A familial progressive neurodegenerative disease with 2-oxoglutaric aciduria

Kohlschütter, Alfried; Behbehani, A. W.; Langenbeck, U.; Albani, M.; Heidemann, P; Hoffmann, Georg F.; Kleineke, Jochen; Lehnert, W.; Wendel, U.

doi:10.1007/bf00442325

Cited by 60 publications

(45 citation statements)

References 31 publications

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“…Indeed, congenital defects in the ␣KGDH complex are fatal (42,43) and E3 o -null mice die at 7.5 days postcoitum as aberrant embryos (41). Although cross-species extrapolation should be viewed with caution, the relative degree of ␣KGDH inhibition reported herein is comparable to that seen in fibroblasts taken from ␣KGDH-deficient patients (43). To conclude, TFEC-mediated cell death and organ damage can be accounted for by perturbations to oxidative metabolism, which is fundamental for organism viability.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial stress protein recognition of inactivated dehydrogenases during mammalian cell death

Bruschi

Lindsay

Crabb

1998

Proc. Natl. Acad. Sci. U.S.A.

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The mammalian renal toxicant tetraf luoroethylcysteine (TFEC) is metabolized to a reactive intermediate that covalently modifies the lysine residues of a select group of mitochondrial proteins, forming dif luorothioamidyl lysine protein adducts. Cellular damage is initiated by this process and cell death ensues. NH 2 -terminal sequence analysis of purified mitochondrial proteins containing dif luorothioamidyl lysine adducts identified the lipoamide succinyltransferase and dihydrolipoamide dehydrogenase subunits of the ␣-ketoglutarate dehydrogenase complex (␣KGDH), a key regulatory component of oxidative metabolism, as targets for TFEC action. Adduct formation resulted in marked inhibition of ␣KGDH enzymatic activity, whereas the related pyruvate dehydrogenase complex was unmodified by TFEC and its activity was not inhibited in vivo. Covalent modification of ␣KGDH subunits also resulted in interactions with mitochondrial chaperonin HSP60 in vivo and with HSP60 and mitochondrial HSP70 in vitro. These observations confirm the role of mammalian stress proteins in the recognition of abnormal proteins and provide supporting evidence for reactive metabolite-induced cell death by modification of critical protein targets.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial stress protein recognition of inactivated dehydrogenases during mammalian cell death

Bruschi

Lindsay

Crabb

1998

Proc. Natl. Acad. Sci. U.S.A.

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“…The origin of 2-oxoglutaric aciduria : ' o~ ing a common transport system in the tubulus (7,17). This is …”

Section: Resultsmentioning

confidence: 99%

“…2-Oxoglutaric aciduria has been found incidentally in patients with enzyme defects of both the 2-oxoglutarate dehydrogenase complex and the pyruvate dehydrogenase complex (3)(4)(5) and in one patient with GSD-IA and one patient with GSD-IB (6). Urinary citrate excretion has been studied in various inborn errors of metabolism with inconclusive results (6,7). Citric acid is a major camer of C2 units from the mitochondria where they are produced from pyruvate during carbohydrate oxidation, to the cytosol, where they are utilized in fatty acid synthesis.…”

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confidence: 99%

Urinary Excretion of Lactate, 2-Oxoglutarate, Citrate, and Glycerol in Patients with Glycogenosis Type I

