Sphingosine 1-phosphate (S1P) promotes mitochondrial biogenesis in Hep G2 cells by activating Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α)

Sphingosine 1-phosphate (S1P), a potent bioactive phospholipid, has been reported to regulate a broad spectrum of biological processes. However, little is known regarding S1P's effects on mitochondrial function. In this study, we investigated the S1P's effects on the Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) signaling pathway and mitochondrial biogenesis in Hep G2 cells. Our results indicate that administration of S1P leads to a significant upregulation of mitochondrial DNA replication and transcription, increased mitochondrial mass, and elevated adenosine triphosphate synthesis. In addition, we found that treatment with S1P stimulates expression of PGC-1 alpha, a master regulator of mitochondrial biogenesis, as well as its downstream targets: nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Moreover, our data demonstrate that S1P's effects on PGC-1 alpha and mitochondrial biogenesis are mediated by the protein kinase A/cAMP response element-binding protein (PKA/CREB) pathway. Importantly, we also revealed that S1P's effects on mitochondrial biogenesis are dependent on its type 2 receptor (S1P(2)), though not on either its type 1 (S1P(1)) or type 3 (S1P(3)) receptors. Based on these observations, we concluded that S1P activates the PKA/CREB pathway through S1P(2), which then promotes expression of PGC-1 alpha/NRF1/TFAM and subsequent mitochondrial biogenesis in Hep G2 cells.