Hydroperoxides can modulate the redox state of pyridine nucleotides and the calcium balance in rat liver mitochondria

Lotscher, Hans Ruedi; Winterhalter, Kaspar H.; Carafoli, Ernesto; Richter, Christoph

doi:10.1073/pnas.76.9.4340

Cited by 163 publications

(67 citation statements)

References 29 publications

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“…Thus, the involvement of GSH in the protection of tumour cells against cytotoxic treatment appears to have been convincingly demonstrated. The maintenance of a high GSH/GSSG ratio has been shown to be vital for the functional integrity of cell membranes (Lotscher et al, 1979;Harris & Baum, 1980). It was shown that unless membrane sulphydryls were kept in a highly reduced state, the membranes could become leaky, resulting in the uncontrolled release of Ca2 + into the cytoplasm from the mitochondria as well as influx from the extracellular spaces (Lotscher et al, 1979) and this had been postulated as a 'common pathway' of cytotoxicity for chemicals that induce oxidative stress (Schanne et al, 1979).…”

Section: Discussionmentioning

confidence: 99%

Changes in cellular glutathione content during adriamycin treatment in human ovarian cancer – a possible indicator of chemosensitivity

Lee

Siemann²,

Sutherland³

1989

Br J Cancer

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Summary Patients with ovarian cancer often respond well to combination chemotherapy initially but the majority eventually relapse when, with further treatment, the initially successful regimen proves ineffectual. The cause of such failures frequently has been attributed to the development of drug resistance. Although the mechanisms of acquired resistance in situ are still poorly understood, studies in vitro have shown that cells selected for resistance to one drug often exhibit cross-resistance to other seemingly unrelated agents, suggesting a somewhat generalised mechanism of resistance. We have studied the role of glutathione (GSH) and drug transport in determining the sensitivity to adriamycin (ADR) of a panel of human ovarian cell lines established directly from biopsies of patients with diverse treatment histories. These cell lines exhibited inherent differences in sensitivity to ADR by a dose factor of up to 3; a difference that was considerably less than what has been reported when cells were selected for drug resistance in vitro. The differences in drug sensitivity reported here among the various cell lines appeared to be unrelated to drug transport, in terms of both influx and efflux. Moreover, although these cell lines have a wide range of GSH content, there was only a poor correlation between drug sensitivity and cellular GSH content per se. However, when exposed to a clinically relevant dose of ADR, the GSH content of cell lines that were 'sensitive' decreased, whereas that of cell lines that were 'resistant' increased. To take these time-dependent changes in GSH into consideration, the area under the GSH content versus time curve (AUC), with and without ADR treatment, was calculated for each cell line. When this latter factor was included in the analysis, greatly improved correlations were found between GSH kinetic parameters and responses to ADR. In particular, ADR resistance was found to be closely correlated with the positive changes in absolute GSH AUC following ADR treatment (r=0.92; P<0.01). Using 35S-labelled cysteine and methionine as tracers, it was found that the essential difference between the 'resistant' and 'sensitive' lines was that the 'resistant' lines had higher steady-state rates of GSH synthesis than the 'sensitive' lines. These results demonstrate that changes in cellular GSH concentration during treatment may be an important indicator of tumour cell response to ADR.The role of glutathione (GSH) in the development of drug and radiation resistance in cancer cells is a subject of much current research effort. Although the mechanism(s) by which GSH protects cells from the damaging effects of cytotoxic agents is still not fully understood, it is now clear that GSH can greatly influence the intrinsic sensitivity of tumour cells to radiation (Biaglow et al., 1983;Shrieve et al., 1985;Revesz, 1985) and to a variety of cytotoxic drugs (Hamilton et al., 1985;Suzukake et al., 1982;Green et al., 1984;Crook et al., 1986;Lee et al., 1988;Kramer et al., 1987. However, previous studies have fo...

