Ganglioside GD3 and its mimetics induce cytochrome c release from mitochondria

Ganglioside GD3 induced the release of cytochrome c from isolated rat liver mitochondria. This process was completely prevented by cyclosporin A and p artially prevented by a cysteine protease inhibitor, n-acetyl-leu-leu-norle ucinal. Cyclosporin A is a potent inhibitor of the permeability transition pore, whereas n-acetyl-leu-leu-norleucinal has no effect on this pore. Thes e results indicate that the release of cytochrome c from mitochondria requi res both the opening of the permeability transition pore and a cysteine pro tease inhibitor-sensitive mechanism. Gangliosides GD1a, GD1b, GT1b, and GQ1 b along with the synthetic GD3 mimetics TMS-42 and CI-22, which are glycero phospholipids carrying a disialo residue, also induced cytochrome c release . In contrast, gangliosides GM1, GM2, and GM3 did not induce cytochrome c r elease. These results indicate that two sialo residues must play an importa nt role in the induction of cytochrome c release by gangliosides. (C) 2000 Academic Press.