Membrane protein thiol cross-linking associated with the permeabilization of the inner mitochondrial membrane by Ca2+ plus prooxidants.

Fagian, Márcia M.; Pereira-Da-Silva, Lucia; Martins, Ione Salgado; Vercesi, Aníbal E.

doi:10.1016/s0021-9258(17)45467-6

Cited by 181 publications

(25 citation statements)

References 28 publications

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“…Reversible permeabilization of the inner mitochondrial membrane induced by Ca 21 ions plus prooxidants is under the regulatory influence of the redox status of both mitochondrial nucleotides, matrix sulfhydryl groups and membrane protein thiols forming cross-linked protein aggregates (Fagian et al, 1990;Petronilli et al, 1994;Bernardi, 1996;Halestrap et al, 1997). In addition to the oxidation of sulfhydryl groups and nucleotides [NAD(P)H], the generation of reactive oxygen species (ROS) within mitochondria (or a decreasing in their detoxification) contributes to the induction of the MPT, as shown by studies with several MPT inducers, including t-BuOOH (Castilho et al, 1996;Nieminen et al, 1995;Kowaltowski et al, 2000) and P i (Kowaltowski et al, 1996(Kowaltowski et al, , 1998.…”

Section: Discussionmentioning

confidence: 99%

“…7A, t-BuOOH), according to what has also been observed by Kushnareva and Sokolove (2000), suggesting that this cation is essential and must act in additional steps in the sequence of events that lead to mitochondrial permeabilization. The binding of Ca 21 to the inner membrane may cause conformational changes to critical proteins that expose thiol groups to the action of oxidants (Fagian et al, 1990;Valle et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

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4-Hydroxytamoxifen is a potent inhibitor of the mitochondrial permeability transition

2002

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The effects of 4-hydroxytamoxifen (OHTAM), the major active metabolite of the antiestrogen tamoxifen used in the breast cancer therapy, were studied on the mitochondrial permeability transition (MPT) and bioenergetic functions of mitochondria to evaluate the mechanisms underlying the cell death and toxic effects. The MPT was induced in vitro by incubating rat liver mitochondria with 1 mM inorganic phosphate plus Ca2+ and with tert-butyl hydroperoxide. OHTAM provides protection against the Ca2+-induced mitochondrial swelling, depolarization of the mitochondrial membrane potential (deltapsi), loss of electrophoretic Ca2+ uptake capacity and uncoupling of respiration, similarly to cyclosporine A. The concentrations of OHTAM used do not significantly affect deltapsi, respiratory control and adenosine diphosphate/oxygen ratios and induce repolarization and Ca2+ re-uptake, suggesting that such inhibitory effects of OHTAM were due to the prevention of the MPT induction and not due to the inhibition of the mitochondrial Ca2+ uniporter. Since the MPT induction has been linked to an oxidized shift in the mitochondrial redox state and/or increase in the generation of reactive oxygen species, the MPT prevention by OHTAM may be related to its high antioxidant capacity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

4-Hydroxytamoxifen is a potent inhibitor of the mitochondrial permeability transition

2002

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“…Our findings are, at first sight, in contradiction to earlier work reporting a loss of Ca 2+ from the mitochondrial matrix upon exposure to oxidants. In these previous studies, oxidizing agents induced Ca 2+ release from isolated mitochondria secondary to the opening of the transition pore (Crompton et al, 1988;Fagian et al, 1990) or via a selective oxidant-dependent pathway (Schlegel et al, 1992), with a resultant collapse of membrane potential. In the present work, H2O2 and HX-XO did not damage the mitochondria, as demonstrated by preserved ∆ψm, a reliable criterion for functional integrity of mitochondria, as well as normal ATP levels, at least during the first 30 minutes of exposure.…”

Section: Discussionmentioning

confidence: 95%

“…Opening of the pore, referred to as the permeability transition, is regulated by matrix Ca 2+ , but is also enhanced by oxidants and inorganic phosphate (Gunter and Pfeiffer, 1990;Zoratti and Szabò, 1995). Meanwhile, evidence is accumulating that under conditions of oxidative stress, mitochondria rapidly lose their Ca 2+ pool (Vlessis and Mela-Riker, 1989;Fagian et al, 1990;Richter and Kass, 1991;Schlegel et al, 1992) and ∆ψm (Fagian et al, 1990; Schlegel et al, 1992;Nieminen et al, 1995). This is followed by a depletion of cellular ATP content and a loss of cell viability.…”

Section: Introductionmentioning

confidence: 99%

Reactive oxygen metabolites increase mitochondrial calcium in endothelial cells: Implication of the Ca2+/Na+ exchanger

