Pyruvate and related α-ketoacids protect mammalian cells in culture against hydrogen peroxide-induced cytotoxicity

Andrae, U.; Singh, Jaswanth; Ziegler‐Skylakakis, Kyriakoula

doi:10.1016/0378-4274(85)90015-3

Cited by 152 publications

(75 citation statements)

References 12 publications

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“…It is known pyruvate and other ketoacids are rapidly decarboxylated by HzO 2 producing acetate, carbondioxide and water (13), all non toxic compounds. The protective effect of these ketoacids has been confirmed by other workers (14,15,16). Other advantages of using these ketoacids are .…”

Section: -95supporting

confidence: 73%

Effect of ketoacids on H2O2 induced cataract

Jain

Bulakh

2003

Indian J Clin Biochem

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Cataract is one of the leading causes of visual disability often leading to blindness in the elderly population. One of the causes is oxidation of proteins present in lens, by hydrogen peroxide (H202 ). In the present study 100 goat lenses were analyzed to determine the protective efficacy of ketoacids, against the oxidative insult by H202. The ketoacids used were (pyruvate, alpha ketoglutarate and oxaloacetate), that are constantly produced endogenously. The lenses were incubated as control and experimental groups in TC-199 media for 72 hrs. H202 concentration of 10mM was used to induce cataract. The biochemical parameters measured were levels of malondialdehyde (MDA), a lipid peroxidation product and activity of glutathione peroxidase (G-Px), an enzymatic antioxidant. The results showed a significant increase in the levels of MDA and significant decrease in the activity of G-Px in the cataractous lenses as compared to control. After addition of ketoacids (pyruvate (10mM), alpha ketoglutarate (20mM) and oxaloacetate (20mM)) separately, the levels of MDA decreased significantly and the activity of G-Px increased significantly. The results suggest that the ketoacids can be very promising antioxidants for the treatment of cataract. They may also be useful in treating other disabilities related to acute and chronic oxidative stress.

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Section: -95supporting

confidence: 73%

Effect of ketoacids on H2O2 induced cataract

Jain

Bulakh

2003

Indian J Clin Biochem

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“…However, aerobic glycolysis is likely advantageous to rapidly growing cells because it renders them less dependent on oxygen, thereby improving their survival in an environment that may become hypoxic as cell numbers increase. Further, the transition to aerobic glycolysis by proliferating cells minimizes exposure to reactive oxygen species, i.e., diminished oxidative metabolism (35,36). Despite many years of investigation, however, it is still unclear as to what regulatory mechanisms transition proliferating cells from oxidative glucose metabolism to anaerobic glycolysis (33).…”

Section: Discussionmentioning

confidence: 99%

Alterations of cellular bioenergetics in pulmonary artery endothelial cells

Koeck

Lara

et al. 2007

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

359

402

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Idiopathic pulmonary arterial hypertension (IPAH) is pathogenetically related to low levels of the vasodilator nitric oxide (NOcellular respiration ͉ nitric oxide ͉ oxygen consumption ͉ pulmonary hypertension ͉ mitochondrion I diopathic pulmonary arterial hypertension (IPAH) is a fatal disease of unknown etiology characterized by a progressive increase in pulmonary artery pressure and vascular growth (1, 2). Secondary forms of pulmonary arterial hypertension (PAH) are associated with known diseases, such as collagen vascular diseases or portal hypertension but in the absence of an identifiable etiology are classified as IPAH. Abnormalities in vasodilators, specifically nitric oxide (NO), have been implicated in the pathogenesis of pulmonary hypertension (1-5). NO is produced in the lung by NO synthases (NOS; EC 1.14.13.39) (6-8). There is conclusive evidence from animal models of pulmonary hypertension, mice genetically deficient in endothelial NOS (eNOS), and complementation studies with gene transfer of NOSs for the concept that NO is a critical determinant of pulmonary vascular tone (6, 7, 9). Furthermore, pulmonary and total body NO are lower in IPAH patients as compared with healthy controls (3,(10)(11)(12), and the decrease of NO has been linked to increased arginase II and decreased eNOS expression in IPAH pulmonary endothelial cells in vivo (10,13).In addition to effects on vascular tone, NO regulates cellular bioenergetics through effects on glycolysis, oxygen consumption by mitochondrion, and mitochondrial biogenesis (14-17). For example, eNOS-deficient mice, which have mild pulmonary hypertension under normoxia and an exaggerated pulmonary vasoconstrictive response to hypoxia (18), have reduced mitochondria content in a wide range of tissues in association with significantly lower oxygen consumption and ATP content (14-17). Mitochondria are essential to cellular energy production in all higher organisms adapted to an oxygen-containing environment, i.e., ATP produced through oxidative phosphorylation. The electrochemical gradient used by mitochondrial F 0 F 1 ATP synthase to synthesize ATP from ADP is generated by the proton pump action performed by Complexes I, III, and IV of the respiratory chain. The proton pumping is accompanied by electron shuttling, whereby Complexes I and II, along with the flavoprotein-ubiquinone oxidoreductase, transfer electrons from different sources to ubiquinone (coenzyme Q). The electrons are then transferred sequentially to Complex III, cytochrome c, Complex IV, and finally to molecular oxygen, the terminal electron acceptor. All multisubunit complexes of the respiratory chain (I-IV) are located in the mitochondrial inner membrane. Thus, mitochondria are the primary oxygen demand in the body, accounting for Ϸ90% of cellular oxygen consumption. Conversely, under limiting oxygen conditions, cells turn to glycolysis to generate energy. In endothelial cells, ATP is generated nearly equivalently by glycolysis and cellular respiration (19), accounting for a relative tolerance ...

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“…This pathway is essential in nutrient deprived tumor microenvironments and other diverse contexts but the origin of acetate has been unclear [8][9][10][11][12][13][14] . It has been postulated that acetate may be synthesized de novo in cells [15][16][17][18][19] but the pathways and quantitative reaction mechanisms through which this may occur are unknown. Given that alternative carbon sources often arise from overflow metabolism, we suspected that such a mechanism may allow for acetate generation.…”

Section: Introductionmentioning

confidence: 99%

De novo acetate production is coupled to central carbon metabolism in mammals

Liu

et al. 2018

Preprint

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In cases of nutritional excess, there is incomplete catabolism of a nutritional source and secretion of a waste product (overflow metabolism), such as the conversion of glucose to lactate (the Warburg Effect) in tumors. Here we report that excess glucose metabolism generates acetate, a key nutrient whose source has been unclear. Conversion of pyruvate, the product of glycolysis, to acetate occurs through two mechanisms: 1) coupling to reactive oxygen species (ROS), and 2) a neomorphic enzyme activity from keto acid dehydrogenases that enable it to function as a pyruvate decarboxylase. Furthermore, we demonstrate that glucose-derived acetate is sufficient to maintain acetyl-coenzyme A (Ac-CoA) pools and cell proliferation in certain limited metabolic environments such as during mitochondrial dysfunction or ATP citrate lyase (ACLY) deficiency. Thus, de novo acetate production is coupled to the activity of central carbon metabolism providing possible regulatory mechanisms and links to pathophysiology.peer-reviewed)

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Pyruvate and related α-ketoacids protect mammalian cells in culture against hydrogen peroxide-induced cytotoxicity

Cited by 152 publications

References 12 publications

Effect of ketoacids on H2O2 induced cataract

Effect of ketoacids on H2O2 induced cataract

Alterations of cellular bioenergetics in pulmonary artery endothelial cells

De novo acetate production is coupled to central carbon metabolism in mammals

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