scholarly journals Metabolic Outcomes of Anaplerotic Dodecanedioic Acid Supplementation in Very Long Chain Acyl-CoA Dehydrogenase (VLCAD) Deficient Fibroblasts

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 538
Author(s):  
Igor Radzikh ◽  
Erica Fatica ◽  
Jillian Kodger ◽  
Rohan Shah ◽  
Ryan Pearce ◽  
...  
Keyword(s):  
Alternative Energy ◽  
Carbon Sources ◽  
Krebs Cycle ◽  
Dicarboxylic Acids ◽  
High Energy ◽  
Glycolytic Flux ◽  
Chain Acyl ◽  
Krebs Cycle Intermediates ◽  
Dodecanedioic Acid ◽  
Long Chain

Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD, OMIM 609575) is associated with energy deficiency and mitochondrial dysfunction and may lead to rhabdomyolysis and cardiomyopathy. Under physiological conditions, there is a fine balance between the utilization of different carbon nutrients to maintain the Krebs cycle. The maintenance of steady pools of Krebs cycle intermediates is critical formitochondrial energy homeostasis especially in high-energy demanding organs such as muscle and heart. Even-chain dicarboxylic acids are established as alternative energy carbon sources that replenish the Krebs cycle by bypassing a defective β-oxidation pathway. Despite this, even-chain dicarboxylic acids are eliminated in the urine of VLCAD-affected individuals. In this study, we explore dodecanedioic acid (C12; DODA) supplementation and investigate its metabolic effect on Krebs cycle intermediates, glucose uptake, and acylcarnitine profiles in VLCAD-deficient fibroblasts. Our findings indicate that DODA supplementation replenishes the Krebs cycle by increasing the succinate pool, attenuates glycolytic flux, and reduces levels of toxic very long-chain acylcarnitines.

scholarly journals YvcK of Bacillus subtilis is required for a normal cell shape and for growth on Krebs cycle intermediates and substrates of the pentose phosphate pathway

Microbiology ◽  
2005 ◽  
Vol 151 (11) ◽  
pp. 3777-3791 ◽  
Author(s):  
Boris Görke ◽  
Elodie Foulquier ◽  
Anne Galinier
Keyword(s):  
Bacillus Subtilis ◽  
Pentose Phosphate Pathway ◽  
Carbon Metabolism ◽  
Carbon Sources ◽  
Krebs Cycle ◽  
Normal Growth ◽  
Central Carbon Metabolism ◽  
Pentose Phosphate ◽  
Homologous Protein ◽  
Krebs Cycle Intermediates

The HPr-like protein Crh has so far been detected only in the bacillus group of bacteria. In Bacillus subtilis, its gene is part of an operon composed of six ORFs, three of which exhibit strong similarity to genes of unknown function present in many bacteria. The promoter of the operon was determined and found to be constitutively active. A deletion analysis revealed that gene yvcK, encoded by this operon, is essential for growth on Krebs cycle intermediates and on carbon sources metabolized via the pentose phosphate pathway. In addition, cells lacking YvcK acquired media-dependent filamentous or L-shape-like aberrant morphologies. The presence of high magnesium concentrations restored normal growth and cell morphology. Furthermore, suppressor mutants cured from these growth defects appeared spontaneously with a high frequency. Such suppressing mutations were identified in a transposon mutagenesis screen and found to reside in seven different loci. Two of them mapped in genes of central carbon metabolism, including zwf, which encodes glucose-6-phosphate dehydrogenase and cggR, the product of which regulates the synthesis of glyceraldehyde-3-phosphate dehydrogenase. All these results suggest that YvcK has an important role in carbon metabolism, probably in gluconeogenesis required for the synthesis of cell wall precursor molecules. Interestingly, the Escherichia coli homologous protein, YbhK, can substitute for YvcK in B. subtilis, suggesting that the two proteins have been functionally conserved in these different bacteria.

scholarly journals Clinical Applications of Ketogenic Diet-Induced Ketosis in Neurodegenerative and Metabolism-Related Pathologies

Proceedings ◽  
2020 ◽  
Vol 61 (1) ◽  
pp. 29
Author(s):  
Raffaele Pilla
Keyword(s):  
Alternative Energy ◽  
Krebs Cycle ◽  
Synaptic Activity ◽  
Energy Deficit ◽  
Atp Production ◽  
Seizure Disorders ◽  
Metabolic Adaptations ◽  
Krebs Cycle Intermediates ◽  
Species Production ◽  
Antioxidant Effects

Metabolic-based therapies such as nutritional ketosis have been proven effective for seizure disorders and various acute and chronic neurological pathologies. In a healthy brain, glucose is the primary metabolic fuel for cells. However, neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), seizure disorders, and traumatic brain injury (TBI) are associated with impaired glucose transport and metabolism and with mitochondrial dysfunction leading to energy deficit. Therapeutic ketosis can be considered as a form of metabolic therapy by providing alternative energy substrates. In addition, ketosis leads to metabolic adaptations that improve brain metabolism, restore mitochondrial ATP production, decrease reactive oxygen species production, reduce inflammation, and increase the activity of neurotrophic factors. Moreover, the synaptic activity between neurons is also stabilized through the increase of Szent-Györgyi–Krebs cycle intermediates, antioxidant effects, increased GABA-to-glutamate ratio, and activation of ATP-sensitive potassium channels.