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Section: Discussionmentioning

confidence: 99%

Changes in cellular glutathione content during adriamycin treatment in human ovarian cancer – a possible indicator of chemosensitivity

Lee

Siemann²,

Sutherland³

1989

Br J Cancer

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“…However, it is possible that under special circumstances a similar situation may occur in other tissues including liver. Richter and co-workers (73), investigating the effect of t-butyl hydroperoxide on liver mitochondria, showed that a decrease in glutathione peroxidase activity caused by a selenium-deficient diet prevented depolarization and Ca 2ϩ loss caused by hydroperoxide.…”

Section: Fig 2 Effect Of Ca 2؉ On Mitochondrial Function (Respiratimentioning

confidence: 99%

The Characterization of Mitochondrial Permeability Transition in Clonal Pancreatic β-Cells

Koshkin

Bikopoulos

Chan

et al. 2004

Journal of Biological Chemistry

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Mitochondrial permeability transition (MPT), which contributes substantially to the regulation of normal mitochondrial metabolism, also plays a crucial role in the initiation of cell death. It is known that MPT is regulated in a tissue-specific manner. The importance of MPT in the pancreatic ␤-cell is heightened by the fact that mitochondrial bioenergetics serve as the main glucose-sensing regulator and energy source for insulin secretion. In the present study, using MIN6 and INS-1 ␤-cells, we revealed that both Ca 2؉ -phosphate-and oxidant-induced MPT is remarkably different from other tissues. Ca 2؉ -phosphate-induced transition is accompanied by a decline in mitochondrial reactive oxygen species production related to a significant potential dependence of reactive oxygen species formation in ␤-cell mitochondria. Hydroperoxides, which are indirect MPT co-inducers active in liver and heart mitochondria, are inefficient in ␤-cell mitochondria, due to the low mitochondrial ability to metabolize them. Direct cross-linking of mitochondrial thiols in pancreatic ␤-cells induces the opening of a low conductance ion permeability of the mitochondrial membrane instead of the full scale MPT opening typical for liver mitochondria. Low conductance MPT is independent of both endogenous and exogenous Ca 2؉ , suggesting a novel type of nonclassical MPT in ␤-cells. It results in the conversion of electrical transmembrane potential into ⌬pH instead of a decrease in total protonmotive force, thus mitochondrial respiration remains in a controlled state. Both Ca 2؉ -and oxidant-induced MPTs are phosphate-dependent and, through the "phosphate flush" (associated with stimulation of insulin secretion), are expected to participate in the regulation in ␤-cell glucose-sensing and secretory activity.Mitochondrial permeability transition (MPT) 1 is a permeability increase of the inner mitochondrial membrane to solutes of molecular mass up to ϳ1500 Da, which is caused by an opening of specific nonselective proteinaceous pores in the inner mitochondrial membrane (1, 2). Increased permeability of the inner membrane is initiated by an increased level of intramitochondrial Ca 2ϩ and is regulated by multiple effectors, including inorganic phosphate, the redox state of pyridine nucleotides and thiols (oxidative stress), membrane potential, cyclosporin A, and other factors (3). MPT pores are thought to have at least two open conformations and a variable degree of reversibility. Most importantly, MPT in its different forms contributes to both normal cell physiology (regulation of oxidative phosphorylation and Ca 2ϩ metabolism) and to regulatory processes leading to apoptosis (2-4). Specific features of MPT show significant tissue-specific variability (5-8). The most significant and well documented deviation from classical MPT described in liver mitochondria was observed in brain tissue (9). Brain mitochondria demonstrate high resistance to MPT opening (10), low sensitivity to cyclosporin A (5), different responses to MPT modifiers, and a distinctive...

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“…This can be inferred from two findings. (i) Organic peroxides induce mitochondrial Ca2+ efflux and a depletion of mitochondrial pyridine nucleotides with the concomitant appearance of free ADP-Rib and nicotinamide (32,33). (ii) Intact rat liver mitochondria contain an ADP-Rib conjugate that is similar to or identical with the mitochondrial 50-to 55-kDa polypeptide reacting with ADP-Rib in vitro.…”

Section: Reaction Of Free [3h]adp-rib With Mitochondrial Proteinsmentioning

confidence: 99%

Nonenzymic ADP-ribosylation of specific mitochondrial polypeptides.

