Sitagliptin promotes mitochondrial biogenesis in human SH‐SY5Y cells by increasing the expression of PGC‐1α/NRF1/TFAM

: Mitochondrial dysfunction has been associated with the pathogenesis of a variety of neurodegenerative diseases. Sitagliptin is a dipeptidyl-peptidase-4 (DPP-4) inhibitor that has been approved for the treatment of type 2 diabetes (T2DM). In the current study, we report that sitagliptin increased the expression of PGC-1α, NRF1, and TFAM in human SH-SY5Y neuronal cells. Notably, our data indicate that sitagliptin promoted mitochondrial biogenesis by increasing the amount of mtDNA, the levels of mitochondria-related genes such as TOMM20, TOMM40, TIMM9, NDUFS3, ATP5C1, and the expression of oxidative phosphorylation subunits complex I and complex IV. Additionally, we found that sitagliptin induced a "gain of mitochondrial function" in SH-SY5Y cells by increasing the mitochondrial respiratory rate and adenosine triphosphate (ATP) production. Significantly, our results demonstrate that sitagliptin activated the transcriptional factor CREB by inducing its phosphorylation at Ser133. Inhibition of CREB using its specific inhibitor H89 abolished the effects of sitagliptin on the expression of PGC-1α, NRF1, and TFAM, as well as an increase in mtDNA amount and ATP production. These findings suggest that sitagliptin could become a potential agent for the treatment of neurological disorders.