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* Laboratory of Signal Transduction, Department of Experimental Medicine and Biochemical Sciences, University of Rome ‘Tor Vergata’, 00133 Rome;
Centre National de la Recherche Scientifique, UMR 1599, Institut Gustave Roussy, F94805 Villejuif, France; and
Section of Anatomical Sciences, University of Palermo, Italy
1Correspondence: Laboratory of Signal Transduction, Department of Experimental Medicine and Biochemical Sciences, University of Rome ‘Tor Vergata’, via di Tor Vergata 135, 00133 Rome. E-mail: tesrob{at}flashnet.it
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 
m 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
m 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.—Rippo, M. R., Malisan, F., Ravagnan, L., Tomassini, B.,
Condo, I., Costantini, P., Susin, S. A., Rufini, A., Todaro, M.,
Kroemer, G., Testi, R. GD3 ganglioside directly targets mitochondria in
a bcl-2-controlled fashion.
Key Words: apoptosis • permeability transition • AIF • cytochrome c • caspase 9
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