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.

Role of Mitochondrial DNA in Septic AKI via Toll-Like Receptor 9

“…Indeed, a transient decrease in kidney mtDNA was found during sepsis. 28 Thus, the origin and supply route of circulating mtDNA in septic AKI might be multifocal and complicated.…”

“…28 The phase of protective innate immune status starts a few days after the initial TLR9 activation by natural killer cells and certain DC subsets to induce IFN-g secretion. 28,42,43 In addition, IL-12 causes T cells to differentiate into T helper type-1 cells, which are recruited to the sites of inflammation and produce IFN-g. 44 It is controversial whether MTD-induced upregulation of IL-12 caused renal injury. Renal IL-12 contributes in part to ischemia-reperfusion tubular injury 45 and has the potential to be critical for renal injury.…”

Metabolic reprogramming and tolerance during sepsis-induced AKI

“…Sepsis and inflammation at the tissue and cellular level are associated with decreased levels of intracellular adenosine triphosphate (ATP) and with mitochondrial injury in various organs, including the kidney 23,24 . Despite uncontrolled energy imbalance, mitochondrial injury and damage resulting from mitochondria-derived reactive oxygen species (ROS) and reactive nitrogen species, the levels of necrotic and apoptotic cells in the hearts and kidneys of patients with sepsis are surprisingly limited 25 and certainly fail to explain early organ dysfunction.…”

Skeletal Muscle and Lymphocyte Mitochondrial Dysfunctions in Septic Shock Trigger ICU-Acquired Weakness and Sepsis-Induced Immunoparalysis

“…Consecutive to the activation of the mitochondrial biogenesis program, expression of NRF-1, NRF- 2, PGC-1 α , and Tfam accompanies restoration of mtDNA copy number [22]. This has elegantly been demonstrated by Bartz et al in a murine model of Staphylococcus aureus sepsis [47]. …”