Nitric oxide induces apoptosis via triggering mitochondrial permeability transition

Hortelano, Sonsoles; Dallaporta, Bruno; Zamzami, Naoufal; Hirsch, Tamara; Susin, Santos A.; Marzo, Isabel; Boscá, Lisardo; Kroemer, Guido

doi:10.1016/s0014-5793(97)00623-6

Cited by 235 publications

(145 citation statements)

References 37 publications

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“…Therefore, in addition to the oxidation of membrane protein sulfhydryl groups, the oxidation of both GSH and NAD(P)H of mitochondrial matrix [30], followed closely by an increase in the mitochondrial Ca 2 + and ROS generation within mitochondria (or a decreasing in their detoxification), contributes to the MPT induction, as shown by studies with several MPT inducers, including tert-butylhydroperoxide [39][40][41][42] and inorganic phosphate [31,43]. Besides the generation of ROS, NO can also act on mitochondria amplifying the signals promoting the MPT [44,45].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…39,40 The observation that L-NAME significantly blocked the copper-induced mPT suggests NO is one factor responsible for mPT. Moreover, inhibition of mPT by aminoguanidine, but not 7-nitroindazole, suggests the involvement of iNOS in mPT induction.…”

Section: This Study Demonstrates That Exposure Of Primary Cultures Ofmentioning

confidence: 99%

The mitochondrial permeability transition, and oxidative and nitrosative stress in the mechanism of copper toxicity in cultured neurons and astrocytes

Reddy

Rao

Norenberg

2008

Laboratory Investigation

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Copper is an essential element and an integral component of various enzymes. However, excess copper is neurotoxic and has been implicated in the pathogenesis of Wilson's disease, Alzheimer's disease, prion conditions, and other disorders. Although mechanisms of copper neurotoxicity are not fully understood, copper is known to cause oxidative stress and mitochondrial dysfunction. As oxidative stress is an important factor in the induction of the mitochondrial permeability transition (mPT), we determined whether mPT plays a role in copper-induced neural cell injury. Cultured astrocytes and neurons were treated with 20 mM copper and mPT was measured by changes in the cyclosporin A (CsA)-sensitive inner mitochondrial membrane potential (DCm), employing the potentiometric dye TMRE. In astrocytes, copper caused a 36% decrease in the DCm at 12 h, which decreased further to 48% by 24 h and remained at that level for at least 72 h. Cobalt quenching of calcein fluorescence as a measure of mPT similarly displayed a 45% decrease at 24 h. Pretreatment with antioxidants significantly blocked the copper-induced mPT by 48-75%. Copper (24 h) also caused a 30% reduction in ATP in astrocytes, which was completely blocked by CsA. Copper caused death (42%) in astrocytes by 48 h, which was reduced by antioxidants (35-60%) and CsA (41%). In contrast to astrocytes, copper did not induce mPT in neurons. Instead, it caused early and extensive death with a concomitant reduction (63%) in ATP by 14 h. Neuronal death was prevented by antioxidants and nitric oxide synthase inhibitors but not by CsA. Copper increased protein tyrosine nitration in both astrocytes and neurons. These studies indicate that mPT, and oxidative and nitrosative stress represent major factors in copper-induced toxicity in astrocytes, whereas oxidative and nitrosative stress appears to play a major role in neuronal injury.

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“…Many reports have indicated that high levels of NO induce apoptosis in numerous cell types. Apoptosis appears to be mediated largely by an effect of peroxynitrite on mitochondrial permeability either directly 66,67 or through DNA damage with subsequent activation of the PARS pathway. 68,69 Through the mitochondrial permeability transition, cytochrome C is released, which is a signal for apoptosis.…”

Section: No In Apoptosismentioning

confidence: 99%

“…68,69 Through the mitochondrial permeability transition, cytochrome C is released, which is a signal for apoptosis. 62,67,70 Concomitant elevation in reactive oxygen species (ROS) is an essential element in NO-induced apoptosis. Decreased levels of cellular antioxidant systems, particularly Cu-Zn superoxide dismutase enhance the apoptotic response to NO.…”

Section: No In Apoptosismentioning

confidence: 99%

Nitric oxide in liver injury

1999

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Nitric oxide induces apoptosis via triggering mitochondrial permeability transition

Cited by 235 publications

References 37 publications

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

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

The mitochondrial permeability transition, and oxidative and nitrosative stress in the mechanism of copper toxicity in cultured neurons and astrocytes

Nitric oxide in liver injury

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