GD3 ganglioside directly targets mitochondria in a bcl-2-controlled fashion

Lipid and glycolipid diffusible mediators are involved in the intracellular progression and amplification of apoptotic signals. GD3 ganglioside is rap idly synthesized from accumulated ceramide after the clustering of death-in ducing receptors and triggers apoptosis. Here we show that GD3 induces diss ipation of Delta psi(m), and swelling of isolated mitochondria, which resul ts in the mitochondrial release of cytochrome c, apoptosis inducing factor, and caspase 9. Soluble factors released from GD3-treated mitochondria are sufficient to trigger DNA fragmentation in isolated nuclei. All these effec ts can be blocked by cyclosporin A, suggesting that GD3 is acting at the le vel of the permeability transition pore complex. We found that endogenous G D3 accumulates within mitochondria of cells undergoing apoptosis after cera mide exposure. Accordingly, suppression of GD3 synthase (ST8) expression in intact cells substantially prevents ceramide-induced Delta psi(m) dissipat ion, indicating that endogenously synthesized GD3 induces mitochondrial cha nges in vivo. Finally, enforced expression of bcl-2 significantly prevents GD3-induced mitochondrial changes, caspase 9 activation, and apoptosis. The se results show that mitochondria are a key destination for apoptogenic GD3 ganglioside along the lipid pathway to programmed cell death and indicate that relevant GD3 targets are under bcl-2 control.