Activation of Mitochondrial Biogenesis by Heme Oxygenase-1-mediated NF-E2-related Factor-2 Induction Rescues Mice from Lethal Staphylococcus aureus Sepsis

Mitochondrial damage is an important component of multiple organ failure syndrome, a highly lethal complication of severe sepsis that lacks specific therapy. Mitochondrial quality control is regulated in part by the heme oxygenase-1 (HO-1; Hmox1) system through the redox-regulated NF-E2-related fact...

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Bibliographic Details
Published in:American journal of respiratory and critical care medicine 2012-04, Vol.185 (8), p.851-861
Main Authors: CHOU MACGARVEY, Nancy, SULIMAN, Hagir B, BARTZ, Raquel R, PING FU, WITHERS, Crystal M, WELTY-WOLF, Karen E, PIANTADOSI, Claude A
Format: Article
Language:English
Subjects:
Administration, Inhalation
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Animals
Antioxidants
Biological and medical sciences
Biosynthesis
Blotting, Western
Carbon monoxide
Carbon Monoxide - metabolism
Carbon Monoxide - pharmacology
Cytochrome
Cytokines
Disease Models, Animal
Emergency and intensive care: infection, septic shock
Female
Gene expression
Gram-positive bacteria
Heme Oxygenase-1 - genetics
Heme Oxygenase-1 - metabolism
Hypotheses
Intensive care medicine
Kinases
Male
Medical sciences
Mice
Mice, Inbred C57BL
Mitochondria
Mitochondria - genetics
Mitochondria - metabolism
Mitochondrial DNA
Multiple organ dysfunction syndrome
NF-E2-Related Factor 2 - genetics
NF-E2-Related Factor 2 - metabolism
Organelle Biogenesis
Oxidation
Peritonitis
Peritonitis - drug therapy
Peritonitis - microbiology
Peritonitis - mortality
Polymerase chain reaction
Proteins
Random Allocation
Real-Time Polymerase Chain Reaction
Risk Assessment
Sepsis
Sepsis - enzymology
Sepsis - genetics
Sepsis - mortality
Staphylococcal Infections - genetics
Staphylococcal Infections - metabolism
Staphylococcal Infections - therapy
Staphylococcus aureus - genetics
Staphylococcus aureus - metabolism
Survival Rate
Transcription factors
Tumor necrosis factor-TNF
Up-Regulation
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Summary:Mitochondrial damage is an important component of multiple organ failure syndrome, a highly lethal complication of severe sepsis that lacks specific therapy. Mitochondrial quality control is regulated in part by the heme oxygenase-1 (HO-1; Hmox1) system through the redox-regulated NF-E2-related factor-2 (Nrf2) transcription factor, but its role in mitochondrial biogenesis in Staphylococcus aureus sepsis is unknown. To test the hypothesis that Nrf2-dependent up-regulation of the HO-1/carbon monoxide (CO) system would preserve mitochondrial biogenesis and rescue mice from lethal S. aureus sepsis. A controlled murine S. aureus peritonitis model with and without inhaled CO was examined for HO-1 and Nrf2 regulation of mitochondrial biogenesis and the resolution of hepatic mitochondrial damage. Sepsis survival was significantly enhanced using inhaled CO (250 ppm once-daily for 1 h), and linked mechanistically to Hmox1 induction and mitochondrial HO activity through Nrf2 transcriptional and Akt kinase activity. HO-1/CO stimulated Nrf2-dependent gene expression and nuclear accumulation of nuclear respiratory factor-1, -2α (Gabpa), and peroxisome proliferator-activated receptor gamma coactivator-1α; increased mitochondrial transcription factor-A and citrate synthase protein levels; and augmented mtDNA copy number. CO enhanced antiinflammatory IL-10 and reduced proinflammatory tumor necrosis factor-α production. By contrast, Nrf2(-/-) and Akt1(-/-) mice lacked CO induction of Hmox1 and mitochondrial biogenesis, and CO rescued neither strain from S. aureus sepsis. We identify an inducible Nrf2/HO-1 regulatory cycle for mitochondrial biogenesis that is prosurvival and counter-inflammatory in sepsis, and describe targeted induction of mitochondrial biogenesis as a potential multiple organ failure therapy.
ISSN:1073-449X
1535-4970
DOI:10.1164/rccm.201106-1152oc