Generation of Reactive Oxygen Species in the Reaction Catalyzed by α-Ketoglutarate Dehydrogenase

Tretter, László; Ádám-Vizi, Vera

doi:10.1523/jneurosci.1842-04.2004

Cited by 404 publications

(304 citation statements)

References 65 publications

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“…PDHC is closely associated with Complex I of the electron transport chain [47] where much of the endogenous superoxide production is thought to occur. PDHC and α-ketoglutarate dehydrogenase complex may also be important sources of superoxide and, consequently, peroxynitrite [48,49]. The free radical pathways leading to nitration are initiated secondary to the reaction of peroxynitrite with carbon dioxide [50] and PDHC is one of the main sources of carbon dioxide within the mitochondria [51].…”

Section: Discussionmentioning

confidence: 99%

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Richards

Rosenthal

Kristián

et al. 2006

Free Radical Biology and Medicine

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The pyruvate dehydrogenase complex (PDHC) is a mitochondrial matrix enzyme that catalyzes the oxidative decarboxylation of pyruvate and represents the sole bridge between anaerobic and aerobic cerebral energy metabolism. Previous studies demonstrating loss of PDHC enzyme activity and immunoreactivity during reperfusion after cerebral ischemia suggest that oxidative modifications are involved. This study tested the hypothesis that hyperoxic reperfusion exacerbates loss of PDHC enzyme activity, possibly due to tyrosine nitration or S-nitrosation. We used a clinically relevant canine ventricular fibrillation cardiac arrest model in which, after resuscitation and ventilation on either 100% O 2 (hyperoxic) or 21-30% O 2 (normoxic), animals were sacrificed at 2 h reperfusion and the brains removed for enzyme activity and immunoreactivity measurements. Animals resuscitated under hyperoxic conditions exhibited decreased PDHC activity and elevated 3-nitrotyrosine immunoreactivity in the hippocampus but not the cortex, compared to nonischemic controls. These measures were unchanged in normoxic animals. In vitro exposure of purified PDHC to peroxynitrite resulted in a dose-dependent loss of activity and increased nitrotyrosine immunoreactivity. These results support the hypothesis that oxidative stress contributes to loss of hippocampal PDHC activity during cerebral ischemia and reperfusion and suggest that PDHC is a target of peroxynitrite. KeywordsMitochondria; Hyperoxia; Nitrotyrosine; Normoxia; Oxidative stress; Global ischemia; Selective vulnerability; Free radicals Global cerebral ischemia and reperfusion cause severe neurochemical alterations, including oxidative modifications to lipids, proteins, and DNA. These and other covalent modifications can impair enzyme activities, including those necessary for energy metabolism. Alterations in these enzyme activities can limit postischemic aerobic metabolism and cellular ATP regeneration, thereby contributing to the pathophysiology of delayed neuronal cell death [1][2][3][4]. One enzyme known to be targeted and inactivated by reactive oxygen species is the pyruvate dehydrogenase complex (PDHC) [5]. Effects of ischemia/reperfusion on the PDHC can be particularly devastating because this enzyme forms the bridge between glycolysis and the Krebs cycle and can be the rate-limiting step in aerobic cerebral energy metabolism. NIH Public Access Author ManuscriptFree Radic Biol Med. Author manuscript; available in PMC 2008 October 21. Published in final edited form as:Free Radic Biol Med. 2006 June 1; 40(11): 1960-1970. doi:10.1016/j.freeradbiomed.2006.01.022. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe PDHC is located exclusively in the mitochondrial matrix and catalyzes the oxidative decarboxylation of pyruvate to form NADH and acetyl coenzyme A-the primary form of carbon that enters the Krebs cycle in the adult brain. Several laboratories have shown that PDHC enzyme activity is lost during cerebral ischemia/reperfusion [6][7][8]. PDHC im...

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Section: Discussionmentioning

confidence: 99%

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Richards

Rosenthal

Kristián

et al. 2006

Free Radical Biology and Medicine

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“…While under conditions of inhibited electron transfer (e.g., under conditions of cytochrome c release), all these sites are potentially relevant, the relevance of the latter site under the conditions of uninhibited electron flow is still a matter of discussion (39,40). Additionally to the sites within mitochondrial respiratory chain, several flavoproteins in the mitochondrial matrix space, like the a-lipoamide dehydrogenase moiety of the a-ketoglutarate dehydrogenase complex (41,42) or the electron transfer flavoprotein of the b-oxidation pathway (37), are further candidate sites for mitochondrial superoxide production.…”

Section: Mitochondrial Formation Of Ros and Neurodegenerationmentioning

confidence: 99%

Mitochondrial involvement in neurodegenerative diseases

Kunz

2013

IUBMB Life

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The classical bioenergetical view of the involvement of mitochondria in neurogeneration is based on the fact that mitochondria are the central players of ATP synthesis in neurons and their failure leads to neuronal dysfunction and eventually to cell death. Mutations in at least 39 genes in inherited neurodegenerative disorders seem to alter directly or indirectly mitochondrial function. Most of these mutations do not directly affect oxidative phosphorylation, but act through disturbed mitochondrial dynamics and quality control. This, however, does not invalidate the bioenergetic hypothesis.Neurodegeneration is not necessarily associated with a gross failure of ATP production, but might rather be a consequence of local insufficiencies of ATP supply in critical compartments of neurons, like the presynaptic terminal. We hypothesize that slow disease progression, at least in a subgroup of neurodegenerative diseases, can be explained by the parallel action of subcellular ATP insufficiency and clonal expansion of somatic mitochondrial DNA mutations, and particularly deletions. V C 2013 IUBMB Life, 65(3): [263][264][265][266][267][268][269][270][271][272] 2013

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“…Independent studies have demonstrated that a-KGDH could be an important source of ROS (Starkov et al 2004;Tretter & Adam-Vizi 2004).…”

Section: A-kgdh As a Generator Of Oxidative Stressmentioning

confidence: 99%

Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress

Tretter

Ádám-Vizi

2005

Phil. Trans. R. Soc. B

350

264

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Alpha-ketoglutarate dehydrogenase (a-KGDH) is a highly regulated enzyme, which could determine the metabolic flux through the Krebs cycle. It catalyses the conversion of a-ketoglutarate to succinylCoA and produces NADH directly providing electrons for the respiratory chain. a-KGDH is sensitive to reactive oxygen species (ROS) and inhibition of this enzyme could be critical in the metabolic deficiency induced by oxidative stress. Aconitase in the Krebs cycle is more vulnerable than a-KGDH to ROS but as long as a-KGDH is functional NADH generation in the Krebs cycle is maintained. NADH supply to the respiratory chain is limited only when a-KGDH is also inhibited by ROS. In addition being a key target, a-KGDH is able to generate ROS during its catalytic function, which is regulated by the NADH/NAD C ratio. The pathological relevance of these two features of a-KGDH is discussed in this review, particularly in relation to neurodegeneration, as an impaired function of this enzyme has been found to be characteristic for several neurodegenerative diseases.

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Generation of Reactive Oxygen Species in the Reaction Catalyzed by α-Ketoglutarate Dehydrogenase

Cited by 404 publications

References 65 publications

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Mitochondrial involvement in neurodegenerative diseases

Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress

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