Heme oxygenase-1 regulates cardiac mitochondrial biogenesis via Nrf2-mediated transcriptional control of nuclear respiratory factor-1.
Heme oxygenase (HO)-1 is a protective antioxidant enzyme that prevents cardiomyocyte apoptosis, for instance, during progressive cardiomyopathy. Here we identify a fundamental aspect of the HO-1 protection mechanism by demonstrating that HO-1 activity in mouse heart stimulates the bigenomic mitochondrial biogenesis program via induction of NF-E2-related factor (Nrf)2 gene expression and nuclear translocation. Nrf2 upregulates the mRNA, protein, and activity for HO-1 as well as mRNA and protein for nuclear respiratory factor (NRF)-1. Mechanistically, in cardiomyocytes, endogenous carbon monoxide (CO) generated by HO-1 overexpression stimulates superoxide dismutase-2 upregulation and mitochondrial H(2)O(2) production, which activates Akt/PKB. Akt deactivates glycogen synthase kinase-3beta, which permits Nrf2 nuclear translocation and occupancy of 4 antioxidant response elements (AREs) in the NRF-1 promoter. The ensuing accumulation of nuclear NRF-1 protein leads to gene activation for mitochondrial biogenesis, which opposes apoptosis and necrosis caused by the cardio-toxic anthracycline chemotherapeutic agent, doxorubicin. In cardiac cells, Akt silencing exacerbates doxorubicin-induced apoptosis, and in vivo CO rescues wild-type but not Akt1(-/-) mice from doxorubicin cardiomyopathy. These findings consign HO-1/CO signaling through Nrf2 and Akt to the myocardial transcriptional program for mitochondrial biogenesis, provide a rationale for targeted mitochondrial CO therapy, and connect cardiac mitochondrial volume expansion with the inducible network of xenobiotic and antioxidant cellular defenses.
Department of Medicine, Duke University Medical Center, Durham, NC, USA. piant001@mc.duke.edu
Claude A
CA
Piantadosi
Martha Sue
MS
Carraway
Abdelwahid
A
Babiker
Hagir B
HB
Suliman
D000818:Animals; D002248:Carbon Monoxide / Q000627:therapeutic use; D004272:DNA, Mitochondrial / Q000235:genetics; D017930:Genes, Reporter; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000502:physiology*; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics
D004272:DNA, Mitochondrial; D051267:NF-E2-Related Factor 2; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D012333:RNA, Messenger; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt