Opposite role of changes in mitochondrial membrane potential in different apoptotic processes

Salvioli, Stefano; Barbi, Cristiana; Dobrucki, Jurek; Moretti, Laura; Pinti, Marcello; Pedrazzi, Jessica; Pazienza, Teresa Loredana; Bobyleva, Valentina; Franceschi, Claudio; Cossarizza, Andrea

doi:10.1016/s0014-5793(00)01266-7

Cited by 42 publications

(23 citation statements)

References 29 publications

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“…Our preliminary studies indicate that both apoptotic stimuli induce a much deeper decrease in ATP levels in U937 V cells when compared to the reference cells. Additionally, a rapid decrease in MMP might suggest that ATP is depleted and the process of apoptosis might be inhibited [24,26]. Although an MMP decrease can be a consequence of the presence of reactive oxygen species (ROS) [8], in our study the generation of ROS observed in the U937 V cells seemed to be rather the consequence of a decrease in the MMP, similarly to that reported by other authors [9,27,28].…”

Section: Discussionsupporting

confidence: 88%

U937 variant cells as a model of apoptosis without cell disintegration

Stasiłojć

Pinto

Wyszkowska

et al. 2013

Cellular and Molecular Biology Letters

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Abbreviations used: ATCC -American Type Culture Collection; CHX -cycloheximide; DCF -2,7-dichlorofluorescin; DHCF-DA -2',7'-dihydrodichlorofluorescein diacetate; DHE -dihydroethidium; MMP -mitochondrial membrane potential; · O¯2 -superoxide anion; PS -phosphatidylserine; TMRM -tramethylrhodamine methyl ester; TNFα -tumor necrosis factor; U937 V -a variant of the U937 cell line; VP-16 -etoposide Abstract: The variant cell line U937 V was originally identified by a higher sensitivity to the cytocidal action of tumor necrosis factor alpha (TNFα) than that of its reference cell line, U937. We noticed that a typical morphological feature of dying U937 V cells was the lack of cellular disintegration, which contrasts to the formation of apoptotic bodies seen with dying U937 cells. We found that both TNFα, which induces the extrinsic apoptotic pathway, and etoposide (VP-16), which induces the intrinsic apoptotic pathway, stimulated U937 V cell death without cell disintegration. In spite of the distinct morphological differences between the U937 and U937 V cells, the basic molecular events of apoptosis, such as internucleosomal DNA degradation, phosphatidylserine exposure on the outer leaflet of the plasma membrane, caspase activation and cytochrome c release, were evident in both cell types when stimulated with both types of apoptosis inducer. In the U937 V cells, we noted an accelerated release of cytochrome c, an accelerated decrease in mitochondrial membrane potential, and a more pronounced generation of reactive oxygen species compared to the reference cells. We propose that the U937 and U937 V cell lines could serve as excellent comparison models for studies on the mechanisms regulating the processes of cellular disintegration during apoptosis, such as blebbing (zeiosis) and apoptotic body formation.

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Section: Discussionsupporting

confidence: 88%

U937 variant cells as a model of apoptosis without cell disintegration

Stasiłojć

Pinto

Wyszkowska

et al. 2013

Cellular and Molecular Biology Letters

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“…In the latter, decreases in Dw m and thus a reduction in ATP for protein synthesis inhibited or delayed apoptosis until such time that reduced ATP levels were the cause of cellular demise (Salvioli et al 2000). Human osteosarcoma cells were observed to undergo mitochondrial permeability transition and mitochondrial swelling in a reversible manner and with the marked absence of apoptosis (Minamikawa et al 1999).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have however cast doubt on the involvement of mitochondria on regulating apoptosis reporting that cytochrome c release is not necessary for cell death and that its release is not always facilitated by mitochondrial membrane depolarisation (Hatano et al 2000). Further still, there are suggestion that mitochondrial membrane depolarisation is in itself capable of inducing caspase activation and thus apoptosis (Salvioli et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Apoptosis and Its Suppression in Hepatocytes Culture

