Inhibition of adenine nucleotide translocator by lipid peroxidation products

Chen, Juan Juan; Bertrand, Helen A.; Yu, Byung Pal

doi:10.1016/0891-5849(95)00066-7

Cited by 124 publications

(62 citation statements)

References 25 publications

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“…69 The unsaturated aldehydes 4-hydroxynonenal and 4-hydroxyhexenal, which arise as a by-product of lipid peroxidation and have potent cytotoxic and MMP-inducing activities, also inhibit the antiport activity of ANT reconstituted into liposomes. 70 More convincingly, genetic experiments confirm the participation of ANT in the control of cell death. Yeast cells in which the three ANT isoenzymes have been inactivated by homologous recombination are relatively resistant against killing by Bax 37 and Vpr.…”

Section: Viral Effectorsmentioning

confidence: 55%

Permeabilization of the mitochondrial inner membrane during apoptosis: impact of the adenine nucleotide translocator

et al. 2000

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Mitochondrial membrane permeabilization can be a rate limiting step of apoptotic as well as necrotic cell death. Permeabilization of the outer mitochondrial membrane (OM) and/or inner membrane (IM) is, at least in part, mediated by the permeability transition pore complex (PTPC). The PTPC is formed in the IM/OM contact site and contains the two most abundant IM and OM proteins, adenine nucleotide translocator (ANT, in the IM) and voltage-dependent anion channel (VDAC, in the OM), the matrix protein cyclophilin D, which can interact with ANT, as well as apoptosis-regulatory proteins from the Bax/Bcl-2 family. Here we discuss that ANT has two opposite functions. On the one hand, ANT is a vital, specific antiporter which accounts for the exchange of ATP and ADP on IM. On the other hand, ANT can form a non-specific pore, as this has been shown by electrophysiological characterization of purified ANT reconstituted into synthetic lipid bilayers or by measuring the permeabilization of proteoliposomes containing ANT. Pore formation by ANT is induced by a variety of different agents (e.g. Ca 2+ , atractyloside, thiol oxidation, the pro-apoptotic HIV-1 protein Vpr, etc.) and is enhanced by Bax and inhibited by Bcl-2, as well as by ADP. In isolated mitochondria, pore formation by ANT leads to an increase in IM permeability to solutes up to 1500 Da, swelling of the mitochondrial matrix, and OM permeabilization, presumably due to physical rupture of OM. Although alternative mechanisms of mitochondrial membrane permeabilization may exist, ANT emerges as a major player in the regulation of cell death.

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Section: Viral Effectorsmentioning

confidence: 55%

Permeabilization of the mitochondrial inner membrane during apoptosis: impact of the adenine nucleotide translocator

et al. 2000

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Section: Discussionmentioning

confidence: 99%

“…The activity of the adenine nucleotide transporter in mitochondria is inhibited by HNE, which directly results in ATP depletion [77]. Aβ increases lipid derived free radical production [3,4,74,77,78]. HNE rapidly leads to decline in multiple sites of the mitochondrial respiratory chain and modified specific mitochondrial target proteins lead to apoptosis and cell death in AD [79].…”

Section: Discussionmentioning

confidence: 99%

In vivo administration of D609 leads to protection of subsequently isolated gerbil brain mitochondria subjected to in vitro oxidative stress induced by amyloid beta-peptide and other oxidative stressors: Relevance to Alzheimer’s disease and other oxidative stress-related neurodegenerative disorders

