Cells die with increased cytosolic ATP during apoptosis: a bioluminescence study with intracellular luciferase

Zamaraeva, Maria; Sabirov, Ravshan Z.; Maeno, Emi; Ando‐Akatsuka, Yuhko; Bessonova, S V; Okada, Yasunobu

doi:10.1038/sj.cdd.4401661

Cited by 275 publications

(243 citation statements)

References 35 publications

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“…After 96 h, the first signs of apoptosis were observed, the cells were highly active and have maintained their elevated mitochondrial activity. This is consistent with the literature, in which it is known that the apoptotic process demands high energy for its development (Eguchi et al, 1997;Zamaraeva et al, 2005). Recent studies showed that cells undergoing apoptosis show the same or even better energy status as long as the cells maintained a highly active metabolism (such as various biosynthesis processes including lipid biosynthesis, DNA fragmentation and so on; Budd et al, 2000;Zamaraeva et al, 2005).…”

Section: Discussionsupporting

confidence: 80%

Time-dependent effects of imatinib in human leukaemia cells: a kinetic NMR-profiling study

et al. 2009

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The goal of this study was to evaluate the time course of metabolic changes in leukaemia cells treated with the Bcr-Abl tyrosine kinase inhibitor imatinib. Human Bcr-Abl þ K562 cells were incubated with imatinib in a dose-escalating manner (starting at 0.1 mM with a weekly increase of 0.1 mM imatinib) for up to 5 weeks. Nuclear magnetic resonance spectroscopy and liquid-chromatography mass spectrometry were performed to assess a global metabolic profile, including glucose metabolism, energy state, lipid metabolism and drug uptake, after incubation with imatinib. Initially, imatinib treatment completely inhibited the activity of Bcr-Abl tyrosine kinase, followed by the inhibition of cell glycolytic activity and glucose uptake. This was accompanied by the increased mitochondrial activity and energy production. With escalating imatinib doses, the process of cell death rapidly progressed. Phosphocreatine and NAD þ concentrations began to decrease, and mitochondrial activity, as well as the glycolysis rate, was further reduced. Subsequently, the synthesis of lipids as necessary membrane precursors for apoptotic bodies was accelerated. The concentrations of the Kennedy pathway intermediates, phosphocholine and phosphatidylcholine, were reduced. After 4 weeks of exposure to imatinib, the secondary necrosis associated with decrease in the mitochondrial and glycolytic activity occurred and was followed by a shutdown of energy production and cell death. In conclusion, monitoring of metabolic changes in cells exposed to novel signal transduction modulators supplements molecular findings and provides further mechanistic insights into longitudinal changes of the mitochondrial and glycolytic pathways of oncogenesis.

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Section: Discussionsupporting

confidence: 80%

Time-dependent effects of imatinib in human leukaemia cells: a kinetic NMR-profiling study

et al. 2009

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“…17 Additionally, a different study asserted that an elevation in cytosolic ATP, and thus a decline in the ADP/ATP ratio even below levels detected in healthy cells, was necessary for propagation of apoptosis. 18 Therefore, there is even significant disagreement in the literature concerning the meaning of the ADP/ATP ratio as it relates to the quality of a cellular preparation; both high and low ADP/ATP ratios have been associated with increased cell death. It has been hypothesized that the increase in cytosolic ATP in cells undergoing apoptosis will not be sustained and that ATP as well as ADP will be depleted shortly after the execution phase of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

The ATP/DNA Ratio Is a Better Indicator of Islet Cell Viability Than the ADP/ATP Ratio

Suszynski¹,

Wildey²,

Falde³

et al. 2008

Transplantation Proceedings

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Real-time, accurate assessment of islet viability is critical for avoiding transplantation of nontherapeutic preparations. Measurements of the intracellular ADP/ATP ratio have been recently proposed as useful prospective estimates of islet cell viability and potency. However, dead cells may be rapidly depleted of both ATP and ADP, which would render the ratio incapable of accounting for dead cells. Since the DNA of dead cells is expected to remain stable over prolonged periods of time (days), we hypothesized that use of the ATP/DNA ratio would take into account dead cells and may be a better indicator of islet cell viability than the ADP/ATP ratio. We tested this hypothesis using mixtures of healthy and lethally heat-treated (HT) rat insulinoma cells and human islets. Measurements of ATP/DNA and ADP/ATP from the known mixtures of healthy and HT cells and islets were used to evaluate how well these parameters correlated with viability. The results indicated that ATP and ADP were rapidly (within 1 hour) depleted in HT cells. The fraction of HT cells in a mixture correlated linearly with the ATP/DNA ratio, whereas the ADP/ADP ratio was highly scattered, remaining effectively unchanged. Despite similar limitations in both ADP/ADP and ATP/ DNA ratios, in that ATP levels may fluctuate significantly and reversibly with metabolic stress, the results indicated that ATP/DNA was a better measure of islet viability than the ADP/ATP ratio.Islet cell transplantation is emerging as a promising therapy for the treatment of type 1 diabetes. [1][2][3][4][5] Despite recent advances, the transplantation of islets poses a unique challenge with respect to achieving a consistent clinical outcome. Part of this challenge is being able to reliably and rapidly assess clinical islet quality through the quantification of viability and function before transplantation. Current viability assays are limited in their ability to accurately predict transplantation outcomes in vivo. 6 Consequently, to improve the clinical islet transplantation outcomes, it is imperative to develop more accurate viability assays.A proposed method to assess islet viability and potency before transplantation is quantification of the ADP/ATP ratio. 6 -10 This ratio has been specifically applied in discriminating islet preparations that are suitable for clinical transplantation from those that are not. 6 However, this application may be problematic under certain conditions. Intracellular ADP and ATP levels fluctuate rapidly because these high-energy phosphate molecules are rapidly produced and consumed in many intracellular biochemical reactions. It is widely known that viable cells turn over entire ATP stores on the order of minutes, and that dead cells are incapable of replenishing To better account for dead cells and to more accurately assess the viability of an islet preparation, we suggest the use of an ATP/DNA ratio. DNA does not degrade as rapidly as ADP or ATP in a dead cell. Therefore, using direct measurements of DNA, dead cells in an islet preparation...

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“…28 Several reports showed that intracellular ATP levels remain unchanged or even elevated for a short time in STP or in etoposide-induced apoptosis, and then gradually decrease until the very end of the death process. [35][36][37] We first demonstrated that this phenomenon occurs in GzmB-induced apoptosis (Figure 8a). However, we found that, after GzmF treatment, intracellular ATP diminishes at an early stage, which is much earlier than cyt c release.…”

Section: Discussionmentioning

confidence: 99%

Granzyme F induces a novel death pathway characterized by Bid-independent cytochrome c release without caspase activation

Shi

Wang

et al. 2009

Cell Death Differ

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Cells die with increased cytosolic ATP during apoptosis: a bioluminescence study with intracellular luciferase

Cited by 275 publications

References 35 publications

Time-dependent effects of imatinib in human leukaemia cells: a kinetic NMR-profiling study

Time-dependent effects of imatinib in human leukaemia cells: a kinetic NMR-profiling study

The ATP/DNA Ratio Is a Better Indicator of Islet Cell Viability Than the ADP/ATP Ratio

Granzyme F induces a novel death pathway characterized by Bid-independent cytochrome c release without caspase activation

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