Inhibition of the α‐ketoglutarate dehydrogenase complex by the myeloperoxidase products, hypochlorous acid and mono‐<i>N</i>‐chloramine

Jeitner, Thomas M.; Xu, Hui; Gibson, Gary E.

doi:10.1111/j.1471-4159.2004.02868.x

Cited by 51 publications

(39 citation statements)

References 81 publications

(181 reference statements)

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“…Assessment of TD-induced oxidative stress has mostly focused on vulnerable areas , but it may occur to a less extent in non-vulnerable regions such as cortex (Langlais et al, 1997). KGDHC is sensitive to a wide range of oxidants (Humphries et al, 1998;Gibson et al, 2002b;Jeitner et al, 2005). Thus, mild oxidative stress induced by TD may play an important role in mediating the loss of KGDHC activity in cortex.…”

Section: Discussionmentioning

confidence: 99%

Responses of the mitochondrial alpha-ketoglutarate dehydrogenase complex to thiamine deficiency may contribute to regional selective vulnerability

Shi

Karuppagounder

et al. 2007

Neurochemistry International

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Thiamine-dependent enzymes are diminished in multiple neurodegenerative diseases. Thiamine deficiency (TD) reduces the activity of thiamine dependent-enzymes [e.g., the α-ketoglutarate dehydrogenase complex (KGDHC)], induces regional selective neurodegeneration and serves as a model of a mild impairment of oxidative metabolism. The current experiments tested whether changes in KGDHC protein subunits (E1k, E2k and E3) or activity or message levels underlie the selective loss of neurons in particular brain regions. Thus, TD-induced changes in these variables in the brain region most vulnerable to TD [the sub-medial thalamic nucleus (SmTN)] were compared to those in a region that is relatively resistant to TD (cortex) at stages of TD when the neuron loss in SmTN is not present, minimal or severe. Impaired motor performance on rotarod was apparent by 8 days of TD (-32%) and was severe by 10 days of TD (-97%). At TD10, the overall KGDHC activity measured by an in situ histochemical staining method declined 52% in SmTN but only 20% in cortex. Reductions in the E2k and E3 mRNA in SmTN occurred as early as TD6 (-28% and -18%, respectively) and were more severe by TD10 (-61% and -66%, respectively). On the other hand, the level of E1k mRNA did not decline in SmTN until TD10 (-48%). In contrast, TD did not alter mRNA levels of the subunits in cortex at late stages. Western blots and immunocytochemistry revealed different aspects of the changes in protein levels. In SmTN, the immunoreactivity of E1k and E3 by Western blotting increased 34% and 40%, respectively, only at TD8. In cortex, the immunoreactivity of the three subunits was not altered. Immunocytochemical staining of brain sections from TD10 mice indicated a reduction in the immunoreactivity of all subunits in SmTN, but not in cortex. These findings demonstrate that the response of the KGDHC activity, mRNA and immunoreactivity of E1k, E2k and E3 to TD is region-and time-dependent. Loss of KGDHC activity in cortex is likely related to post-translational modification rather than a loss of protein, whereas in SmTN transcriptional and post-translational modifications may account for diminished KGDHC activity. Moreover, the earlier detection in TD induced-changes of the transcripts of KGDHC indicates that transcriptional modification of the two subunits (E2k and E3) of KGDHC may be one of the early events in the cascade leading to selective neuronal death.

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Section: Discussionmentioning

confidence: 99%

Responses of the mitochondrial alpha-ketoglutarate dehydrogenase complex to thiamine deficiency may contribute to regional selective vulnerability

Shi

Karuppagounder

et al. 2007

Neurochemistry International

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“…Genetic studies considered polymorphisms in the DLST (encoding E2k) or DLD (encoding E3) genes to be a risk factor for the manifestation of Parkinson or Alzheimer diseases (43,44). Increased oxidative stress is one plausible link between KGDHc deficiency and neurodegeneration, because KGDHc contains a labile Fe-S center, and is sensitive to a number of oxidants including 4-hydroxy-2-nonenal, H 2 O 2 , NO, peroxynitrite, hypochlorous acid, and mono-N-chloramine (34,(45)(46)(47).…”

Section: Reduction Of Flux Through Tca Cycle Via Inhibition Of Kgdhc Bymentioning

