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

Rippo, Maria Rita; Malisan, Florence; Ravagnan, Luigi; Tomassini, Barbara; Condò, Ivano; Costantini, Paola; Susín, Santos A.; Rufini, Alessandra; Todaro, Matilde; Kroemer, Guido; Testi, Roberto

doi:10.1096/fj.99-1028com

Cited by 178 publications

(185 citation statements)

References 53 publications

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“…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.…”

Section: Discussionmentioning

confidence: 59%

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

Giammarioli²,

et al. 2005

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Plasma membrane lipid microdomains have been considered as a sort of 'closed chamber', where several subcellular activities, including CD95/Fas-mediated proapoptotic signaling, take place. In this work we detected GD3 and GM3 gangliosides in isolated mitochondria from lymphoblastoid CEM cells. Moreover, we demonstrated the presence of microdomains in mitochondria by immunogold transmission electron microscopy. We also showed that GD3, the voltagedependent anion channel-1 (VDAC-1) and the fission protein hFis1 are structural components of a multimolecular signaling complex, in which Bcl-2 family proteins (t-Bid and Bax) are recruited. The disruption of lipid microdomains in isolated mitochondria by methyl-b-cyclodextrin prevented mitochondria depolarization induced by GD3 or t-Bid. Thus, mitochondrion appears as a subcompartmentalized organelle, in which microdomains may act as controllers of their apoptogenic programs, including fission-associated morphogenetic changes, megapore formation and function. These results disclose a new scenario in which mitochondria-associated lipid microdomains can act as regulators and catalysts of cell fate.

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Section: Discussionmentioning

confidence: 59%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Giammarioli²,

et al. 2005

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“…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.…”

Section: Bcl-2 and Ca 2 þ : Establishing The Linkmentioning

confidence: 94%

Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum

2006

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Recent data have revealed an unexpected role of Bcl-2 in modulating the steady-state levels and agonist-dependent fluxes of Ca 2 þ ions. Direct monitoring of endoplasmic reticulum (ER) Ca 2 þ concentration with recombinant probes reveals a lower state of filling in Bcl-2-overexpressing cells and a higher leak rate from the organelle. The broader set of indirect data using cytosolic probes reveals a more complex scenario, as in many cases no difference was detected in the Ca 2 þ content of the intracellular pools. At the same time, Ca 2 þ signals have been shown to affect important checkpoints of the apoptotic process, such as mitochondria, thus tuning the sensitivity of cells to various challenges. In this contribution, we will review (i) the data on the effect of Bcl-2 on [Ca 2 þ ] er , (ii) the functional significance of the Ca 2 þ -signalling alteration and (iii) the current insight into the possible mechanisms of this effect.

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“…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.…”

Section: Gangliosides As Propagators Of the Er Stress-and Mitochondrimentioning

confidence: 99%

Gangliosides as apoptotic signals in ER stress response

d’Azzo

Tessitore²,

Sano

2006

Cell Death Differ

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Renewed attention has been given lately to gangliosides and to their function as intracellular messengers of the adaptive responses to stress. Gangliosides are vital components of cell membranes; therefore, deleterious consequences can result from changes in their chemical composition and concentration, that is, membrane dynamics and structure can be altered as can the behavior of other membrane proteins. The importance of gangliosides in human health is evident in neurodegenerative diseases associated with defects in their degradation. As key modulators of intracellular calcium flux, gangliosides are involved in cellular processes downstream of calcium signaling. In this review, we focus on the effect of ganglioside accumulation on the endoplasmic reticulum calcium homeostasis and on the integrity of the mitochondrial membranes. We discuss how these events elicit an apoptotic program that ultimately leads to cell death. Owing to interorganelle crosstalk, these events are not necessarily self-contained, and gangliosides may serve as the common factor.

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

Cited by 178 publications

References 53 publications

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

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

Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum

Gangliosides as apoptotic signals in ER stress response

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