Jornot¹,

Maechler²,

Wollheim³

et al. 1999

Journal of Cell Science

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In endothelial cells, a bolus of hydrogen peroxide (H2O2) or oxygen metabolites generated by hypoxanthine-xanthine oxidase (HX-XO) increased the mitochondrial calcium concentration [Ca2+]m. Both agents caused a biphasic increase in [Ca2+]m which was preceded by a rise in cytosolic free calcium concentration [Ca2+]c (18 and 6 seconds for H2O2 and HX-XO, respectively). The peak and plateau elevations of [Ca2+] were consistently higher in the mitochondrial matrix than in the cytosol. In Ca2+-free/EGTA medium, the plateau phase of elevated [Ca2+] evoked by H2O2 due to capacitative Ca2+ influx was abolished in the cytosol, but was maintained in the mitochondria. In contrast to H2O2 and HX-XO, ATP which binds the P2Y purinoceptors induced an increase in [Ca2+]m that was similar to that of [Ca2+]c. When cells were first stimulated with inositol 1,4, 5-trisphosphate-generating agonists or the Ca2+-ATPase inhibitor cyclopiazonic acid (CPA), subsequent addition of H2O2 did not affect [Ca2+]c, but still caused an elevation of [Ca2+]m. Moreover, the specific inhibitor of the mitochondrial Ca2+/Na+ exchanger, 7-chloro-3,5-dihydro-5-phenyl-1H-4.1-benzothiazepine-2-on (CGP37157), did not potentiate the effects of H2O2 and HX-XO on [Ca2+]m, while causing a marked increase in the peak [Ca2+]m and a significant attenuation of the rate of [Ca2+]m efflux upon addition of histamine or CPA. In permeabilized cells, H2O2 mimicked the effects of CGP37157 causing an increase in the basal level of matrix free Ca2+ and decreased efflux. Dissipation of the electrochemical proton gradient by carbonylcyanide p-(trifluoromethoxy) phenylhydrazone (FCCP), and blocade of the Ca2+ uptake by ruthenium red prevented [Ca2+]m increases evoked by H2O2. These results demonstrate that the H2O2-induced elevation in [Ca2+]m results from a transfer of Ca2+ secondary to increased [Ca2+]c, and an inhibition of the Ca2+/Na+ electroneutral exchanger of the mitochondria.

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“…Differently from mice mitochondria, which showed a higher susceptibility to PTP when at fasting (Menezes-Filho et al, 2019), nutritional status does not seem to affect the susceptibility to PTP in B. constrictor , as fasting and fed snakes exhibited no differences in mitochondrial Ca 2+ retention. PTP can be sensitized by oxidative stress and oxidized NADPH (NADP + ) (Castilho et al, 1995; Vercesi et al, 1988; Zago et al, 2000), as excess ROS increase oxidation of protein thiols and promotes disulfide bonds and cross-linked protein aggregation in the inner mitochondrial membrane (Castilho et al, 1995; Fagian et al, 1990; Valle et al, 1993; Vercesi, 1984). However, as we will discuss further, we also did not observe changes in NAD(P) redox status, and the increased rate of H 2 O 2 production seems not to be leading to oxidative stress, thus not influencing PTP sensibility.…”

Section: Discussionmentioning

confidence: 99%

Feeding effects on liver mitochondrial bioenergetics of Boa constrictor (Serpentes: Boidae)

Araujo

Sartori

Navarro

et al. 2021

Preprint

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Snakes are interesting examples of overcoming energy metabolism challenges as many species can endure long periods without feeding, and their eventual meals are of reasonably large sizes, thus exhibiting dual extreme adaptations. Consequently, metabolic rate increases considerably to attend to the energetic demand of digestion, absorption and, protein synthesis. These animals should be adapted to transition from these two opposite states of energy fairly quickly, and therefore we investigated mitochondrial function plasticity in these states. Herein we compared liver mitochondrial bioenergetics of the boid snake Boa constrictor during fasting and after meal intake. We fasted the snakes for 60 days, then we fed a subgroup with 30% of their body size and evaluated their maximum postprandial response. We measured liver respiration rates from permeabilized tissue and isolated mitochondria, and from isolated mitochondria, we also measured Ca2+ retention capacity, the release of H2O2, and NAD(P) redox state. Mitochondrial respiration rates were maximized after feeding, reaching until 60% increase from fasting levels when energized with complex I-linked substrates. Interestingly, fasting and fed snakes exhibited similar respiratory control ratios and citrate synthase activity. Furthermore, we found no differences in Ca2+ retention capacity, indicating no increase in susceptibility to mitochondrial permeability transition pore (PTP), or redox state of NAD(P), although fed animals exhibited increases in the release of H2O2. Thus, we conclude that liver mitochondria from B. constrictor snakes increase the maintenance costs during the postprandial period and quickly improve the mitochondrial bioenergetics capacity without compromising the redox balance.

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Membrane protein thiol cross-linking associated with the permeabilization of the inner mitochondrial membrane by Ca2+ plus prooxidants.

Cited by 181 publications

References 28 publications

4-Hydroxytamoxifen is a potent inhibitor of the mitochondrial permeability transition

4-Hydroxytamoxifen is a potent inhibitor of the mitochondrial permeability transition

Reactive oxygen metabolites increase mitochondrial calcium in endothelial cells: Implication of the Ca2+/Na+ exchanger

Feeding effects on liver mitochondrial bioenergetics of Boa constrictor (Serpentes: Boidae)

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