Evidence for a defect in NADH

Parker, W. Davis; Boyson, Sally J.; Luder, Anthony; Parks, Jason C.

doi:10.1212/wnl.40.8.1231

Cited by 220 publications

(94 citation statements)

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“…Mitochondrial dysfunction is considered a common feature in the pathogenesis of neurodegenerative disorders like HD (Kim et al, 2010;Oliveira, 2010;Parker et al, 1990). Mitochondrial dysfunction constitutes a cellular hallmark for neurodegeneration and occurs as a consequence of defective mitochondrial composition, trafficking to synapses, calcium handling, ATP production, transcription abnormalities and/or ETC impairment (Rosenstock et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…In platelets from HD patients, some authors found a decrease in complex I activity (Parker et al, 1990), whereas others reported no changes in the activity of mitochondrial complexes (Gu et al, 1996;Powers et al, 2007a). Moreover, the phosphocreatine/ inorganic phosphate ratio was significantly decreased in resting muscle (Koroshetz et al, 1997) of HD patients, evidencing bioenergetic changes in HD peripheral tissues.…”

Section: Introductionmentioning

confidence: 96%

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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: 99%

Section: Introductionmentioning

confidence: 96%

Bioenergetic dysfunction in Huntington's disease human cybrids

Ferreira¹,

Cunha‐Oliveira²,

Nascimento³

et al. 2011

Experimental Neurology

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“…Some factors contributing to AD include ␤-amyloid precursor protein (APP) mutations, ApoE genotype, transmembrane proteins S182 and STM2, reduced glucose transport, excitotoxins, head trauma, and deficiencies in mitochondrial cytochrome c oxidase (COX or complex IV) activity (Parker et al, 1990b(Parker et al, , 1994aParker, 1991;Chandrasekaran et al, 1992;Kish et al, 1992;Mutisya et al, 1994;Mattson, 1995;Yanker, 1996;Davis et al, 1997). The idea of a mitochondrial component to neurodegenerative diseases is not new, and it has also been proposed for Parkinson's disease and Guam Parkinsonism / Dementia Complex (Parker et al, 1990a(Parker et al, , 1994aBeal, 1995). The complex IV lesion resembles other electron transport chain (ETC) defects known to produce Leber's neuropathy and neuropathy-ataxia-retinitis pigmentosa (Singh et al, 1989;Goto et al, 1990;Shoffner et al, 1990;Howell et al, 1991;Ortiz et al, 1993).…”

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confidence: 99%

Calcium Homeostasis and Reactive Oxygen Species Production in Cells Transformed by Mitochondria from Individuals with Sporadic Alzheimer’s Disease

Sheehan

Swerdlow

Miller³

et al. 1997

J. Neurosci.

242

140

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Alzheimer's disease (AD) is associated with defects in mitochondrial function. Mitochondrial-based disturbances in calcium homeostasis, reactive oxygen species (ROS) generation, and amyloid metabolism have been implicated in the pathophysiology of sporadic AD. The cellular consequences of mitochondrial dysfunction, however, are not known. To examine these consequences, mitochondrially transformed cells (cybrids) were created from AD patients or disease-free controls. Mitochondria from platelets were fused to 0 cells created by depleting the human neuroblastoma line SH-SY5Y of its mitochondrial DNA (mtDNA). AD cybrids demonstrated a 52% decrease in electron transport chain (ETC) complex IV activity but no difference in complex I activity compared with control cybrids or SH-SY5Y cells. This mitochondrial dysfunction suggests a transferable mtDNA defect associated with AD. ROS generation was elevated in the AD cybrids. AD cybrids also displayed an increased basal cytosolic calcium concentration and enhanced sensitivity to inositol-1,4,5-triphosphate (InsP 3 )-mediated release. Furthermore, they recovered more slowly from an elevation in cytosolic calcium induced by the InsP 3 agonist carbachol. Mitochondrial calcium buffering plays a major role after this type of perturbation. ␤-amyloid (25-35) peptide delayed the initiation of calcium recovery to a carbachol challenge and slowed the recovery rate. Nerve growth factor reduced the carbachol-induced maximum and moderated the recovery kinetics. Succinate increased ETC activity and partially restored the AD cybrid recovery rate. These subtle alterations in calcium homeostasis and ROS generation might lead to increased susceptibility to cell death under circumstances not ordinarily toxic.

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“…4, 1992 indirectly, by promoting the recycling of vitamin E (Booth et aI., 1982;Landi et aI., 1984;Frey et aI., 1990;Packer et aI., 199 1). The activity of NADH:u biquinone oxidoreductase (complex I) is reduced in Huntington disease (Parker et al, 1990), where en dogenous excitotoxins are responsible for the wide spread damage of striatal neurons (reviewed in Choi, 1988;Young et aI., 1988). Hence, ubiquinone has a potential interest as a protective agent against excitotoxin-induced neuronal degeneration.…”

Section: Discussionmentioning

confidence: 99%

Ubiquinone Protects Cultured Neurons against Spontaneous and Excitotoxin-Induced Degeneration

Favit

Nicoletti

Scapagnini

et al. 1992

J Cereb Blood Flow Metab

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Summary:Ubiquinone is an endogenous quinone with pharmacological actions mainly related to its antioxidant properties. Here we report that ubiquinone protects cul tured cerebellar granule cells against glutamate-induced neurotoxicity. In control cultures at 9 days of maturation in vitro (DIY), a 30-min exposure to 100 fLM glutamate induced neuronal degeneration, as reflected by the great percentage (>90%) of cells labeled with propidium iodide 24 h after the exposure. Glutamate-induced neuronal death was dramatically reduced in cultures treated daily with Ubiquinone since the second DIV. In these cultures, glutamate failed to induce a "delayed" increase in the An excessive activation of glutamate receptors has been implicated in the pathophysiology of neu ronal damage in acute and chronic degenerative dis eases of the central nervous system (CNS) (re viewed in Choi, 1988). The neurotoxic action of glu tamate is mostly mediated by an exaggerated activation of N-methyl-D-aspartate (NMDA) recep tors, which leads to a persistent perturbation of in tracellular Ca2+ homeostasis. The excessive rise in cytosolic free Ca2+ results in a sustained activation of a variety of Ca2 + -dependent enzymes, including neutral proteases, protein kinases, phospholipases, and endonucleases. These enzymes may trigger a cascade of intracellular reactions that are ultimately responsible for neuronal degeneration and death (Vaccarino et ai

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Evidence for a defect in NADH

Cited by 220 publications

References 0 publications

Bioenergetic dysfunction in Huntington's disease human cybrids

Bioenergetic dysfunction in Huntington's disease human cybrids

Calcium Homeostasis and Reactive Oxygen Species Production in Cells Transformed by Mitochondria from Individuals with Sporadic Alzheimer’s Disease

Ubiquinone Protects Cultured Neurons against Spontaneous and Excitotoxin-Induced Degeneration

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