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EnglishMitochondria are essential for cell survival and health, utilizing about 90% of the oxygen we breathe for OXPHOS. Previous studies showed a strong relationship between mitochondrial alterations and hypoxia signaling pathway [1]. POLG-related disorders are a group of diseases characterized by the dysfunction of DNA polymer- ase gamma, crucial for mtDNA replication, repair and stability [2]. Danio rerio (zebrafish) is an ideal vertebrate model of human mitochondrial diseases because of its high conservation of physio- logical processes and genomic structure, transgenic lines availability and embryonic transparency. Using zebrafish embryos, we have performed transient knock-down of the polg gene, inducing a dilated cardiomyopathy and an increased heart bit rate. Moreover, we have developed a transgenic line able to show in vivo the activation of hypoxia-inducible factor 1 (Hif1) signaling. Taking advantage of this reporter line, we established that Hypoxia pathway is up-regulated in polg morphants, maybe due to an increase in ROS production. In addition, using a pharmacological approach targeting OXPHOS complexes, we observed that the inhibition of complexes I and II induces a decrease in Hif1 activation, also in hypoxic conditions. In conclusion, the evidence of Hypoxia reporter activation in polg knock-down embryos suggests the existence of cross-talk mechanisms sensing mitochondrial dysfunction and changing hypoxia signaling, as also confirmed by the OXPHOS complex inhibitors analysis.
| Titolo: | Mitochondrial DNA depletion and OXPHOS complex impairment modify Hypoxia signaling pathway activity in zebrafish |
| Autori: | |
| Data di pubblicazione: | 2016 |
| Rivista: | |
| Abstract: | Mitochondria are essential for cell survival and health, utilizing about 90% of the oxygen we breathe for OXPHOS. Previous studies showed a strong relationship between mitochondrial alterations and hypoxia signaling pathway [1]. POLG-related disorders are a group of diseases characterized by the dysfunction of DNA polymer- ase gamma, crucial for mtDNA replication, repair and stability [2]. Danio rerio (zebrafish) is an ideal vertebrate model of human mitochondrial diseases because of its high conservation of physio- logical processes and genomic structure, transgenic lines availability and embryonic transparency. Using zebrafish embryos, we have performed transient knock-down of the polg gene, inducing a dilated cardiomyopathy and an increased heart bit rate. Moreover, we have developed a transgenic line able to show in vivo the activation of hypoxia-inducible factor 1 (Hif1) signaling. Taking advantage of this reporter line, we established that Hypoxia pathway is up-regulated in polg morphants, maybe due to an increase in ROS production. In addition, using a pharmacological approach targeting OXPHOS complexes, we observed that the inhibition of complexes I and II induces a decrease in Hif1 activation, also in hypoxic conditions. In conclusion, the evidence of Hypoxia reporter activation in polg knock-down embryos suggests the existence of cross-talk mechanisms sensing mitochondrial dysfunction and changing hypoxia signaling, as also confirmed by the OXPHOS complex inhibitors analysis. |
| Handle: | http://hdl.handle.net/11577/3208642 |
| Appare nelle tipologie: | 01.05 - Abstract in rivista |
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