreased mitochondrial transcription factor A (Tfam) mRNA, Tfam protein, and mtDNA-encoded mRNAs. Morphological studies showed mild hepatic inflammation. The LPS (5 mg/kg)-induced mtDNA depletion, complex I inactivation, ATP depletion, and alanine aminotransferase increase were prevented in MnSOD(+++) mice or in WT mice cotreated with 1400W (a NOS inhibitor), (2-(2,2,6,6-tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride, monohydrate (a superoxide scavenger) or uric acid (a peroxynitrite scavenger). The MnSOD overexpression delayed death in mice challenged by a higher, lethal dose of LPS (25 mg/kg). In conclusion, LPS administration damages mtDNA and alters mitochondrial function. The protective effects of MnSOD, NOS inhibitors, and superoxide or peroxynitrite scavengers point out a role of the superoxide anion reacting with NO to form mtDNA- and protein-damaging peroxynitrite. In addition to the acute damage caused by reactive species, decreased levels of mitochondrial transcripts contribute to mitochondrial dysfunction.
authors.affiliation: INSERM, U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, Paris, France.
authors.forename: Amal
authors.initials: A
authors.lastname: Choumar
authors.forename: Arige
authors.initials: A
authors.lastname: Tarhuni
authors.forename: Philippe
authors.initials: P
authors.lastname: Lettéron
authors.forename: Florence
authors.initials: F
authors.lastname: Reyl-Desmars
authors.forename: Nismah
authors.initials: N
authors.lastname: Dauhoo
authors.forename: Julie
authors.initials: J
authors.lastname: Damasse
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vadrot
authors.forename: Pierre
authors.initials: P
authors.lastname: Nahon
authors.forename: Richard
authors.initials: R
authors.lastname: Moreau
authors.forename: Dominique
authors.initials: D
authors.lastname: Pessayre
authors.forename: Abdellah
authors.initials: A
authors.lastname: Mansouri
mesh_terms: D025181:ATP Synthetase Complexes / Q000378:metabolism; D000154:Aconitate Hydratase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D042967:Electron Transport Complex I / Q000378:metabolism; D014450:Electron Transport Complex III / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D056945:Hep G2 Cells; D006609:High Mobility Group Proteins / Q000378:metabolism; D006801:Humans; D016899:Interferon-beta / Q000097:blood / Q000494:pharmacology; D007501:Iron / Q000097:blood / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009566:Nitrates / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D017382:Reactive Oxygen Species / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D017382:Reactive Oxygen Species; C495345:TLR4 protein, human; C081930:Tfam protein, mouse; D017392:Thiobarbituric Acid Reactive Substances; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; C002744:3-nitrotyrosine; D014443:Tyrosine; D016899:Interferon-beta; D000255:Adenosine Triphosphate; D007501:Iron; D052247:Nitric Oxide Synthase Type II; D013482:Superoxide Dismutase; D003576:Electron Transport Complex IV; D000410:Alanine Transaminase; D025181:ATP Synthetase Complexes; D000154:Aconitate Hydratase; D042967:Electron Transport Complex I; D014450:Electron Transport Complex III