Mitochondrial bioenergetics as affected by DDT

Moreno, António J.; Madeira, Vı́tor M.C.

doi:10.1016/s0005-2728(09)91004-0

Cited by 76 publications

(63 citation statements)

References 31 publications

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“…Mitochondrial membrane potential (⌬⌿) was estimated with an ion-selective electrode of TPP ϩ prepared according to Kamo et al (1979) to measure the transmembrane distribution of TPP ϩ as previously established (Kamo et al, 1979;Moreno and Madeira, 1991), using an Ag/AgCl-saturated electrode as reference (Model MI 402; Microelectrodes, Inc., Bedford, NH). The reactions were carried out in an open vessel with magnetic stirring at 25°C and performed with 1 mg mitochondrial protein in 2 ml of the standard respiratory medium supplemented with 2 M rotenone and 4 M TPP ϩ .…”

Section: Methodsmentioning

confidence: 99%

“…Control assays were conducted in the presence of an identical volume of ethanol to that used in the experiments with TAM. ⌬⌿ is expressed in mV and was estimated from the decrease of TPP ϩ concentration in the reaction medium, as described elsewhere (Moreno and Madeira, 1991). Preliminary calibrations in the presence of TAM revealed no direct interference with the electrode signal.…”

Section: Methodsmentioning

confidence: 99%

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Mechanisms of the Deleterious Effects of Tamoxifen on Mitochondrial Respiration Rate and Phosphorylation Efficiency

Cardoso

Custódio

Almeida

et al. 2001

Toxicology and Applied Pharmacology

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Tamoxifen (TAM), the widely prescribed drug in the prevention and therapy of breast cancer, is a well-known modulator of estrogen receptor (ER) that also inhibits the proliferation of different cell types that lack the ER. However, the ER-independent action mechanisms of TAM and its side effects have not been yet clarified. Mitochondria are essential in supporting the energy-dependent regulation of cell functions. Changes in mitochondria result in bioenergetic deficits leading to the loss of vital functions to cell survival. Therefore, this study describes the effects of TAM on mitochondrial bioenergetics, contributing to a better understanding of the biochemical mechanisms underlying the multiple antiproliferative and toxic effects of this drug. TAM at concentrations above 20 nmol/mg protein, preincubated with isolated rat liver mitochondria at 25°C for 3 min, significantly depresses, in a dose-dependent manner, the phosphorylation efficiency of mitochondria as inferred from the decrease in the respiratory control and ADP/O ratios, the perturbations in mitochondrial transmembrane potential (⌬⌿), the fluctuations associated with mitochondrial energization, and the phosphorylative cycle induced by ADP. Furthermore, TAM at up to 40 nmol/mg protein stimulates the rate of state 4 respiration and at higher concentrations it strongly inhibits state 3 and uncouples the mitochondrial respiration. The stimulation of state 4 respiration parallels the decrease of ⌬⌿ as a consequence of proton permeability. The TAM-stimulatory action of ATPase is also observed in intact mitochondria, suggesting that TAM promotes extensive permeability to protons due to destructive effects in the structural integrity of the mitochondrial inner membrane. These multiple effects of TAM on mitochondrial bioenergetic functions, causing changes in the respiration, phosphorylation efficiency, and membrane structure, may explain the cell death induced by this drug in different cell types, its anticancer activity in ER-negative cells, and its side effects. © 2001 Academic Press Key Words: tamoxifen; anticancer drug; mitochondria; respiration rate; mitochondrial transmembrane potential; mitochondrial proton leak; membrane disruption.Tamoxifen (TAM) is the most used nonsteroidal antiestrogen drug for chemotherapy and chemoprevention of breast cancer (Neven and Vernaeve, 2000;Radmacher and Simon, 2000). The antiproliferative effects of TAM in estrogen-dependent breast cancer cells are mediated by high-affinity binding to the estrogen receptor (ER) (Coezy et al., 1982). However, TAM inhibits also the growth of ER-negative breast cancer cells and other cell types that lack ER (Couldwell et al., 1993;Croxtall et al., 1994;Charlier et al., 1995). Actually, TAM has been reported to have several physiological effects that are ER independent, including sensitization of resistant tumor cells to many chemotherapeutic agents (Altan et al., 1999) and several pleiotropic effects both in vivo and in vitro and references therein). Moreover, it has been reported that...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Mechanisms of the Deleterious Effects of Tamoxifen on Mitochondrial Respiration Rate and Phosphorylation Efficiency

