Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.3.14 (ATP synthase)
 7,042 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

When cells undergo nuclear apoptosis (chromatin condensation, DNA fragmentation), they already manifest at least three alterations that can be quantified cytofluorometrically at the single-cell level: 1) a loss of mitochondrial transmembrane potential (delta psi m), 2) an increased production of superoxide anions, and 3) the aberrant exposure of phosphatidylserine (PS) residues on the outer plasma membrane leaflet. This latter alteration allows for the phagocytic recognition/elimination of apoptotic cells. In this work, we show that cells first undergo the delta psi m disruption and that PS exposure only affects cells that already have a low delta psi m. Pharmacologic modulation of apoptosis with inhibitors of macromolecule synthesis or proteases, as well as with drugs stabilizing the delta psi m, indicates that delta psi m disruption and PS exposure are coregulated. Interventions on apoptosis-regulatory genes (p53, bcl-2) confirm the coregulation of delta-psi-m disruption, PS exposure, and nuclear signs of apoptosis. In all conditions in which apoptosis is prevented, the delta psi m remains stable and PS cannot be detected on the cell surface. Reactive oxygen species do not contribute to PS exposure, based on two lines of evidence. First, among thymocytes undergoing apoptosis in response to dexamethasone, delta psi mlow cells first expose PS and then hyperproduce superoxide anion. Second, exogenous sources of reactive oxygen species or the superoxide anion-generating drug menadione fail to cause rapid PS exposure. Instead, direct interventions on mitochondria using inhibitors of the respiratory chain or the F1 ATP synthase cause PS exposure in cells subsequent to delta psi m disruption. This effect is also obtained in anucleate cells, indicating that the nucleus does not intervene in the sequence of events coupling mitochondrial dysfunction to PS exposure. Altogether, these data underline the functional impact of mitochondrial alterations on the apoptotic process.
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PMID:Sequential acquisition of mitochondrial and plasma membrane alterations during early lymphocyte apoptosis. 875 96

Toxic bile salts cause hepatocyte necrosis at high concentrations and apoptosis at lower concentrations. Although fructose prevents bile salt-induced necrosis, the effect of fructose on bile salt-induced apoptosis is unclear. Our aim was to determine if fructose also protects against bile salt-induced apoptosis. Fructose inhibited glycochenodeoxycholate (GCDC)-induced apoptosis in a concentration-dependent manner with a maximum inhibition of 72% +/- 10% at 10 mmol/L. First, we determined if fructose inhibited apoptosis by decreasing adenosine triphosphate (ATP) and intracellular pH (pHi). Although fructose decreased ATP to <25% of basal values, oligomycin (an ATP synthase inhibitor) did not inhibit apoptosis despite decreasing ATP to similar values. Fructose (10 mmol/L) decreased intracellular pH (pHi) by 0.2 U. However, extracellular acidification (pH 6.8), which decreased hepatocyte pHi 0.35 U and is known to inhibit necrosis, actually potentiated apoptosis 1.6-fold. Fructose cytoprotection also could not be explained by induction of bcl-2 transcription or metal chelation. Because we could not attribute fructose cytoprotection to metabolic effects, alterations in the expression of bcl-2, or metal chelation, we next determined if the poorly metabolized ketohexoses, tagatose and sorbose, also inhibited apoptosis; unexpectedly, both ketohexoses inhibited apoptosis. Because bile salt-induced apoptosis and necrosis are inhibited by fructose, these data suggest that similar processes initiate bile salt-induced hepatocyte necrosis and apoptosis. In contrast, acidosis, which inhibits necrosis, potentiates apoptosis. Thus, ketohexose-sensitive pathways appear to initiate both bile salt-induced cell apoptosis and necrosis, whereas dissimilar, pH-sensitive, effector mechanisms execute these two different cell death processes.
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PMID:Cytoprotection by fructose and other ketohexoses during bile salt-induced apoptosis of hepatocytes. 898 69

We have investigated cell metabolism during apoptosis in the murine interleukin-3 (IL-3)-dependent cell line Bo and two derivative clones (B14 and B15) overexpressing human bcl-2a. On removal of IL-3, Bo cells underwent apoptosis within 8 h, whereas B14 and B15 cells were resistant for at least 24 h. Metabolically, Bo, B14, and B15 cells were indistinguishable from each other. All were insensitive to mitochondrial poisons, derived ATP entirely by glycolysis, and maintained similar mitochondrial membrane potentials measured by rhodamine-123 fluorescence with or without IL-3. All virtually ceased glycolysis and production of lactic acid on IL-3 withdrawal but maintained intracellular [ATP] until in Bo cultures the cells began to apoptose. B14 and B15 cells became glycolytically arrested but maintained stable ATP levels during protection from apoptosis. Depletion of intracellular ATP by uncoupling the mitochondrial ATPase with 2,4-dinitrophenol or carbonyl cyanide p-trifluoromethoxyphenylhydrazone induced apoptosis in Bo cells with or without IL-3, but not in B14 or B15 cells. bcl-2-overexpressing cells were recoverable with high plating efficiency even after prolonged exposure to 2,4-dinitrophenol. We conclude that IL-3 withdrawal leads to arrest of energy metabolism in which ATP levels are maintained. In Bo cells this is followed by apoptosis, whereas in bcl-2-overexpressing cells this state is stably prolonged. ATP depletion is a strong apoptotic signal which overrides IL-3 signaling in normal cells but is ineffective in bcl-2-overexpressing cells. Prolonged metabolic arrest and resistance to ATP depletion facilitated by bcl-2 are both reversible. Persistent reversible metabolic dormancy would provide cells with a survival advantage in nonsustainable environments (e.g. hypoxia or substrate lack) and suggests a mechanism for the survival advantage displayed by cells overexpressing bcl-2.
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PMID:Energy metabolism during apoptosis. Bcl-2 promotes survival in hematopoietic cells induced to apoptose by growth factor withdrawal by stabilizing a form of metabolic arrest. 903 May 19

The relationship is investigated between mitochondrial membrane potential (Delta Psi(M)), respiration and cytochrome c (cyt c) release in single neural bcl-2 transfected cells (GT1-7bcl-2) or GT1-7puro cells during apoptosis induced by staurosporine (STS). Bcl-2 inhibited the mitochondrial release of cyt c and apoptosis. Three different cell responses to STS were identified in GT1-7puro cells: (i) neither Delta Psi(M) nor cyt c were significantly affected; (ii) a decrease in Delta Psi(M) was accompanied by a complete release of cyt c; or (iii) cyt c release occurred independently of a loss of Delta Psi(M). The endogenous inner membrane proton leak of the in situ mitochondria, monitored by respiration in the presence of oligomycin, was increased by STS by 92% in puro cells, but by only 23% in bcl-2 cells. STS decreased respiratory capacity, in the presence of protonophore, by 31% in puro cells and by 20% in bcl-2 cells. In the absence of STS, oligomycin hyperpolarized mitochondria within both puro and bcl-2-transfected cells, indicating that the organelles were net generators of ATP. However after 15 h exposure to STS oligomycin rapidly collapsed residual mitochondrial polarization in the puro cells, indicating that Delta Psi(M) had been maintained by ATP synthase reversal. bcl-2 cells in contrast, maintained Delta Psi(M) until protonophore was added. These results indicate that the maintenance of Delta Psi(M) following release of cyt c may be a consequence of ATP synthase reversal and cytoplasmic ATP hydrolysis in STS-treated GT1-7 cells.
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PMID:The mechanism of mitochondrial membrane potential retention following release of cytochrome c in apoptotic GT1-7 neural cells. 1159 97