Protective effect of monosialoganglioside GM1 against chemically induced apoptosis through targeting of mitochondrial function and iron transport

Abstract

Exogenous treatment with monosialoganglioside GM1 has been described to afford protection against different apoptotic insults. However, the underlying mechanisms remain to be determined. In this study, we focused on the effect of GM1 on the apoptotic cascade induced by benzo[a]pyrene (B[a]P) in rat hepatic F258 epithelial cells. We first demonstrated that a co-treatment with GM1 (80 microM) reduced B[a]P (50 nM)-induced apoptosis as evidenced by a decrease of both cell population exhibiting nuclear fragmentation and caspase 3 cleavage and activity. We next showed that the p53 phosphorylation and nuclear translocation as well as the intracellular alkalinization related to Na+/H+ exchanger 1 (NHE1) activation, two early events of the apoptosis induced by B[a]P, were not inhibited by GM1. In contrast, the late mitochondria-dependent acidification elicited by B[a]P was inhibited by GM1 co-treatment, and an inhibition of the oxidative stress was also observed. Because GM1 has been shown to reduce the low-molecular weight iron content related to ethanol-induced oxidative stress, we finally investigated the involvement of iron under our conditions. Using the two iron chelators deferiprone and desferrioxamine, we clearly showed that iron played an important role in B[a]P-induced apoptosis in F258 cells, and that B[a]P-treatment resulted in a significant GM1-sensitive increase in (55)Fe uptake. In conclusion, our results indicate that exogenous GM1 partly prevents B[a]P-induced apoptosis by interfering with mitochondria-related intracellular acidification and iron transport.

Protective and Antioxidative Effects of GM1 Ganglioside in PC12 Cells Exposed to Hydrogen Peroxide are Mediated by Trk Tyrosine Kinase

“…If apoptosis and oxidative stress were induced by benzo[a]pyren in cultures of hepatocyte and rat liver epithelial cell lines F258, exposure to GM1 inhibited ROS and LPO production in these cells [36,37]. GT1b ganglioside was shown to abolish the increased production and accumulation of LPO products in mouse brain homogenates initiated by kainic acid; in vivo GT1b, as well as melatonin, prevented the DNA damage induced by kainic acid administration to mice [38].…”

“…Very interesting data were obtained studying antioxidative effects of GM1 in rat hepatic F258 epithelial cells and hepatocytes [37]. GM1 was shown to inhibit chemically induced apoptosis in these cells through targeting of mitochondrial function, GM1 decreased the late mitochondria-dependent acidification, mitochondrial ROS production and LPO product accumulation produced by benzo[a]pyren [37].…”

Regulation of Na+/H+ exchanger 1 allosteric balance by its localization in cholesterol‐ and caveolin‐rich membrane microdomains

“…However, few studies have considered the influence of membrane lipids on its activity. Membrane fluidity has been identified as one such modulator (Bookstein et al, 1997;Gorria et al, 2006). Recently, we have obtained evidence that osmotic regulation modifies the allosteric balance of NHE-1 and that membrane curvature and/or tension would by itself modulate NHE-1 (Lacroix et al, unpublished work).…”

Protective effects of exogenous gangliosides on ROS-induced changes in human spermatozoa

“…35 In vivo, GT1b prevents chemically induced DNA damage in mice. 41 There is evidence that the antioxidative properties of GM1 are dependent on its effect on iron ion exchange 35,42 because iron ions are involved in ROS and LPO product formation in many cell types.…”