GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization

Tarze, Agathe; Deniaud, Aurélien; Bras, Morgane Le; Maillier, Evelyne; Mollé, Daniel; Larochette, Nathanaël; Zamzami, Naoufal; Jan, Gwénaël; Kroemer, Guido; Brenner, Catherine

doi:10.1038/sj.onc.1210074

Cited by 317 publications

(232 citation statements)

References 60 publications

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“…In contrast to NAC, the effects of which do not coincide with those induced by the downregulation of VDAC1, we found that 4,4 0 -diisothiocyanostilbene-2,2 0 -disulfonic acid, a chemical inhibitor of VDAC1 (Thinnes et al, 1990;ShoshanBarmatz et al, 1996;Shafir et al, 1998;Tarze et al, 2007), can faithfully mimic VDAC1 depletion and hence inhibit CDDP-induced cell death (Figures 6a and b) as well as the activation of Bax (but not Bak) and caspase-3 (Figures 6c and d).…”

Section: Hierarchical Relationship Between Vdac1 Bax and Bakmentioning

confidence: 51%

Hierarchical involvement of Bak, VDAC1 and Bax in cisplatin-induced cell death

et al. 2008

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Following the screening of a battery of distinct smallinterfering RNAs that target various components of the apoptotic machinery, we found that knockdown of the voltage-dependent anion channel 1 (VDAC1) was particularly efficient in preventing cell death induced by cisplatin (CDDP) in non-small cell lung cancer cells. Both the downregulation of VDAC1 and its chemical inhibition with 4,4 0 -diisothiocyanatostilbene-2,2 0 -disulfonic acid reduced the apoptosis-associated modifications induced by CDDP, including mitochondrial transmembrane potential dissipation and plasma membrane permeabilization. VDAC1 inhibition strongly reduced the CDDP-induced conformational activation of Bax, yet had no discernible effect on the activation of Bak, suggesting that VDAC1 acts downstream of Bak and upstream of Bax. Accordingly, knockdown of Bak abolished the activation of Bax, whereas Bax downregulation had no effect on Bak activation. In VDAC1-depleted cells, the failure of CDDP to activate Bax could be reversed by means of the Bcl-2/ Bcl-X L antagonist ABT-737, which concomitantly restored CDDP cytotoxicity. Altogether, these results delineate a novel pathway for the induction of mitochondrial membrane permeabilization (MMP) in the course of CDDPinduced cell death that involves a hierarchical contribution of Bak, VDAC1 and Bax. Moreover, our data suggest that VDAC1 may act as a facultative regulator/effector of MMP, depending on the initial cytotoxic event.

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Section: Hierarchical Relationship Between Vdac1 Bax and Bakmentioning

confidence: 51%

Hierarchical involvement of Bak, VDAC1 and Bax in cisplatin-induced cell death

et al. 2008

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“…It has been shown that under stressful cellular conditions, GAPDH interacts with the voltage-dependent anion channel (VDAC), promoting the cytochrome c and apoptosis-inducing factor release, leading to apoptotic cell death. 39 TG2 interacts with key elements of the fission/fusion molecular pathway. In order to define the molecular mechanisms at the basis of above described effects of TG2 on mitophagy, we analysed the interaction of the enzyme with the mitochondrial Drp1 and Fis1, two key (Figures 6a and c, respectively).…”

Section: Resultsmentioning

confidence: 99%

Transglutaminase 2 ablation leads to mitophagy impairment associated with a metabolic shift towards aerobic glycolysis

et al. 2014

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Macroautophagy selectively degrades dysfunctional mitochondria by a process known as mitophagy. Here we demonstrate the involvement of transglutaminase 2 (TG2) in the turnover and degradation of damaged mitochondria. In TG2-ablated cells we observed the presence of a large number of fragmented mitochondria that display decreased membrane potential, downregulation of IF1 along with increased Drp1 and PINK1 levels, two key proteins regulating the mitochondrial fission. Of note, we demonstrate that in healthy mitochondria, TG2 interacts with the dynamic proteins Drp1 and Fis1; interestingly, their interaction is largely reduced upon induction of the fission process by carbonyl cyanide m-chlorophenyl hydrazine (CCCP). In keeping with these findings, mitochondria lacking TG2 are more susceptible to CCCP treatment. As a consequence of accumulation of damaged mitochondria, cells lacking TG2 increased their aerobic glycolysis and became sensitive to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). In contrast, TG2-proficient cells are more resistant to 2-DG-induced apoptosis as the caspase 3 is inactivated through the enzyme's crosslinking activity. The data presented in this study show that TG2 plays a key role in cellular dynamics and consequently influences the energetic metabolism.

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“…The error bars are shown in one direction to avoid visual confusion. C: Western blots of purified mitochondrial and cytosolic fractions showing the distribution of the mitochondrial markers cytochrome c and VDAC-1, and for the loading control GAPDH which is found in various cellular locations including the cytosol and mitochondria (Tarze et al, 2007). Relative levels of GSH in cells exposed to various concentrations of Na 2 Cr(VI)O 4 or to diamide as indicated.…”

Section: Discussionmentioning

confidence: 99%

Hexavalent chromium causes the oxidation of thioredoxin in human bronchial epithelial cells

2008

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Hexavalent chromium [Cr(VI)] species such as chromates are cytotoxic. Inhalational exposure is a primary concern in many Cr-related industries and their immediate environments, and bronchial epithelial cells are directly exposed to inhaled Cr(VI). Chromates are readily taken up by cells and are reduced to reactive Cr species which may also result in the generation of reactive oxygen species (ROS). The thioredoxin (Trx) system has a key role in the maintenance of cellular thiol redox balance and is essential for cell survival. Cells normally maintain the cytosolic (Trx1) and mitochondrial (Trx2) thioredoxins largely in the reduced state. Redox western blots were used to assess the redox status of the thioredoxins in normal human bronchial epithelial cells (BEAS-2B) incubated with soluble Na 2 CrO 4 or insoluble ZnCrO 4 for different periods of time. Both chromates caused a doseand time-dependent oxidation of Trx2 and Trx1. Trx2 was more susceptible in that it could all be converted to the oxidized form, whereas a small amount of reduced Trx1 remained even after prolonged treatment with higher Cr concentrations. Only one of the dithiols, presumably the active site, of Trx1 was oxidized by Cr(VI). Cr(VI) did not cause significant GSH depletion or oxidation indicating that Trx oxidation does not result from a general oxidation of cellular thiols. With purified Trx and thioredoxin reductase (TrxR) in vitro, Cr(VI) also resulted in Trx oxidation. It was determined that purified TrxR has pronounced Cr(VI) reducing activity, so competition for electron flow from TrxR might impair its ability to reduce Trx. The in vitro data also suggested some direct redox interaction between Cr(VI) and Trx. The ability of Cr(VI) to cause Trx oxidation in cells could contribute to its cytotoxic effects, and could have important implications for cell survival, redoxsensitive cell signaling, and the cells' tolerance of other oxidant insults.

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GAPDH, a novel regulator of the pro-apoptotic mitochondrial membrane permeabilization

Cited by 317 publications

References 60 publications

Hierarchical involvement of Bak, VDAC1 and Bax in cisplatin-induced cell death

Hierarchical involvement of Bak, VDAC1 and Bax in cisplatin-induced cell death

Transglutaminase 2 ablation leads to mitophagy impairment associated with a metabolic shift towards aerobic glycolysis

Hexavalent chromium causes the oxidation of thioredoxin in human bronchial epithelial cells

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