Fernandes

Berger

1987

Pediatr Res

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ABSTRACT. Growth retardation and lactic aciduria are well-known abnormalities in patients with a deficiency of either glucose-6-phosphatase or glucose-6-phosphate translocase. In 19 patients with glucose-6-phosphatase and two patients with glucose-6-phosphate translocase, growth retardation was quantified by calculating the height standard deviation score. The urinary excretion of lactate and some other metabolites was quantified by calculating the lactatelcreatinine, 2-oxoglutarate/creatinine, citratelcreatinine, and glycerollcreatinine ratios in urine. Significant correlations were found between the lacthtelcreatinine ratio, the 2-oxoglutarate/creatinine ratio, and height SD score. Urinary lactate appeared to respond promptly to changes of the diet, while urinary 2-oxoglutarate responded only slowly, as did growth itself. The citratelcreatinine ratio and the glycerollcreatinine ratio were within the normal range and varied little. It was concluded that the urinary 2-oxoglutarate excretion primarily reflects the severity of the disease as expressed in stunted growth. Thus, while urinary lactate levels are more suitable for monitoring the diet, urinary 2-oxoglutarate levels can be used as an indication for intensive treatment with hyperalimentation. (Pediatr Res 21: 279-282,1987) Abbreviations GSD-IA, glycogen storage disease caused by deficiency of glucose-6-phosphatase GSD-IB, glycogen storage disease caused by deficiency of glucose-6-phosphate translocase HSDS, height standard deviation score GDF, gastric drip feeding Since 1975 we treat our patients with GSD-IA by means of GDF during the night (I). Most patients showed spectacular catch-up growth. Some patients, however, were less sensitive to this treatment, and a few were even resistant. Struck by the fact that two patients of the latter category showed excessive urinary excretion of 2-oxoglutarate besides excretion of lactate, we investigated whether the difference~ in growth response of the patients in GDF were reflected by differences in the excretion of particular metabolites in the urine.Lactic aciduria has been found in many inborn errors of carbohydrate metabolism. In GSD-IA the urinary lactate excretion appeared to be a useful parameter to estimate the glucose

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“…When the E3 component was deficient, patients suffered from a progressive neural degeneration (Kohlschutter et al, 1982), pointing to a possible role of ␣-KGDH deficiency in the pathogenesis of neurodegenerative diseases. This enzyme was found to be inhibited in postmortem brain tissues from patients who suffered from Parkinson's or Alzheimer's disease (Gibson et al, 1988;Mizuno et al, 1990Mizuno et al, , 1994Mastrogiacoma et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

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

Tretter¹,

Ádám-Vizi²

2004

J. Neurosci.

413

304

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␣-Ketoglutarate dehydrogenase (␣-KGDH), a key enzyme in the Krebs' cycle, is a crucial early target of oxidative stress (Tretter and Adam-Vizi, 2000). The present study demonstrates that ␣-KGDH is able to generate H 2 O 2 and, thus, could also be a source of reactive oxygen species (ROS) in mitochondria. Isolated ␣-KGDH with coenzyme A (HS-CoA) and thiamine pyrophosphate started to produce H 2 O 2 after addition of ␣-ketoglutarate in the absence of nicotinamide adenine dinucleotide-oxidized (NAD ϩ ). NAD ϩ , which proved to be a powerful inhibitor of ␣-KGDH-mediated H 2 O 2 formation, switched the H 2 O 2 forming mode of the enzyme to the catalytic [nicotinamide adenine dinucleotide-reduced (NADH) forming] mode. In contrast, NADH stimulated H 2 O 2 formation by ␣-KGDH, and for this, neither ␣-ketoglutarate nor HS-CoA were required. When all of the substrates and cofactors of the enzyme were present, the NADH/NAD ϩ ratio determined the rate of H 2 O 2 production. The higher the NADH/NAD ϩ ratio the higher the rate of H 2 O 2 production. H 2 O 2 production as well as the catalytic function of the enzyme was activated by Ca 2ϩ . In synaptosomes, using ␣-ketoglutarate as respiratory substrate, the rate of H 2 O 2 production increased by 2.5-fold, and aconitase activity decreased, indicating that ␣-KGDH can generate H 2 O 2 in in situ mitochondria. Given the NADH/NAD ϩ ratio as a key regulator of H 2 O 2 production by ␣-KGDH, it is suggested that production of ROS could be significant not only in the respiratory chain but also in the Krebs' cycle when oxidation of NADH is impaired. Thus ␣-KGDH is not only a target of ROS but could significantly contribute to generation of oxidative stress in the mitochondria.

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A familial progressive neurodegenerative disease with 2-oxoglutaric aciduria

Cited by 60 publications

References 31 publications

Mitochondrial stress protein recognition of inactivated dehydrogenases during mammalian cell death

Mitochondrial stress protein recognition of inactivated dehydrogenases during mammalian cell death

Urinary Excretion of Lactate, 2-Oxoglutarate, Citrate, and Glycerol in Patients with Glycogenosis Type I

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

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