A new activating role for CO in cardiac mitochondrial biogenesis.
To investigate a possible new physiological role of carbon monoxide (CO), an endogenous gas involved in cell signaling and cytotoxicity, we tested the hypothesis that the mitochondrial generation of reactive oxygen species by CO activates mitochondrial biogenesis in the heart. In mice, transient elevations of cellular CO by five- to 20-fold increased the copy number of cardiac mitochondrial DNA, the content of respiratory complex I-V and interfibrillar mitochondrial density within 24 hours. Mitochondrial biogenesis is activated by gene and protein expression of the nuclear respiratory factor 1 (NRF1) and NRF2, of peroxisome proliferator-activated receptor gamma co-activator-1alpha, and of mitochondrial transcription factor A (TFAM), which augmented the copy number of mitochondrial DNA (mtDNA). This is independent of nitric oxide synthase (NOS), as demonstrated by the identical responses in wild-type and endothelial NOS (eNOS)-deficient mice, and by the inhibition of inducible NOS (iNOS). In the heart and in isolated cardiomyocytes, CO activation involved both guanylate cyclase and the pro-survival kinase Akt/PKB. Akt activation was facilitated by mitochondrial binding of CO and by production of hydrogen peroxide (H(2)O(2)). Interference with Akt activity by blocking PI 3-kinase and by mitochondrial targeting of catalase to scavenge H(2)O(2) prevented binding of NRF1 to the Tfam promoter, thereby connecting mitochondrial H(2)O(2) to the pathway leading to mtDNA replication. The findings disclose mitochondrial CO and H(2)O(2) as new activating factors in cardiac mitochondrial biogenesis.
Suliman
Hagit B
HB
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Carraway
Martha S
MS
Tatro
Lynn G
LG
Piantadosi
Claude A
CA
D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004272:DNA, Mitochondrial / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D051268:GA-Binding Protein Transcription Factor / Q000235:genetics / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D006609:High Mobility Group Proteins / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D008752:Methylene Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000187:drug effects; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D051268:GA-Binding Protein Transcription Factor; D006609:High Mobility Group Proteins; D051266:Nuclear Respiratory Factor 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C081930:Tfam protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D008752:Methylene Chloride; D002248:Carbon Monoxide; D006861:Hydrogen Peroxide; D006419:Heme Oxygenase (Decyclizing); D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D006162:Guanylate Cyclase