Mukwena

Al‐Rubeai

2004

Cytotechnology

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In order to achieve the goal of developing extracorporeal liver support devices, it is necessary to optimise bioprocess environment such that viability and function are maximised. Optimising culture medium composition and controlling the constitution of the cellular microenvironment within the bioreactor have for many years been considered vital to achieving these aims. Coupled to this is the need to understand apoptosis, the prime suspect in the demise of animal cultures, including those of hepatocytes. Results presented here show that absent nutrients including glucose and amino acids play a substantial part in the induction of apoptosis. The use of chemical apoptosis inhibitors was utilised to investigate key components of hepatic apoptosis where caspases, predominantly caspase 8, were implicated in staurosporine (STS)-induced HepZ apoptosis. Caspase 9 and 3 activation although recorded was of less significance. Interestingly, these results were not consistent with those of mitochondrial membrane depolarisation where inhibition of caspase activation appeared to drive depolarisation. Inhibition of mitochondrial permeability transition and use of anti-oxidants was unsuccessful in reducing apoptosis, caspase activation and mitochondrial membrane depolarisation. In further studies, the anti-apoptotic gene bcl-2 was over-expressed in HepZ, resulting in a cell line that was more robust and resistant to death induced by glucose and cystine deprivation and treatment with STS. Bcl-2 did not however show significant cytoprotectivity where apoptosis was stimulated by deprivation of glutamine and serum. Overall, results indicated that although apoptosis can be curbed by use of chemical inhibitors and genetic manipulation, their success is dependent on apoptotic stimuli.

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“…on induction of MPT (Pastorino et al, 1998). Some questions have been raised about the involvement of mitochondrial ÁÉ collapse and cytochrome c release as markers for apoptosis, since they are cell type-and inducer-dependent phenomena (Tang et al, 1998;Salvioli et al, 2000). However, several studies point out that mitochondria play a key role in apoptotic cascade and that the induction of MPT leads to cell death by releasing several activators of apoptosis (Fadeel et al, 1999;Tafani et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial permeability transition induced by the anticancer drug etoposide

Custódio

Cardoso

Madeira

et al. 2001

Toxicology in Vitro

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Etoposide (VP-16) is widely used for the treatment of several forms of cancer. The cytotoxicity of VP-16 has been assigned to the induction of apoptotic cell death but the signaling pathway for VP-16-induced apoptosis is essentially unknown. There is some evidence that this process depends on events associated with the loss of mitochondrial membrane potential (ÁÉ) and/or release of apoptogenic factors, putatively as a consequence of mitochondrial permeability transition (MPT) induction. This work evaluates the interference of VP-16 with MPT in vitro, which is characterized by the Ca 2+ -dependent depolarization of ÁÉ, the release of matrix Ca 2+ and by extensive swelling of mitochondria. ÁÉ depolarization and Ca 2+ release were measured with ion-selective electrodes, and mitochondrial swelling was monitored spectrophotometrically. Incubation of rat liver mitochondria with VP-16 results in a concentration-dependent induction of MPT, evidenced by an increased sensitivity to Ca 2+ -induced swelling, depolarization of ÁÉ, Ca 2+ release by mitochondria and stimulation of state 4 oxygen consumption. All of these effects are prevented by preincubating the mitochondria with cyclosporine A, a potent and specific inhibitor of the MPT. Therefore, VP-16 increases the sensitivity of isolated mitochondria to the Ca 2+ -dependent induction of the MPT. Together, these data provide a possible mechanistic explanation for the previously reported effects of VP-16 on apoptosis induction. #

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Opposite role of changes in mitochondrial membrane potential in different apoptotic processes

Cited by 42 publications

References 29 publications

U937 variant cells as a model of apoptosis without cell disintegration

U937 variant cells as a model of apoptosis without cell disintegration

Apoptosis and Its Suppression in Hepatocytes Culture

Mitochondrial permeability transition induced by the anticancer drug etoposide

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