confidence: 99%

Bioenergetics in Glutaryl-Coenzyme A Dehydrogenase Deficiency

Sauer

Okun

Schwab

et al. 2005

Journal of Biological Chemistry

111

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Inherited deficiency of glutaryl-CoA dehydrogenase results in an accumulation of glutaryl-CoA, glutaric, and 3-hydroxyglutaric acids. If untreated, most patients suffer an acute encephalopathic crisis and, subsequently, acute striatal damage being precipitated by febrile infectious diseases during a vulnerable period of brain development (age 3 and 36 months). It has been suggested before that some of these organic acids may induce excitotoxic cell damage, however, the relevance of bioenergetic impairment is not yet understood. The major aim of our study was to investigate respiratory chain, tricarboxylic acid cycle, and fatty acid oxidation in this disease using purified single enzymes and tissue homogenates from Gcdh-deficient and wild-type mice. In purified enzymes, glutaryl-CoA but not glutaric or 3-hydroxyglutaric induced an uncompetitive inhibition of ␣-ketoglutarate dehydrogenase complex activity. Notably, reduced activity of ␣-ketoglutarate dehydrogenase activity has recently been demonstrated in other neurodegenerative diseases, such as Alzheimer, Parkinson, and Huntington diseases. In contrast to ␣-ketoglutarate dehydrogenase complex, no direct inhibition of glutaryl-CoA, glutaric acid, and 3-hydroxyglutaric acid was found in other enzymes tested. In Gcdh-deficient mice, respiratory chain and tricarboxylic acid activities remained widely unaffected, virtually excluding regulatory changes in these enzymes. However, hepatic activity of very long-chain acyl-CoA dehydrogenase was decreased and concentrations of long-chain acylcarnitines increased in the bile of these mice, which suggested disturbed oxidation of long-chain fatty acids. In conclusion, our results demonstrate that bioenergetic impairment may play an important role in the pathomechanisms underlying neurodegenerative changes in glutaryl-CoA dehydrogenase deficiency.

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“…Diminished KGDHC activity has been well documented in AD by several independent groups. Although a direct link between inactivation of KGDHC activity and various oxidants has been established in isolated enzymes, cell and animal models, 64,143,144 whether oxidative stress regulates the gene expression of KGDHC has not been tested. Our studies on the gene expression of KGDHC in TD mice reveal a region and time-dependent profile.…”

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confidence: 99%

Oxidative Stress and Transcriptional Regulation in Alzheimer Disease

Shi

Gibson

2007

Alzheimer Disease &Amp; Associated Disorders

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145

107

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Alzheimer's disease (AD) is defined by progressive impairments in memory and cognition and by the presence of extra-cellular neuritic plaques and intracellular neurofibrillary tangles. However, oxidative stress and impaired mitochondrial function always accompany AD. Mitochondria are a major site of production of free radicals [i.e., reactive oxygen species (ROS)] and primary targets of ROS. ROS are cytotoxic, and evidence of ROS-induced damage to cell membranes, proteins and DNA in AD is overwhelming. Nevertheless, therapies based on antioxidants have been disappointing. Thus, alternative strategies are necessary. ROS also act as signaling molecules including for transcription. Thus, chronic exposure to ROS in AD could activate cascades of genes. Although initially protective, prolonged activation may be damaging. Thus, therapeutic approaches based on modulation of these gene cascades may lead to effective therapies. Genes involved in several pathways including antioxidant defense, detoxification, inflammation, etc. are induced in response to oxidative stress and in AD. However, genes that are associated with energy metabolism, which is necessary for normal brain function, are mostly down-regulated. Redox sensitive transcription factors such as activator protein-1 (AP-1), nuclear factor κB (NF-κB), specificity protein-1 and hypoxia-inducible factor (HIF) are important in redox-dependent gene regulation. PPARγ co-activator (PGC-1α) is a co-activator of several transcription factors and is a potent stimulator of mitochondrial biogenesis and respiration. Down-regulated expression of PGC-1α has been implicated in Huntington's disease (HD) and in several HD animal models. Its role in regulation of ROS metabolism makes it a potential candidate player between ROS, mitochondria and neurodegenerative diseases. This review summarizes the current progress on how oxidative stress regulates the expression of genes that might contribute to AD pathophysiology and the implications of the transcriptional modifications for AD. Finally, potential therapeutic strategies based on the updated understandings of redox state-dependent gene regulation in AD are proposed to overcome the lack of efficacy of antioxidant therapies. KeywordsOxidative stress; transcription factors; Kreb's cycle; redox; metabolism; Alzheimer's disease Oxidative stress and Alzheimer's diseaseAD is defined by progressive impairments in memory and cognition and by the presence of extracellular neuritic plaques and intracellular neurofibrillary tangles. β-amyloid peptide (Aβ) is the major component of the plaque, while the tangles are composed of hyperphosphorylated tau proteins. Since these three features define AD, any hypothesis Address correspondence to: Qingli Shi, Dept. of Neurology and Neuroscience, Weill Medical College of Cornell University, Burke Medical Research Institute, 785 Mamaroneck Ave., White Plains, New York 10605, USA, Tel: 914-368-3129; Fax: 914-597-2757.cornell.edu. NIH Public Access Author ManuscriptAlzheimer Dis Assoc Disord. Author...

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Inhibition of the α‐ketoglutarate dehydrogenase complex by the myeloperoxidase products, hypochlorous acid and mono‐N‐chloramine

Cited by 51 publications

References 81 publications

Responses of the mitochondrial alpha-ketoglutarate dehydrogenase complex to thiamine deficiency may contribute to regional selective vulnerability

Responses of the mitochondrial alpha-ketoglutarate dehydrogenase complex to thiamine deficiency may contribute to regional selective vulnerability

Bioenergetics in Glutaryl-Coenzyme A Dehydrogenase Deficiency

Oxidative Stress and Transcriptional Regulation in Alzheimer Disease

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