Lixisenatide enhances mitochondrial biogenesis and function through regulating the CREB/PGC-1α pathway.

Mitochondrial dysregulation has been associated with vascular endothelial dysfunction and pathophysiological development of cardiovascular diseases. Lixisenatide is a drug approved by the US Food and Drug Administration for the treatment of type 2 diabetes (T2D). Little information regarding the effects of lixisenatide on mitochondrial function in endothelial cells has been reported before. In the current study, we found that treatment with lixisenatide significantly increased the expression of PGC-1α, a "molecular switch" of mitochondrial biogenesis in human umbilical vein endothelial cells (HUVECs). Lixisenatide treatment also promoted the expressions of NRF1 and TFAM, which are the target genes of PGC-1α and executors of mitochondrial biogenesis. Importantly, our results indicate that lixisenatide treatment promoted mitochondrial biogenesis by elevating the ratio of mitochondrial-to-nuclear DNA (mtDNA/nDNA), mitochondrial mass, cytochrome B expression, and citrate synthase activity in HUVECs. Correspondingly, we found that lixisenatide treatment led to a functional gain and improvement in mitochondria by increasing the mitochondrial respiration rate and ATP generation. Mechanistically, lixisenatide treatment induced the phosphorylation of CREB at Ser133. Blockage of CREB phosphorylation using its inhibitor H89 abolished the effects of lixisenatide on the activation of PGC-1α/NRF-1/TFAM as well as the increase in mtDNA/nDNA. These findings suggest that lixisenatide promoted mitochondrial biogenesis in endothelial cells through activating the PGC-1α signaling pathway, which is mediated by the transcriptional factor CREB.