title: Staphylococcus aureus sepsis induces early renal mitochondrial DNA repair and mitochondrial biogenesis in mice.
abstract: Acute kidney injury (AKI) contributes to the high morbidity and mortality of multi-system organ failure in sepsis. However, recovery of renal function after sepsis-induced AKI suggests active repair of energy-producing pathways. Here, we tested the hypothesis in mice that Staphyloccocus aureus sepsis damages mitochondrial DNA (mtDNA) in the kidney and activates mtDNA repair and mitochondrial biogenesis. Sepsis was induced in wild-type C57Bl/6J and Cox-8 Gfp-tagged mitochondrial-reporter mice via intraperitoneal fibrin clots embedded with S. aureus. Kidneys from surviving mice were harvested at time zero (control), 24, or 48 hours after infection and evaluated for renal inflammation, oxidative stress markers, mtDNA content, and mitochondrial biogenesis markers, and OGG1 and UDG mitochondrial DNA repair enzymes. We examined the kidneys of the mitochondrial reporter mice for changes in staining density and distribution. S. aureus sepsis induced sharp amplification of renal Tnf, Il-10, and Ngal mRNAs with decreased renal mtDNA content and increased tubular and glomerular cell death and accumulation of protein carbonyls and 8-OHdG. Subsequently, mtDNA repair and mitochondrial biogenesis was evidenced by elevated OGG1 levels and significant increases in NRF-1, NRF-2, and mtTFA expression. Overall, renal mitochondrial mass, tracked by citrate synthase mRNA and protein, increased in parallel with changes in mitochondrial GFP-fluorescence especially in proximal tubules in the renal cortex and medulla. Sub-lethal S. aureus sepsis thus induces widespread renal mitochondrial damage that triggers the induction of the renal mtDNA repair protein, OGG1, and mitochondrial biogenesis as a conspicuous resolution mechanism after systemic bacterial infection.
authors.affiliation: Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, United States of America; Durham Veterans Affairs Medical Center, Durham, North Carolina, United States of America.
authors.forename: Raquel R
authors.initials: RR
authors.lastname: Bartz
authors.affiliation: Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors.forename: Ping
authors.initials: P
authors.lastname: Fu
authors.affiliation: Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors.forename: Hagir B
authors.initials: HB
authors.lastname: Suliman
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Crowley
authors.affiliation: Department of Medicine, Drexel College of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Nancy Chou
authors.initials: NC
authors.lastname: MacGarvey
authors.affiliation: Durham Veterans Affairs Medical Center, Durham, North Carolina, United States of America; Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Welty-Wolf
authors.affiliation: Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, United States of America; Durham Veterans Affairs Medical Center, Durham, North Carolina, United States of America; Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors.forename: Claude A
authors.initials: CA
authors.lastname: Piantadosi
mesh_terms: D000818:Animals; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D009102:Multiple Organ Failure / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018805:Sepsis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013203:Staphylococcal Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013211:Staphylococcus aureus
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins