Effects of disialoganglioside GD3 on the mitochondrial membrane potential

Higuchi, Yu; Miura, Tsuyoshi; Kajimoto, Tetsuya; Ohta, Yoshihiro

doi:10.1016/j.febslet.2005.04.054

Cited by 22 publications

(16 citation statements)

References 19 publications

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“…22,23 The direct effect of ceramide on mitochondria was reproduced with GD3 ganglioside that leads to a marked loss of mitochondrial DCm and apoptosis. 24 These studies led us to assume that the mitochondrial dysfunction that we observed was not an artefact but was secondary to the GM3 synthase deficiency. This hypothesis was strengthened by the demonstration of a significant decrease in mitochondrial membrane potential and a significant increase in apoptosis, in response to rotenone, in the patient's fibroblasts compared with control cells.…”

Section: Discussionmentioning

confidence: 82%

Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

et al. 2012

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We report two children, born from consanguineous parents, who presented with early-onset refractory epilepsy associated with psychomotor delay, failure to thrive, blindness and deafness. Polarographic and spectrophotometric analyses in fibroblasts and liver revealed a respiratory chain (RC) dysfunction. Surprisingly, we identified a homozygous nonsense mutation in the GM3 synthase gene by using exome sequencing. GM3 synthase catalyzes the formation of GM3 ganglioside from lactosylceramide, which is the first step in the synthesis of complex ganglioside species. Mass spectrometry analysis revealed that the complete absence of GM3 ganglioside and its biosynthetic derivatives was associated with an upregulation of the alternative globoside pathway in fibroblasts. The accumulation of Gb3 and Gb4 globosides likely has a role in RC dysfunction and in the decrease of mitochondrial membrane potential leading to apoptosis, which we observed in fibroblasts. We show for the first time that GM3 synthase deficiency, responsible for early-onset epilepsy syndrome, leads to a secondary RC dysfunction. Our study highlights the role of secondary mitochondrial disorders that can interfere with the diagnosis and the evolution of other metabolic diseases.

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Section: Discussionmentioning

confidence: 82%

Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

et al. 2012

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“…It has been reported that the disialoganglioside GD3 is one of the mediators between the Golgi apparatus and the mitochondria [74–77]. GD3 plays an important role as an intracellular mediator of the apoptotic program in several cell types, and it is likely required for stimulating the trans-Golgi network (TGN) to protect the mitochondrial membrane [78–81]. It is well known that mitochondria are associated with the progression of apoptosis via the loss of mitochondrial membrane potential [81–83].…”

Section: Discussionmentioning

confidence: 99%

The Endoplasmic Reticulum-Resident Chaperone Heat Shock Protein 47 Protects the Golgi Apparatus from the Effects of O-Glycosylation Inhibition

et al. 2013

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The Golgi apparatus is important for the transport of secretory cargo. Glycosylation is a major post-translational event. Recognition of O-glycans on proteins is necessary for glycoprotein trafficking. In this study, specific inhibition of O-glycosylation (Golgi stress) induced the expression of endoplasmic reticulum (ER)-resident heat shock protein (HSP) 47 in NIH3T3 cells, although cell death was not induced by Golgi stress alone. When HSP47 expression was downregulated by siRNA, inhibition of O-glycosylation caused cell death. Three days after the induction of Golgi stress, the Golgi apparatus was disassembled, many vacuoles appeared near the Golgi apparatus and extended into the cytoplasm, the nuclei had split, and cell death assay-positive cells appeared. Six hours after the induction of Golgi stress, HSP47-knockdown cells exhibited increased cleavage of Golgi-resident caspase-2. Furthermore, activation of mitochondrial caspase-9 and ER-resident unfolded protein response (UPR)-related molecules and efflux of cytochrome c from the mitochondria to the cytoplasm was observed in HSP47-knockdown cells 24 h after the induction of Golgi stress. These findings indicate that (i) the ER-resident chaperon HSP47 protected cells from Golgi stress, and (ii) Golgi stress-induced cell death caused by the inhibition of HSP47 expression resulted from caspase-2 activation in the Golgi apparatus, extending to the ER and mitochondria.

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“…AIF and cytochrome c, some studies have been performed [83,86,87]. In this regard, GD3 specifically induces gradual depolarization of the inner mitochondrial membrane that is suppressed by cyclosporin A, a mitochondrial pore opening inhibitor [86]. Furthermore, it has been shown that the mitochondrial effects of GD3 ganglioside are selective, since they cannot be mimicked by either GD1a or GM3 gangliosides and lead to the opening of the permeability transition pore [87].…”

Section: Raft-like Microdomains On Mitochondriamentioning

confidence: 99%

Section: Raft-like Microdomains On Mitochondriamentioning

confidence: 99%

Dynamics of lipid raft components during lymphocyte apoptosis: The paradigmatic role of GD3

et al. 2007

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Several investigations have been carried out since many years in order to precisely address the function of lipid rafts in cell life and death. On the basis of the biochemical nature of lipid rafts, composed by sphingolipids, including gangliosides, sphingomyelin, cholesterol and signaling proteins, a plethora of possible interactions with various subcellular structures has been suggested. Their structural and functional role at the plasma membrane as well as in cell organelles such as endoplasmic reticulum and Golgi apparatus has been analyzed in detail in several studies. In particular, a specific activity of lipid rafts has been hypothesized to contribute to cell death by apoptosis. Although detected in various cell types, the role of lipid rafts in apoptosis has however been mostly studied in lymphocytes where the physiological apoptotic program occurs after CD95/Fas triggering. In this review, the possible contribution of lipid rafts to the cascade of events leading to T cell apoptosis after CD95/Fas ligation are summarized. Particular attention has been given to the mitochondrial raft-like microdomains, which may represent preferential sites where some key reactions can take place and can be catalyzed, leading to either survival or death of T cells.

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Effects of disialoganglioside GD3 on the mitochondrial membrane potential

Cited by 22 publications

References 19 publications

Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

Refractory epilepsy and mitochondrial dysfunction due to GM3 synthase deficiency

The Endoplasmic Reticulum-Resident Chaperone Heat Shock Protein 47 Protects the Golgi Apparatus from the Effects of O-Glycosylation Inhibition

Dynamics of lipid raft components during lymphocyte apoptosis: The paradigmatic role of GD3

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