Activation of mitochondrial biogenesis by heme oxygenase-1-mediated NF-E2-related factor-2 induction rescues mice from lethal Staphylococcus aureus sepsis.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Nancy Chou
NC
MacGarvey
Hagir B
HB
Suliman
Raquel R
RR
Bartz
Ping
P
Fu
Crystal M
CM
Withers
Karen E
KE
Welty-Wolf
Claude A
CA
Piantadosi
D000280:Administration, Inhalation; D000818:Animals; D015153:Blotting, Western; D002248:Carbon Monoxide / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D001678:Organelle Biogenesis; D010538:Peritonitis / Q000188:drug therapy / Q000382:microbiology / Q000401:mortality; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D018570:Risk Assessment; D018805:Sepsis / Q000201:enzymology* / Q000235:genetics / Q000401:mortality; D013203:Staphylococcal Infections / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D013211:Staphylococcus aureus / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D015854:Up-Regulation
D051267:NF-E2-Related Factor 2; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1