Ansari

Joshi

Huang

et al. 2006

Free Radical Biology and Medicine

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Tricyclodecan-9-yl-xanthogenate (D609) has in vivo and in vitro antioxidant properties. D609 mimics glutathione (GSH), has a free thiol group, which upon oxidation forms a disulfide. The resulting dixanthate is a substrate for glutathione reductase, regenerating D609. Recent studies have also shown that D609 protects brain in vivo and neuronal cultures in vitro against the potential Alzheimer's disease (AD) causative factor, Aβ (1-42)-induced oxidative stress and cytotoxicity. Mitochondria are important organelles with both pro-and anti-apoptotic factor proteins. The present study was undertaken to test the hypothesis that i.p. injection of D609 would provide neuroprotection against free radical-induced, mitochondria-mediated apoptosis in vitro. Brain mitochondria were isolated from gerbils 1 h post injection intraperitonially (i.p.) with D609 and subsequently treated in vitro with the oxidants Fe 2+ /H 2 O 2 (hydroxyl free radicals), 2,2-azobis-(2-amidinopropane) dihydrochloride (AAPH, alkoxyl and peroxyl free radicals) and AD-relevant amyloid β-peptide 1-42 [Aβ (1-42)]. Brain mitochondria isolated from the gerbils previously injected i.p. with D609 and subjected to these oxidative stress inducers, in vitro, showed significant reduction in levels of protein carbonyls, protein-bound hydroxynonenal (HNE) [a lipid peroxidation product], 3-nitrotyrosine (3-NT), and cytochrome-c release compared to oxidant-treated brain mitochondria isolated from salineinjected gerbils. D609 treatment significantly maintains the GSH/GSSG ratio in oxidant-treated mitochondria. Increased activity of glutathione-S-transferase (GST), glutathione peroxidase (GPx) and glutathione reductase (GR) in brain isolated from D609-injected gerbils is consistent with the notion that D609 acts like GSH. These anti-apoptotic findings are discussed with reference to the potential use of this brain-accessible glutathione mimetic in the treatment of oxidative stress-related neurodegenerative disorders, including AD.

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“…One milliliter of cytosolic sample was added to each column, centrifuged at 900 g for an additional 2 min and the eluant collected (24). Aliquots of column fraction were saved for protein assay as described (13).…”

Section: Animals and Dietary Regimen: Specific Pathogen-freementioning

confidence: 99%

“…Among the many reactive aldehydes, the by-products of lipid peroxidation process of long polyunsaturated fatty acid and 4-hydroxy-2-alkenals are of special interest (12). 4-Hydroxy-2-nonenal has received a recent attention because of its potent cytotoxic properties (13)(14)(15). From the standpoint of oxidative stress, it is important to recognize that XOD is involved in catabolism of these reactive aldehydes to acetate, thereby reducing cytotoxicity (16).…”

Section: Introductionmentioning

confidence: 99%

Significance of hepatic xanthine oxidase and uric acid in aged and dietary restricted rats

Chung

2000

AGE

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Xanthine oxidase (XOD), one of the major intracellular sources of superoxide production, is well characterized as a causative factor in ischemia/ reperfusion related damage. In the present study, we investigated age-effect on the status of XOD, an enzyme interconvertible with xanthine dehydrogenase (XDH) under oxidative stress. We also examined the modulation of the enzyme using the antioxidative action of dietary restriction (DR). We obtained evidence showing XOD activity to be significantly increased by DR, peaking at 24 months, although no progressive, age-related changes were noticed. On the other hand, while XDH activity decreased in ad libitum fed rats with age, DR maintained higher activity levels at 18 and 24 months of age. During aging, the conversion of XDH to XOD was slightly increased, as indicated by the XOD/ XDH ratio. One novel finding of the present study is DR's ability to elevate the uric acid level, which likely augments the anti-oxidative defense system, thereby buffering against oxidatively stressed conditions during aging. Based on what is known about the antioxidative abilities of DR and uric acid, we propose that the high uric acid levels we observed in DR rats may well serve as part of a defense strategy to protect redox balance.

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Inhibition of adenine nucleotide translocator by lipid peroxidation products

Cited by 124 publications

References 25 publications

Permeabilization of the mitochondrial inner membrane during apoptosis: impact of the adenine nucleotide translocator

Permeabilization of the mitochondrial inner membrane during apoptosis: impact of the adenine nucleotide translocator

Significance of hepatic xanthine oxidase and uric acid in aged and dietary restricted rats

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