Studies on the Isocitrate Dehydrogenase*

Higashi, Taneaki; Maruyama, Etsuko; Otani, Toru; Sakamoto, Yukiya

doi:10.1093/oxfordjournals.jbchem.a128146

Cited by 16 publications

(8 citation statements)

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“…Both isoenzymes were inhibited to a similar extent by Hg2+ whereas differences were seen with Cu2+ andp-chloromercuribenzoate. The strong inhibition produced by metal ions and p-chloromercuribenzoate shows the thiol nature of both heart and liver isocitrate dehydrogenase and is in agreement with reports by Lotspeich &Peters (1951) andHigashi et al (1965). Most reports on purification of NADP-isocitrate dehydrogenase have been concerned with the total isocitrate dehydrogenase content of the tissue and the purification achieved was less than in the present paper (Moyle & Dixon, 1956;Siebert et al, 1957;Rose, 1960).…”

Section: Discussionsupporting

confidence: 90%

Purification and comparative properties of isoenzymes of nicotinamide–adenine dinucleotide phosphate–isocitrate dehydrogenase from rat heart and liver

Islam

Bell

Baron

1972

Biochemical Journal

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1. Rat liver and heart major isoenzymes of NADP-isocitrate dehydrogenase have each been purified about 100-fold by a combination of ammonium sulphate fractionation and chromatography on ion-exchange cellulose and their properties compared. 2. The properties were similar in respect of pH, inhibition by Hg(2+) and Michaelis constants for isocitrate and NADP. 3. Some of the properties of the isoenzymes were different. 4. The heart isoenzyme was activated about 210% by 0.8m-ammonium sulphate whereas the liver isoenzyme was unaffected. The heart isoenzyme showed greater sensitivity to inactivation by heat (30 degrees C for 30min), whereas the liver isoenzyme was more sensitive to inactivation by p-chloromercuribenzoate and by Cu(2+). 5. The Michaelis constants with 3-acetylpyridine-adenine dinucleotide phosphate showed a twofold difference between liver and heart isoenzyme. 6. The differential sensitivity to heat and its mainly non-cytoplasmic location may be an explanation of the failure of plasma isocitrate dehydrogenase activity to increase after a myocardial infarction.

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Section: Discussionsupporting

confidence: 90%

Purification and comparative properties of isoenzymes of nicotinamide–adenine dinucleotide phosphate–isocitrate dehydrogenase from rat heart and liver

Islam

Bell

Baron

1972

Biochemical Journal

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“…Growing evidence indicates that mitochondria are an important cellular target of arsenic toxicity. Arsenite can enter mitochondria via aquaglyceroporins, where it can bind and inhibit numerous enzymes involved in energy production, including pyruvate, succinate, isocitrate, and a-ketoglutarate dehydrogenases (Bergquist et al, 2009;HigashiI et al, 1965;Hosseini et al, 2013), as well as complexes II and IV of the electron transport chain (ETC) (Naranmandura et al, 2011), suggesting arsenic-induced mitochondrial dysfunction may play a role in arsenic-related pathologies.…”

Section: Introductionmentioning

confidence: 99%

From the Cover: Arsenite Uncouples Mitochondrial Respiration and Induces a Warburg-like Effect inCaenorhabditis elegans

Luz

Godebo

Bhatt³

et al. 2016

Toxicol. Sci.

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Millions of people worldwide are chronically exposed to arsenic through contaminated drinking water. Despite decades of research studying the carcinogenic potential of arsenic, the mechanisms by which arsenic causes cancer and other diseases remain poorly understood. Mitochondria appear to be an important target of arsenic toxicity. The trivalent arsenical, arsenite, can induce mitochondrial reactive oxygen species production, inhibit enzymes involved in energy metabolism, and induce aerobic glycolysis in vitro, suggesting that metabolic dysfunction may be important in arsenic-induced disease. Here, using the model organism Caenorhabditis elegans and a novel metabolic inhibition assay, we report an in vivo induction of aerobic glycolysis following arsenite exposure. Furthermore, arsenite exposure induced severe mitochondrial dysfunction, including altered pyruvate metabolism; reduced steady-state ATP levels, ATP-linked respiration and spare respiratory capacity; and increased proton leak. We also found evidence that induction of autophagy is an important protective response to arsenite exposure. Because these results demonstrate that mitochondria are an important in vivo target of arsenite toxicity, we hypothesized that deficiencies in mitochondrial electron transport chain genes, which cause mitochondrial disease in humans, would sensitize nematodes to arsenite. In agreement with this, nematodes deficient in electron transport chain complexes I, II, and III, but not ATP synthase, were sensitive to arsenite exposure, thus identifying a novel class of gene-environment interactions that warrant further investigation in the human populace.

