Journal ArticleDOI
Selective inactivation of alpha-ketoglutarate dehydrogenase and pyruvate dehydrogenase: reaction of lipoic acid with 4-hydroxy-2-nonenal.
TLDR
Treatment of rat heart mitochondria with HNE resulted in the selective inhibition of KGDH and pyruvate dehydrogenase (PDH), while other NADH-linked dehydrogenases and electron chain complexes were unaffected.Abstract:
Previous research has established that 4-hydroxy-2-nonenal (HNE), a highly toxic product of lipid peroxidation, is a potent inhibitor of mitochondrial respiration. HNE exerts its effects on respiration by inhibiting alpha-ketoglutarate dehydrogenase (KGDH). Because of the central role of KGDH in metabolism and emerging evidence that free radicals contribute to mitochondrial dysfunction associated with numerous diseases, it is of great interest to further characterize the mechanism of inhibition. In the present study, treatment of rat heart mitochondria with HNE resulted in the selective inhibition of KGDH and pyruvate dehydrogenase (PDH), while other NADH-linked dehydrogenases and electron chain complexes were unaffected. KGDH and PDH are structurally and catalytically similar multienzyme complexes, suggesting a common mode of inhibition. To determine the mechanism of inhibition, the effects of HNE on purified KGDH and PDH were examined. These studies revealed that inactivation by HNE was greatly enhanced in the presence of substrates that reduce the sulfur atoms of lipoic acid covalently bound to the E2 subunits of KGDH and PDH. In addition, loss of enzyme activity induced by HNE correlated closely with a decrease in the availability of lipoic acid sulfhydryl groups. Use of anti-lipoic acid antibodies indicated that HNE modified lipoic acid in both purified enzyme preparations and mitochondria and that this modification was dependent upon the presence of substrates. These results therefore identify a potential mechanism whereby free radical production and subsequent lipid peroxidation lead to specific modification of KGDH and PDH and inhibition of NADH-linked mitochondrial respiration.read more
Citations
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Oxidative stress in bacteria and protein damage by reactive oxygen species.
TL;DR: This paper reviews major key points in the generation of reactive oxygen species in bacteria, defense mechanisms and genetic responses to oxidative stress, with special attention to oxidative damage to proteins.
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Mitochondrial abnormalities in Alzheimer's disease.
Keisuke Hirai,Gjumrakch Aliev,Akihiko Nunomura,Akihiko Nunomura,Hisashi Fujioka,Robert L. Russell,Craig S. Atwood,Anne B. Johnson,Yvonne Kress,Harry V. Vinters,Massimo Tabaton,Shun Shimohama,Adam D. Cash,Sandra L. Siedlak,Peggy L.R. Harris,Paul K. Jones,Robert B. Petersen,George Perry,Mark A. Smith +18 more
TL;DR: Morphometric analysis showed that mitochondria are significantly reduced in Alzheimer's disease, and the relationship shown here between the site and extent of mitochondrial abnormalities and oxidative damage suggests an intimate and early association between these features in dementia.
Journal ArticleDOI
Oxidative stress in brain aging: Implications for therapeutics of neurodegenerative diseases
TL;DR: Novel therapeutics based on blocking neuron damaging neuroinflammatory processes show great promise for abating dementia progression although they have yet to make it to clinical practice and non-steroidal anti-inflammatory drugs show significant promise.
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Lipid peroxidation of membrane phospholipids generates hydroxy-alkenals and oxidized phospholipids active in physiological and/or pathological conditions
TL;DR: These aldehydes exhibit great reactivity with biomolecules, such as proteins, DNA, and phospholipids, generating a variety of intra and intermolecular covalent adducts, which can diffuse within or even escape from the cell and attack targets far from the site of the original event.
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Aldehyde sources, metabolism, molecular toxicity mechanisms, and possible effects on human health.
TL;DR: The human health risks from clinical and animal research studies are reviewed, including aldehydes as haptens in allergenic hypersensitivity diseases, respiratory allergies, and idiosyncratic drug toxicity; the potential carcinogenic risks of the carbonyl body burden.
References
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TL;DR: This review provides a comprehensive summary on the chemical properties of 4-hydroxyalkenals and malonaldehyde, the mechanisms of their formation and their occurrence in biological systems and methods for their determination, as well as the many types of biological activities described so far.
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Journal ArticleDOI
The Free Radical Theory of Aging Matures
Kenneth B. Beckman,Bruce N. Ames +1 more
TL;DR: The status of the free radical theory of aging is reviewed, by categorizing the literature in terms of the various types of experiments that have been performed, which include phenomenological measurements of age-associated oxidative stress, interspecies comparisons, dietary restriction, and the ongoing elucidation of the role of active oxygen in biology.
Journal ArticleDOI
Do Mitochondria Produce Oxygen Radicals in vivo
Hans Nohl,D. Hegner +1 more
TL;DR: The results are discusssed in terms of a radical-generating mechanism which functions in vivo at the level of the mitochondrial electron-transferring system, which is closer to physiological states than previously thought.
Journal ArticleDOI
Evidence that mitochondrial respiration is a source of potentially toxic oxygen free radicals in intact rabbit hearts subjected to ischemia and reflow.
Giuseppe Ambrosio,Jay L. Zweier,Carlo Duilio,Periannan Kuppusamy,Giuseppe E. Santoro,P. P. Elia,Isabella Tritto,Plinio Cirillo,Mario Condorelli,Massimo Chiariello +9 more
TL;DR: The hypothesis that resumption of mitochondrial respiration upon reperfusion might be a mechanism of oxygen radical formation in postischemic hearts, and that treatment with inhibitors of mitochondrialrespiration might prevent this phenomenon is tested, is tested.