Phoenixin 20 promotes neuronal mitochondrial biogenesis via CREB-PGC-1α pathway

Neurodegenerative disorders are dreadful diseases that affect millions of people worldwide. Mitochondrial dysfunction is closely associated with the development of neurodegenerative disorders. Phoenixin 20 is a newly discovered neuropeptide with a pleiotropic effect. This study showed that the presence of Phoenixin 20 promoted neuronal mitochondrial biogenesis in vitro. In cultured neuronal M17 cells, Phoenixin 20 increased the expression of mitochondrial regulators PGC-1α, NRF-1, and TFAM at both mRNA and protein levels. The treatment of Phoenixin 20 increased the ratio of mitochondrial vs nuclear DNA (mtDNA/nDNA) and the multiple mitochondrial gene expression as revealed by increasing mRNA expression of Tomm22, Timm50, Atp5d, Ndufs3, and protein expression of NDUFB8. At a cellular level, Phoenixin 20 promoted mitochondrial respiratory rate and cellular ATP production. Mechanistically, we found that Phoenixin 20 induced the phosphorylation of CREB, which suggests that Phoenixin 20 promoted the activation of the CREB pathway. The blockage of CREB by its selective inhibitor H89 prevented the effect of Phoenixin 20 on mitochondrial regulators and biogenesis. Moreover, the study showed that Phoenixin 20 induced the expression of its tentative receptor GPR173 at the mRNA and protein level, and the silence of GPR173 in neuronal cells ablated all its effect on mitochondrial regulation. Collectively, we showed that Phoenixin 20 promoted neuronal mitochondrial biogenesis via the regulation of CREB-PGC-1α pathway. This study revealed a new role and underlying mechanism of Phoenixin 20 in neuronal cells, suggesting it influences the therapeutic implication of neurodegenerative diseases.