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First published online 19 December 2006
doi: 10.1242/jcs.03318

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A new activating role for CO in cardiac mitochondrial biogenesis

Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA

^* Author for correspondence (e-mail: piant001{at}mc.duke.edu)

Accepted 26 October 2006

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-1, 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 (H₂O₂). Interference with Akt activity by blocking PI 3-kinase and by mitochondrial targeting of catalase to scavenge H₂O₂ prevented binding of NRF1 to the Tfam promoter, thereby connecting mitochondrial H₂O₂ to the pathway leading to mtDNA replication. The findings disclose mitochondrial CO and H₂O₂ as new activating factors in cardiac mitochondrial biogenesis.

Key words: Reactive oxygen species, Carbon monoxide, Heme oxygenase, Nitric oxide, Mitochondrial DNA

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