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

Abstract

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 γ coactivator 1α (PGC-1α) 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-1α, 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-1α 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 (S1P2), though not on either its type 1 (S1P1) or type 3 (S1P3) receptors. Based on these observations, we concluded that S1P activates the PKA/CREB pathway through S1P2, which then promotes expression of PGC-1α/NRF1/TFAM and subsequent mitochondrial biogenesis in Hep G2 cells.

Sphingosine 1-phosphate is a ligand for peroxisome proliferator-activated receptor-γ that regulates neoangiogenesis

“…Interestingly, a recent study using HepG2 cells (a human hepatocellular carcinoma line) has shown that S1P increases mitochondrial biogenesis and stimulates the expression of PGC1a (68). This study also showed the effects of S1P on mitochondrial biogenesis (e.g., up-regulation of mitochondrial DNA replication) to be S1P 2 dependent (68). Although limited literature is available on a vascular role for PGC1b, PGC1b overexpression in vascular smooth muscle cells inhibits proliferation and neointima hyperplasia, with a reduction in PGC1b detected in the arteries following balloon injury (69).…”

Lysophospholipids and Their G-Coupled Protein Signaling in Alzheimer’s Disease: From Physiological Performance to Pathological Impairment

“…respiratory dysfunction and subsequent energy metabolism disorders, which can be restored by exogenous S1P treatment (Strub et al, 2011). Furthermore, S1P has been proved to promote mitochondrial biogenesis by increasing mitochondrial DNA replication, transcription and mitochondrial mass (Shen et al, 2014). There is also evidence showing that S1P treatment can alleviate oxygen-glucose deprivation (OGD) induced inner membrane depolarization, which can induce the formation of MMP (mitochondrial membrane permeability) and directly affect mitochondrial function (Agudo-López et al, 2010).…”

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

“…Increased production of reactive oxygen species (ROS) and neurotoxins under pathological circumstances has a negative effect in mitochondrial abundance and the copy number of mitochondrial DNA (mtDNA) . Mitochondrial biogenesis plays a critical role in maintaining normal energy metabolism, mitochondrial homeostasis, and quality control . Mitochondrial biogenesis is mainly regulated by the peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α) and its downstream molecules nuclear respiratory factor 1 (NRF‐1) and the mitochondrial transcription factor A (TFAM).…”

“…3,4 Mitochondrial biogenesis plays a critical role in maintaining normal energy metabolism, mitochondrial homeostasis, and quality control. 5 Mitochondrial biogenesis is mainly regulated by the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and its downstream molecules nuclear respiratory factor 1 (NRF-1) and the mitochondrial transcription factor A (TFAM). NRF-1 is a nuclear transcriptional factor that is responsible for the transcription of nuclear genes that code subunits of the oxidative phosphorylation system.…”