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.

Mitochondrial DNA depletion and OXPHOS complex impairment modify Hypoxia signaling pathway activity in zebrafish

TISO, NATASCIA;MARTORANO, LAURA;BUSOLIN, GIORGIA;EK, OLIVIER FREDERIC D;FACCHINELLO, NICOLA;VETTORI, ANDREA;ARGENTON, FRANCESCO
2016

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.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11577/3208642
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