Ganglioside GD3 and Its Mimetics Induce Cytochrome c Release from Mitochondria

Inoki, Yutaka; Miura, Tsuyoshi; Kajimoto, Tetsuya; Kawase, Makoto; Kawase, Yuji; Yoshida, Yasuko; Tsuji, S.; Kinouchi, Tsuyoshi; Endo, Hitoshi; Kagawa, Yasuo; Hamamoto, Toshiro

doi:10.1006/bbrc.2000.3601

Cited by 17 publications

(16 citation statements)

References 33 publications

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“…GM3 causes apoptosis, decreases BrdUrd incorporation, and up-regulates the cdk inhibitor p27 kip in proliferating astrocytes [31]. Many studies also demonstrate that, GD3 disrupts mitochondria membrane potential [32,33], induces cell death and activates caspases in HuT78, derived from a human cutaneous T cell lymphoma [34]. Similarly, neurotoxicity of major brain gangliosides, such as GD1a and GD1b against dopaminergic neurons in mesencephalic cultures has been reported [35].…”

Section: Discussionmentioning

confidence: 99%

GT1b-induced neurotoxicity is mediated by the Akt/GSK-3/tau signaling pathway but not caspase-3 in mesencephalic dopaminergic neurons

et al. 2010

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BackgroundGangliosides, sialic acid-containing glycosphingolipids exist in mammalian cell membranes particularly neuronal membranes. The trisialoganglioside (GT1b) is one of the major brain gangliosides and acts as an endogenous regulator in the brain. We previously showed GT1b induces mesencephalic dopaminergic (DA) neuronal death, both in vivo and in vitro. We further investigate the underlying mechanisms of GT1b neurotoxicity.ResultsConsistent with earlier findings, GT1b attenuated the DA neuron number and dopamine uptake level in mesencephalic cultures. Morphological evidence revealed GT1b-induced chromatin condensation and nuclear fragmentation as well as an increased number of TUNEL-positive cells, compared to control cultures. Interestingly, while GT1b enhanced caspase-3 activity, DEVD, a caspase-3 inhibitor, failed to rescue DA neuronal death. Immunoblot analysis revealed that GT1b inactivates Akt through dephosphorylation at both Ser473 and Thr308, subsequent dephosphorylation of GSK-3β, a substrate of Akt, and hyperphosphorylation of tau, downstream of GSK-3β. Moreover, a GSK-3β specific inhibitor, L803-mt, attenuated tau phosphorylation and rescued DA neurons from cell death in mesencephalic cultures.ConclusionOur data provide novel evidence that a Akt/GSK-3β/tau-dependent, but not caspase-3 signaling pathway plays a pivotal role in GT1b-mediated neurotoxic actions on mesencephalic DA neurons.

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Section: Discussionmentioning

confidence: 99%

GT1b-induced neurotoxicity is mediated by the Akt/GSK-3/tau signaling pathway but not caspase-3 in mesencephalic dopaminergic neurons

et al. 2010

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“…[41] Cellular levels of ceramide are determined either by de novo synthesis or generation by ASMase via the desipramine-inhibitable mechanism. Both pathways have been shown to participate in the mechanism of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Ceramide in the Mechanism of Cr(VI)-induced Apoptosis of CHO Cells

Muranaka

Kanno

Fujita

et al. 2004

Free Radical Research

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Mitochondria reduce Cr(VI) to Cr(V) with concomitant generation of reactive oxygen species, thereby exhibiting cytotoxic effects leading to apoptosis in various types of cells. To clarify the mechanism by which Cr(VI) induces apoptosis, we examined the effect of Cr(VI) on Chinese hamster ovary (CHO) cells. Cr(VI) increased cellular levels of ceramide by activating acid sphingomyelinase (ASMase) and inhibiting the phosphorylation of pleckstrin homology domain-containing protein kinase B (Akt). Cr(VI) also induced cyclosporin A- and trifluoperazine-sensitive depolarization of mitochondria and activated caspase-3, 8 and 9, thereby causing fragmentation of cellular DNA. The presence of desipramine, an inhibitor of ASMase, and membrane permeable pCPT-cAMP suppressed the Cr(VI)-induced activation of caspases and DNA fragmentation. These results suggested that accumulation of ceramide play an important role in the Cr(VI)-induced apoptosis of CHO cells through activation of mitochondrial membrane permeability transition.

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“…In cells, it disrupts mitochondrial membrane potential in a Bcl-2-sensitive manner (Rippo et al, 2000) and induces ROS production (Colell et al, 2001). At the level of isolated mitochondria, it inhibits the mitochondrial respiratory chain at the level of Complex III (Scorrano et al, 1999), increases ROS production (Garcia-Ruiz et al, 2000), opens the MPTP with the subsequent release of cytochrome c (Inoki et al, 2000;Kristal and Brown, 1999;Scorrano et al, 1999), and potentiates interaction of Bax with mitochondria (Pastorino et al, 1999b). Interestingly, while the effect of CD3 on ROS production is relatively nonspecific (lactosylceramide, GM1, GD1a and glucosylceramide produce a similar response (GarciaRuiz et al, 1997)), the effect of GD3 in the induction of apoptosis and MPTP opening shows considerable specificity.…”

Section: Ceramide and Mitochondria In Cell Deathmentioning

confidence: 99%