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.
Piantadosi
Claude A
CA
Department of Medicine, Duke University Medical Center, Durham, NC, USA. piant001@mc.duke.edu
Carraway
Martha Sue
MS
Babiker
Abdelwahid
A
Suliman
Hagir B
HB
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