_-Ketoglutarate Dehydrogenase Complex in Neurodegeneration

Gibson, Gary E.; Starkov, Anatoly A.; Shi, Qingli; Beal, M. Flint

doi:10.1201/b12308-24

Cited by 20 publications

(26 citation statements)

References 133 publications

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“…Similarly to PDH, KGDH is affected by oxidative stress, being a mediator between mitochondria and oxidative stress in neurodegeneration (Gibson et al, 2005). Decreased KGDH activity was previously described in Alzheimer's and Parkinson's diseases (Gibson et al, 2000); however, and in contrast with PDH, no changes have been reported in HD. KGDH catalyzed reaction is important for energy production, neurotransmitter metabolism (e.g.…”

Section: Discussionmentioning

confidence: 96%

Bioenergetic dysfunction in Huntington's disease human cybrids

Ferreira¹,

Cunha‐Oliveira²,

Nascimento³

et al. 2011

Experimental Neurology

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In this work we studied the mitochondrial-associated metabolic pathways in Huntington's disease (HD) versus control (CTR) cybrids, a cell model in which the contribution of mitochondrial defects from patients is isolated. HD cybrids exhibited an interesting increase in ATP levels, when compared to CTR cybrids. Concomitantly, we observed increased glycolytic rate in HD cybrids, as revealed by increased lactate/pyruvate ratio, which was reverted after inhibition of glycolysis. A decrease in glucose-6-phosphate dehydrogenase activity in HD cybrids further indicated decreased rate of the pentose-phosphate pathway. ATP levels of HD cybrids were significantly decreased under glycolysis inhibition, which was accompanied by a decrease in phosphocreatine. Nevertheless, pyruvate supplementation could not recover HD cybrids' ATP or phosphocreatine levels, suggesting a dysfunction in mitochondrial use of that substrate. Oligomycin also caused a decrease in ATP levels, suggesting a partial support of ATP generation by the mitochondria. Nevertheless, mitochondrial NADH/NAD t levels were decreased in HD cybrids, which was correlated with a decrease in pyruvate dehydrogenase activity and protein expression, suggesting decreased tricarboxylic acid cycle (TCA) input from glycolysis. Interestingly, the activity of alpha-ketoglutarate dehydrogenase, a critical enzyme complex that links the TCA to amino acid synthesis and degradation, was increased in HD cybrids. In accordance, mitochondrial levels of glutamate were increased and alanine was decreased, whereas aspartate and glutamine levels were unchanged in HD cybrids. Conversely, malate dehydrogenase activity from total cell extracts was unchanged in HD cybrids. Our results suggest that inherent dysfunction of mitochondria from HD patients affects cellular bioenergetics in an otherwise functional nuclear background.

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Section: Discussionmentioning

confidence: 96%

Bioenergetic dysfunction in Huntington's disease human cybrids

Ferreira¹,

Cunha‐Oliveira²,

Nascimento³

et al. 2011

Experimental Neurology

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“…SN56 is a line of cholinergic neurons which are highly sensitive to several stressors and to metabolic alterations. The interest about cholinergic neurons is connected to Alzheimer's disease, where their early loss is associated with a metabolic impairment in brain, whose extent is proportional to the severity of the cognitive deficits [24,25]. Furthermore, RA treatment increases SN56 vulnerability to oxidative stress, as demonstrated by an increase of caspase-3 mediated cell death [26,27] and lactate dehydrogenase activity, which is responsible for lactate production and consumption [28].…”

Section: Measurements In Glucose Deprivationmentioning

confidence: 99%

Targeting of multiple metabolites in neural cells monitored by using protein-based carbon nanotubes

Boero

Carrara

Vecchio

et al. 2011

Sensors and Actuators B: Chemical

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a b s t r a c tMicrodevices dedicated to monitor metabolite levels have recently enabled many applications in the field of cell analysis, to monitor cell growth and development of numerous cell lines. By combining the traditional technology used for electrochemical biosensors with nanoscale materials, it is possible to develop miniaturized metabolite biosensors with unique properties of sensitivity and detection limit. In particular, enzymes tend to adsorb onto carbon nanotubes and their optical or electrical activity can perturb the electronic properties. In the present work we propose multi-walled carbon nanotube-based biosensors to monitor a cell line highly sensitive to metabolic alterations, in order to evaluate lactate production and glucose uptake during different cell states. We achieve sensors for both lactate and glucose, with sensitivities of 40.1 A mM −1 cm −2 and 27.7 A mM −1 cm −2 , and detection limits of 28 M and 73 M, respectively. This nano-biosensing technology is used to provide new information on cell line metabolism during proliferation and differentiation, which are unprecedented in cell biology.

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“…It participates in the tricarboxylic acid (TCA) cycle, where it irreversibly catalyzes the conversion of α‐ketoglutarate, CoASH, and NAD + to succinyl‐CoA, NADH, and CO 2 . It may exhibit a high flux‐control coefficient in the generation of reducing equivalents (1) and is also crucial for maintenance of the mitochondrial redox state (2). In addition, KGDHC is involved in transaminations, glutamate metabolism (3).…”

mentioning

confidence: 99%

The negative impact ofα‐ketoglutarate dehydrogenase complex deficiency on matrix substrate‐level phosphorylation

Kiss¹,

Konràd²,

Dóczi³

et al. 2013

FASEB j.

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A decline in α-ketoglutarate dehydrogenase complex (KGDHC) activity has been associated with neurodegeneration. Provision of succinyl-CoA by KGDHC is essential for generation of matrix ATP (or GTP) by substrate-level phosphorylation catalyzed by succinyl-CoA ligase. Here, we demonstrate ATP consumption in respiration-impaired isolated and in situ neuronal somal mitochondria from transgenic mice with a deficiency of either dihydrolipoyl succinyltransferase (DLST) or dihydrolipoyl dehydrogenase (DLD) that exhibit a 20-48% decrease in KGDHC activity. Import of ATP into the mitochondrial matrix of transgenic mice was attributed to a shift in the reversal potential of the adenine nucleotide translocase toward more negative values due to diminished matrix substrate-level phosphorylation, which causes the translocase to reverse prematurely. Immunoreactivity of all three subunits of succinyl-CoA ligase and maximal enzymatic activity were unaffected in transgenic mice as compared to wild-type littermates. Therefore, decreased matrix substrate-level phosphorylation was due to diminished provision of succinyl-CoA. These results were corroborated further by the finding that mitochondria from wild-type mice respiring on substrates supporting substrate-level phosphorylation exhibited ~30% higher ADP-ATP exchange rates compared to those obtained from DLST(+/-) or DLD(+/-) littermates. We propose that KGDHC-associated pathologies are a consequence of the inability of respiration-impaired mitochondria to rely on "in-house" mitochondrial ATP reserves.

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_-Ketoglutarate Dehydrogenase Complex in Neurodegeneration

Cited by 20 publications

References 133 publications

Bioenergetic dysfunction in Huntington's disease human cybrids

Bioenergetic dysfunction in Huntington's disease human cybrids

Targeting of multiple metabolites in neural cells monitored by using protein-based carbon nanotubes

The negative impact ofα‐ketoglutarate dehydrogenase complex deficiency on matrix substrate‐level phosphorylation

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