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“…Arsenite inhibits enzymes involved in pyruvate metabolism and the Krebs cycle, including pyruvate, succinate, isocitrate, and α-ketoglutarate dehydrogenases (Bergquist et al 2009; Higashi et al 1965; Hosseini et al 2013; Luz et al 2016a). We measured the activity of pyruvate (PDH) and isocitrate dehydrogenase (IDH); activity of both was inhibited by arsenite in fzo-1 and eat-3 (Fig 5A–B), but not in drp-1 or wild-type nematodes.…”

Section: Resultsmentioning

confidence: 99%

Deficiencies in mitochondrial dynamics sensitize Caenorhabditis elegans to arsenite and other mitochondrial toxicants by reducing mitochondrial adaptability

et al. 2017

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Mitochondrial fission, fusion, and mitophagy are interlinked processes that regulate mitochondrial shape, number, and size, as well as metabolic activity and stress response. The fundamental importance of these processes is evident in the fact that mutations in fission (DRP1), fusion (MFN2, OPA1), and mitophagy (PINK1, PARK2) genes can cause human disease (collectively >1/10,000). Interestingly, however, the age of onset and severity of clinical manifestations varies greatly between patients with these diseases (even those harboring identical mutations), suggesting a role for environmental factors in the development and progression of certain mitochondrial diseases. Using the model organism Caenorhabditis elegans, we screened ten mitochondrial toxicants (2, 4-dinitrophenol, acetaldehyde, acrolein, aflatoxin B1, arsenite, cadmium, cisplatin, doxycycline, paraquat, rotenone) for increased or decreased toxicity in fusion (fzo-1, eat-3)-, fission (drp-1)-, and mitophagy (pdr-1, pink-1)-deficient nematodes using a larval growth assay. In general, fusion-deficient nematodes were the most sensitive to toxicants, including aflatoxin B1, arsenite, cisplatin, paraquat, and rotenone. Because arsenite was particularly potent in fission- and fusion-deficient nematodes, and hundreds of millions of people are chronically exposed to arsenic, we investigated the effects of these genetic deficiencies on arsenic toxicity in more depth. We found that deficiencies in fission and fusion sensitized nematodes to arsenite-induced lethality throughout aging. Furthermore, low-dose arsenite, which acted in a “mitohormetic” fashion by increasing mitochondrial function (in particular, basal and maximal oxygen consumption) in wild-type nematodes by a wide range of measures, exacerbated mitochondrial dysfunction in fusion-deficient nematodes. Analysis of multiple mechanistic changes suggested that disruption of pyruvate metabolism and Krebs cycle activity underlie the observed arsenite-induced mitochondrial deficits, and these disruptions are exacerbated in the absence of mitochondrial fusion. This research demonstrates the importance of mitochondrial dynamics in limiting arsenite toxicity by permitting mitochondrial adaptability. It also suggests that individuals suffering from deficiencies in mitodynamic processes may be more susceptible to the mitochondrial toxicity of arsenic and other toxicants.

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Studies on the Isocitrate Dehydrogenase*

Cited by 16 publications

References 0 publications

Purification and comparative properties of isoenzymes of nicotinamide–adenine dinucleotide phosphate–isocitrate dehydrogenase from rat heart and liver

Purification and comparative properties of isoenzymes of nicotinamide–adenine dinucleotide phosphate–isocitrate dehydrogenase from rat heart and liver

From the Cover: Arsenite Uncouples Mitochondrial Respiration and Induces a Warburg-like Effect inCaenorhabditis elegans

Deficiencies in mitochondrial dynamics sensitize Caenorhabditis elegans to arsenite and other mitochondrial toxicants by reducing mitochondrial adaptability

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