Aluminum toxicity elicits a dysfunctional TCA cycle and succinate accumulation in hepatocytes

Mailloux, Ryan J.; Hamel, Robert; Appanna, Vasu D.

doi:10.1002/jbt.20137

Cited by 79 publications

(62 citation statements)

References 35 publications

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“…The soluble fraction was diluted to 2 mg/ml in double-distilled water and then treated with 200 l of 0.5% (vol/vol) perchloric acid. Following the removal of the precipitate, the supernatant was injected into an Alliance HPLC (Waters) equipped with a C 18 reverse-phase column (4-m Synergi Hydro-RP column [250 by 4.6 mm]; Phenomenex) operating at a flow rate of 0.7 ml/min (16). KG and succinate were detected using a dual wavelength absorbance detector operating at 210 nm for organic acids.…”

Section: Methodsmentioning

confidence: 99%

“…Sodium dodecyl sulfate-PAGE and immunoblotting were performed as previously described (10,16,27). Upon completion of electroblotting, the nonspecific binding sites on the membrane were blocked using 5% (wt/vol) nonfat skim milk in TTBS (20 mM Tris-HCl, 0.8% NaCl, 1% Tween 20 [pH 7.6]) for 1 h. Polyclonal antibodies directed against GDH (Abcam, Cambridge, MA) were used to probe the membrane.…”

Section: Methodsmentioning

confidence: 99%

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α-Ketoglutarate Dehydrogenase and Glutamate Dehydrogenase Work in Tandem To Modulate the Antioxidant α-Ketoglutarate during Oxidative Stress in Pseudomonas fluorescens

et al. 2009

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␣-Ketoglutarate (KG) is a crucial metabolite in all living organisms, as it participates in a variety of biochemical processes. We have previously shown that this keto acid is an antioxidant and plays a key role in the detoxification of reactive oxygen species (ROS). In an effort to further confirm this intriguing phenomenon, Pseudomonas fluorescens was exposed to menadione-containing media, with various amino acids as the sources of nitrogen. Here, we demonstrate that KG dehydrogenase (KGDH) and NAD-dependent glutamate dehydrogenase (GDH) work in tandem to modulate KG homeostasis. While KGDH was sharply decreased in cells challenged with menadione, GDH was markedly increased in cultures containing arginine (Arg), glutamate (Glu), and proline (Pro). When ammonium (NH 4 ) was utilized as the nitrogen source, both KGDH and GDH levels were diminished. These enzymatic profiles were reversed when control cells were incubated in menadione media.13 C nuclear magnetic resonance and high-performance liquid chromatography studies revealed how KG was utilized to eliminate ROS with the concomitant formation of succinate. The accumulation of KG in the menadione-treated cells was dependent on the redox status of the lipoic acid residue in KGDH. Indeed, the treatment of cellular extracts from the menadione-exposed cells with dithiothreitol, a reducing agent, partially restored the activity of KGDH. Taken together, these data reveal that KG is pivotal to the antioxidative defense strategy of P. fluorescens and also point to the ROS-sensing role for KGDH.All aerobic organisms have to contend with the dangers associated with reactive oxygen species (ROS), toxic moieties that are routinely generated as a consequence of ATP production via oxidative phosphorylation (34). The transfer of electrons from NADH and reduced flavin adenine dinucleotide to oxygen is mediated by the respiratory complexes, the major sites of intracellular ROS generation (1). These by-products of oxidative phosphorylation are very harmful and have to be nullified if organisms are to survive in an aerobic environment (24). If left unchecked, ROS can damage biological macromolecules, leading to the demise of the cell. Hence, it is not surprising that all aerobic organisms have devised intricate antioxidative defense strategies in an effort to proliferate in the presence of oxygen.Enzymes such as superoxide dismutase and catalase are uniquely bestowed with the task of eliminating superoxide and hydrogen peroxide, two important ROS (11, 12, 21). Glutathione (GSH), a tripeptide, also plays a pivotal role in the detoxification of ROS (22). However, to be effective, all these ROS disposal processes have to be regenerated with the aid of NADPH. This nicotinamide dinucleotide is the main power behind all antioxidative defense strategies, as it provides the reducing fuel necessary to recharge all effectors involved in combating ROS (32). Thus, various enzyme systems and metabolic networks that orchestrate the biogenesis of NADPH have to be activated if an organism is to...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

