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

Abstract

Lipid and glycolipid diffusible mediators are involved in the intracellular progression and amplification of apoptotic signals. GD3 ganglioside is rapidly synthesized from accumulated ceramide after the clustering of death-inducing receptors and triggers apoptosis. Here we show that GD3 induces dissipation of DeltaPsim and swelling of isolated mitochondria, which results 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 effects can be blocked by cyclosporin A, suggesting that GD3 is acting at the level of the permeability transition pore complex. We found that endogenous GD3 accumulates within mitochondria of cells undergoing apoptosis after ceramide exposure. Accordingly, suppression of GD3 synthase (ST8) expression in intact cells substantially prevents ceramide-induced DeltaPsim dissipation, indicating that endogenously synthesized GD3 induces mitochondrial changes in vivo. Finally, enforced expression of bcl-2 significantly prevents GD3-induced mitochondrial changes, caspase 9 activation, and apoptosis. These 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.

Lipid microdomains contribute to apoptosis-associated modifications of mitochondria in T cells

“…31 Till now, it was hypothesized that GD3 can contribute to the apoptotic program by directly targeting mitochondria in a Bcl-2-controlled manner and inducing the mitochondrial release of apoptogenic factors. 15 Our results provide the first evidence that GD3 acts at the level of the VDAC, where a local perturbation of specific mitochondrial lipid microdomains influencing the permeability transition pore complex and Cyt c release occurs. In this concern, a relevant role may be played by Bax and t-Bid, which relocate to lipid microdomains, as revealed by the analysis of linear sucrose gradient fractions from whole cells.…”

“…13 Thus, GD3 has been reported to propagate CD95/Fas-mediated apoptotic signals 10,14 and act on the mitochondrial permeability transition pore, leading to cytochrome c (Cyt c) release. 15,16 However, the actual role of the GD3 action and its subcellular targets still remain to be elucidated.…”

Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum

“…41 Rather, the cells overexpressing Bcl-2 displayed an enhanced survival upon ceramide treatment, 42 in agreement with previous reports. 43,44 Bcl-2 showed the expected heterogeneous distribution, most of it being located on the ER membrane. As to Ca 2 þ homeostasis (Figure 1), we detected a B30% reduction in the Ca 2 þ levels within the agonist-sensitive Ca 2 þ stores (i.e.…”

Gangliosides as apoptotic signals in ER stress response

“…5,87 Interestingly, Scorrano et al 84 have demonstrated that GD3 preferentially affect mitochondrial function, while other gangliosides such as GD1a, GM3 have no effect. Acetylation of GD3 nullifies its apoptotic effect and this mechanism is suggested to confer resistance to tumors.…”