Cardoso

Custódio

Almeida

et al. 2001

Toxicology and Applied Pharmacology

Self Cite

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“…Mitochondrial Ca 2+ fluxes were measured by monitoring the changes in Ca 2+ concentration in the reaction medium using a Ca 2+ -selective electrode [25]. The reactions were conducted in an open vessel with magnetic stirring in 1 ml of the standard reaction medium supplemented with 5 mM glutamate/2.5 mM malate and 90 nmol/mg protein of CaCl 2 .…”

Section: Measurements Of Ca 2+ Fluxesmentioning

confidence: 99%

Metformin promotes isolated rat liver mitochondria impairment

et al. 2007

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Metformin, a drug widely used in the treatment of type 2 diabetes, has recently received attention due to the new and contrasting findings regarding its effects on mitochondrial function. In the present study, we evaluated the effect of metformin in isolated rat liver mitochondria status. We observed that metformin concentrations ‡8 mM induce an impairment of the respiratory chain characterized by a decrease in RCR and state 3 respiration. However, only metformin concentrations ‡10 mM affect the oxidative phosphorylation system by decreasing the mitochondrial transmembrane potential and increasing the repolarization lag phase. Moreover, our results show that metformin does not prevent H 2 O 2 production, neither protects against lipid peroxidation induced by the prooxidant pair ADP/Fe 2+ . In addition, we observed that metformin exacerbates Ca 2+ -induced permeability transition pore opening by decreasing the capacity of mitochondria to accumulate Ca 2+ and increasing the oxidation of thiol groups. Taken together, our results show that metformin can promote liver mitochondria injury predisposing to cell death.

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“…2 min of recording), Ca 2 + (200 nmol/mg protein) was added and Dc recorded for 12 additional minutes. Mitochondrial Dc was evaluated by the transmembrane distribution of TPP + as previously described [23,25].…”

Section: Measurement Of Mitochondrial Membrane Potentialmentioning

confidence: 99%

Thiol protecting agents and antioxidants inhibit the mitochondrial permeability transition promoted by etoposide: implications in the prevention of etoposide-induced apoptosis

Custódio

Cardoso

Almeida

2002

Chemico-Biological Interactions

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Etoposide (VP-16) is known to promote cell apoptosis either in cancer or in normal cells as a side effect. This fact is preceded by the induction of several mitochondrial events, including increase in Bax/Bcl-2 ratio followed by cytochrome c release and consequent activation of caspase-9 and -3, reduction of ATP levels, depolarization of membrane potential (Dc) and rupture of the outer membrane. These events are apoptotic factors essentially associated with the induction of the mitochondrial permeability transition (MPT). VP-16 has been shown to stimulate the Ca 2 + -dependent MPT induction similarly to prooxidants and to promote apoptosis by oxidative stress mechanisms, which is prevented by glutathione (GSH) and N-acetylcysteine (NAC). Therefore, the aim of this work was to study the effects of antioxidants and thiol protecting agents on MPT promoted by VP-16, (2002) 169-184 170 attempting to identify the underlying mechanisms on VP-16-induced apoptosis. The increased sensitivity of isolated mitochondria to Ca 2 + -induced swelling, Ca 2 + release, depolarization of Dc and uncoupling of respiration promoted by VP-16, which are prevented by cyclosporine A proving that VP-16 induces the MPT, are also efficiently prevented by ascorbate, the primary reductant of the phenoxyl radicals produced by VP-16. The thiol reagents GSH, dithiothreitol and N-ethylmaleimide, which have been reported to prevent the MPT induction, also protect this event promoted by VP-16. The inhibition of the VP-16-induced MPT by antioxidants agrees with the prevention of etoposide-induced apoptosis by GSH and NAC and suggests the generation of oxidant species as a potential mechanism underlying the MPT that may trigger the release of mitochondrial apoptogenic factors responsible for apoptotic cascade activation.

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Mitochondrial bioenergetics as affected by DDT

Cited by 76 publications

References 31 publications

Mechanisms of the Deleterious Effects of Tamoxifen on Mitochondrial Respiration Rate and Phosphorylation Efficiency

Mechanisms of the Deleterious Effects of Tamoxifen on Mitochondrial Respiration Rate and Phosphorylation Efficiency

Metformin promotes isolated rat liver mitochondria impairment

Thiol protecting agents and antioxidants inhibit the mitochondrial permeability transition promoted by etoposide: implications in the prevention of etoposide-induced apoptosis

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