Hilz¹,

Koch²,

Fanick³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

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The apparent NAD:protein ADP-ribosyl transferase activity of mitochondria and submitochondrial particles from beef heart and rat liver is simulated by a reaction sequence that consists of an enzymic hydrolysis of NAD to ADP-ribose (ADP-Rib) by NAD glycohydrolase(s) and a nonenzymic ADP-ribosylation of acceptor proteins by the free ADP-Rib formed. The nonenzymic ADP-ribosylation of mitochondrial proteins showed two pH optima and exhibited the same remarkable selectivity as the reaction with NAD. The predominant acceptor in beef heart mitochondria was a 30-kDa protein, whereas in mitochondrial extracts of rat liver a 50-55 kDa polypeptide served as an acceptor. No authentic ADP-Rib transferase activity could be detected even when free ADP-Rib was trapped by NH2OH. Once formed, the mitochondrial ADP-Rib conjugates were resistant to hydroxylamine. NH2OH-resistant mono(ADP-Rib)-protein conjugates as found in most cells may also be products of nonenzymic ADP-ribosylation. In mouse tissues, their amounts relate to protein and NAD contents, and they increase specifically and reversibly in the hypothyroid status. Furthermore, intact rat liver mitochondria contain a mono(ADP-Rib)-polypeptide (50-55 kDa) that appeared to be identical with the polypeptide reacting with ADP-Rib in vitro.Various phage enzymes and bacterial toxins catalyze the transfer of single ADP-ribose (ADP-Rib) residues from NAD to one or several protein acceptors (for reviews, see refs. 1-4). Eukaryotic cells also contain endogenous proteins that are modified by single ADP-Rib residues (cf. ref. 5). In rat liver, most of these mono(ADP-Rib)-protein conjugates are located in the cytoplasm, whereas poly(ADP-Rib)-protein conjugates appear to be confined to the nucleus (6). Two types of endogenous mono(ADP-Rib)-conjugates can be distinguished by their sensitivity towards neutral hydroxylamine. They show independent changes and they are distributed unevenly in various organs of the mouse (5, 7).Interest in cytoplasmic ADP-ribosylation was greatly stimulated when diphtheria toxin-and cholera toxin-catalyzed ADP-ribosylation was detected (7-12) and when membrane-bound (12, 13), cytosolic (14), and mitochondrial (15, 16) ADP-ribosyl transferase activities were described. It was also reported that free ADP-Rib can form Schiff bases with amino groups of proteins, especially of the histones, when incubated at slightly alkaline conditions (17), while true ADP-Rib transferase activity in mitochondria was said to be operating at pH values <7 (18). However, the use of various inhibitors in mitochondrial preparations indicated to us that nonenzymic ADP-ribosylation was occurring at lower pH values as well.This paper describes a reaction sequence found in mitochondria (and plasma membranes) that involves the hydrolysis of NAD by NAD glycohydrolases and the nonezymic ADP-ribosylation of specific acceptors to form acid-stable conjugates. This reaction sequence simulated ADP-Rib transferase activity, and the similarity of acceptors in vivo and in vitro provides sugg...

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Hydroperoxides can modulate the redox state of pyridine nucleotides and the calcium balance in rat liver mitochondria

Cited by 163 publications

References 29 publications

Changes in cellular glutathione content during adriamycin treatment in human ovarian cancer – a possible indicator of chemosensitivity

Changes in cellular glutathione content during adriamycin treatment in human ovarian cancer – a possible indicator of chemosensitivity

The Characterization of Mitochondrial Permeability Transition in Clonal Pancreatic β-Cells

Nonenzymic ADP-ribosylation of specific mitochondrial polypeptides.

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