A new activating role for CO in cardiac mitochondrial biogenesis

Abstract

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-1α, 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.

Heme oxygenase‐1 induction attenuates senescence in chronic obstructive pulmonary disease lung fibroblasts by protecting against mitochondria dysfunction

“…HO‐1 can induce mitophagy pathways through nuclear respiratory factor‐dependent (NRF‐1‐dependent) expression of the PINK1/PARK2 genes, as demonstrated recently by Suliman, Keenan, and Piantadosi (2017). This effect extends the described activation of mitochondrial biogenesis by CO produced by HO‐1 (Suliman, Carraway, Tatro, & Piantadosi, 2007). Nevertheless, we observed a decreased expression of NRF‐1 in fibroblasts from COPD patients treated with hemin, suggesting that another mechanism could be involved.…”

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

“…Protection by HO-1 requires Akt1, as mtDNA was not protected in DOX-treated cells preincubated with Akt inhibitor (Akt8; data not shown) or cells transfected with HO-1 and treated with Akt inhibitor (Akt8) before DOX ( Figure 7B). It has been demonstrated that HO-1 activates GC and that cGMP is involved in CO-activating mitochondrial biogenesis in these cells (16). In the present studies, losses in cellular mtDNA content after DOX correlated negatively with cell viability (P < 0.01; r 2 = -0.7).…”

“…Mitochondrial fluorescence intensity was enhanced by CO treatment, and the 2-dose protocol prevented the loss of fluorescence after DOX. The distribution of GFP also substantiated mitochondrial proliferation morphologically after CO treatment, as multiple new fluorescent aggregates that appeared within the cardiomyocytes were confirmed by EM as having mitochondrial structure (16).…”

“…CO also has endogenous signaling properties, for instance, in the vasculature, where it relaxes smooth muscle by activating soluble guanylate cyclase (sGC), which is similar to but less potent than NO (13). Moreover, the eNOS-sGC system regulates mitochondrial biogenesis (14,15), as does CO, also in part via sGC, but independently of eNOS (16). CO further binds the reduced a 3 heme of cytochrome c oxidase (COX), which enhances mitochondrial H 2 O 2 release and contributes to retrograde activation of the nuclear mitochondrial biogenesis program via binding of the nuclear respiratory factor 1 (NRF-1) transcription factor with the PGC-1α coactivator to target genes (16,17).…”

“…Moreover, the eNOS-sGC system regulates mitochondrial biogenesis (14,15), as does CO, also in part via sGC, but independently of eNOS (16). CO further binds the reduced a 3 heme of cytochrome c oxidase (COX), which enhances mitochondrial H 2 O 2 release and contributes to retrograde activation of the nuclear mitochondrial biogenesis program via binding of the nuclear respiratory factor 1 (NRF-1) transcription factor with the PGC-1α coactivator to target genes (16,17). These genes include the mitochondrial DNA (mtDNA) transcription factor Tfam, which is essential for mtDNA replication in oxidative phosphorylation (OXPHOS), genome maintenance, and mitochondrial biogenesis (16).…”