α-Ketoglutarate Dehydrogenase and Glutamate Dehydrogenase Work in Tandem To Modulate the Antioxidant α-Ketoglutarate during Oxidative Stress in Pseudomonas fluorescens

et al. 2009

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“…The aforementioned mechanisms of ROS detoxification work in tandem to enable cells to thrive even in toxic oxygenated environments. In recent times the role of metabolism and metabolic shifts in combatting oxidative stress has been greatly studied and elucidated (Mailloux et al, 2006;Ralser et al, 2009). By modulating the catabolic and anabolic pathways, organisms are able to produce key metabolites in the fight against ROS as well as limit the production of pro-oxidants by the TCA cycle.…”

Section: Detoxification Mechanismsmentioning

confidence: 99%

The role of formate in combatting oxidative stress

Thomas

Alhasawi

Auger

et al. 2015

Antonie van Leeuwenhoek

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As all aerobic organisms are exposed to oxidative stress, they are known to devise intricate mechanisms to counter reactive oxygen species (ROS). Metabolic networks contributing to the production of ketoacids are prominent in alleviating the oxidative burden. When glyoxylate detoxifies ROS, formate is the principal by-product generated.In this study the contribution of formate in enabling the survival of the microbe Pseudomonas fluorescens challenged by hydrogen peroxide (H2O2) has been elucidated.When grown in the presence of H2O2 (stressed culture), the levels of formate were higher in the spent fluid and the soluble cell-free extracts compared to the controls. Formate was subsequently utilized as a reducing factor to produce NADPH and succinate. The former is mediated by formate dehydrogenase (FDH-NADP), whose activity was enhanced in the stressed cells. Fumarate reductase (FRD) that catalyzes the conversion of fumarate into succinate was also markedly increased in the stressed cells. Metabolic adaptation is a pivotal tool in combatting oxidative stress. Formate, a by-product of glyoxylate-mediated detoxification of ROS is recuperated as a potent reductive fuel. It is becoming quite evident that this simple metabolite has other biological roles that have not been fully appreciated.

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“…Mg ion might be an important component of characterizing the physiology of Al resistance. Al 3+ toxicity may also provoke similar mitochondrial dysfunction [71] and ROS production in many plant species [72][73][74][75][76] presumably by causing Mg deficiency inside the mitochondria or by substituting Mg for Al 3+ in Mg 2+ -dependent enzymes [77,78]. Thus, mitochondrial Mg porters could be the target site for Al 3+ toxicity.…”

Section: Mitochondriamentioning

confidence: 99%

Molecular Basis of Aluminium Toxicity in Plants: A Review

Gupta¹,

Gaurav²,

Kumar³

2013

AJPS

159

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Aluminium toxicity in acid soils having pH below 5.5, affects the production of staple food crops, vegetables and cash crops worldwide. About 50% of the world's potentially arable lands are acidic. It is trivalent cationic form i.e. Al 3+ that limits the plant's growth. Absorbed Aluminium inhibits root elongation and adversely affects plant growth. Recently researches have been conducted to understand the mechanism of Aluminium toxicity and resistance which is important for stable food production in future. Aluminium resistance depends on the ability of the plant to tolerate Aluminium in symplast or to exclude it to soil. Physiological and molecular basis of Aluminium toxicity and resistance mechanism are important to understand for developing genetically engineered plants for Al toxicity resistance. This paper provides an overview of the state of art in this field.

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Aluminum toxicity elicits a dysfunctional TCA cycle and succinate accumulation in hepatocytes

Cited by 79 publications

References 35 publications

α-Ketoglutarate Dehydrogenase and Glutamate Dehydrogenase Work in Tandem To Modulate the Antioxidant α-Ketoglutarate during Oxidative Stress in Pseudomonas fluorescens

α-Ketoglutarate Dehydrogenase and Glutamate Dehydrogenase Work in Tandem To Modulate the Antioxidant α-Ketoglutarate during Oxidative Stress in Pseudomonas fluorescens

The role of formate in combatting oxidative stress

Molecular Basis of Aluminium Toxicity in Plants: A Review

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