A Simple Spectrophotometric Assay for Long-Chain Acyl-CoA Dehydrogenase Activity Measurements in Human Skin Fibroblasts

1993 ◽  
Vol 30 (3) ◽  
pp. 293-297 ◽  
Author(s):  
Lodewijk Ijlst ◽  
Ronald J A Wanders
Keyword(s):  
Correct Diagnosis ◽  
White Blood Cells ◽  
Dicarboxylic Acids ◽  
Autosomal Recessive Disorder ◽  
Skin Fibroblasts ◽  
Dicarboxylic Aciduria ◽  
Cultured Skin ◽  
Activity Measurements ◽  
Chain Acyl ◽  
Long Chain

Long-chain acyl-CoA dehydrogenase (LCAD) deficiency is an autosomal recessive disorder of fatty acid metabolism characterized by hypoglycemia, muscle weakness and hepato- and cardiomegaly to varying extents. Analysis of organic acids in urine usually reveals dicarboxylic aciduria with elevated levels of adipic, suberic and sebacic acids as well as longer chain dicarboxylic acids. Correct diagnosis of suspected patients requires measurement of LCAD in tissue or preferably, white blood cells and/or cultured skin fibroblasts. In this paper we present a simple spectrophotometric enzyme assay based on the use of ferricenium hexafluorophosphate as electron acceptor. Under optimized conditions the method presented allowed unequivocal identification of LCAD-deficiency in Fibroblast homogenates.

scholarly journals A mitochondrial long-chain fatty acid oxidation defect leads to uncharged tRNA accumulation and activation of the integrated stress response in the mouse heart

2021 ◽  
Author(s):  
Pablo Ranea-Robles ◽  
Natalya N Pavlova ◽  
Aaron Bender ◽  
Brandon Stauffer ◽  
Chunli Yu ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Stress Response ◽  
High Energy ◽  
Acid Oxidation ◽  
Mouse Heart ◽  
Integrated Stress Response ◽  
Mitochondrial Fatty Acid ◽  
Short Period ◽  
Chain Acyl ◽  
Long Chain

The heart relies mainly on mitochondrial fatty acid β-oxidation (FAO) for its high energy requirements. Cardiomyopathy and arrhythmias can be severe complications in patients with inherited defects in mitochondrial long-chain FAO, reinforcing the importance of FAO for cardiac health. However, the pathophysiological mechanisms that underlie the cardiac abnormalities in long-chain FAO disorders remain largely unknown. Here, we investigated the cardiac transcriptional adaptations to the FAO defect in the long-chain acyl-CoA dehydrogenase (LCAD) knockout (KO) mouse. We found a prominent activation of the integrated stress response (ISR) mediated by the eIF2α/ATF4 axis in both fed and fasted states, accompanied by a reduction in cardiac protein synthesis during a short period of food withdrawal. Notably, we found an accumulation of uncharged tRNAs in LCAD KO hearts, consistent with a reduced availability of cardiac amino acids, in particular, glutamine. Our results show that perturbations in amino acid metabolism caused by long-chain FAO deficiency impact cardiac metabolic signaling, in particular the ISR, and may play a role in the associated cardiac pathology

Cold-sensitive mutant with defective growth at 5 °C from a psychrotrophic bacterium

1980 ◽  
Vol 26 (1) ◽  
pp. 1-6 ◽  
Author(s):  
W. D. Murray ◽  
W. E. Inniss
Keyword(s):  
Atpase Activity ◽  
Specific Activity ◽  
Carbon Sources ◽  
Krebs Cycle ◽  
Effect Of Temperature ◽  
Restrictive Temperature ◽  
Permissive Temperature ◽  
Wild Type ◽  
Cold Sensitive ◽  
Krebs Cycle Intermediates

A cold-sensitive (CS) mutant of the psychrotroph, Bacillus psychrophilus, was obtained by N-methyl-N′-nitro-N-nitrosoguanidine mutagenization and penicillin counterselection. In the presence of citrate, the wild type grew well at both 5 and 20 °C whereas the CS mutant grew well at 20 °C (the permissive temperature) but, at 5 °C (the restrictive temperature), grew at a reduced rate for two to three generations followed by a complete plateau in growth. Upon return of the CS mutant to 20 °C, after a delay of about 40 h, growth resumed at the appropriate rate. The CS mutant exhibited growth rates similar to parental rates on a wide variety of carbon sources at 5 °C, but when Krebs cycle intermediates were used as substrates and in the presence of an equimolar amount of citrate, the typical cold-sensitive growth pattern occurred. Comparison of oxidative phosphorylation in the parent and CS mutant indicated that no phosphorylation occurred at 5 °C in the CS mutant during the plateau in growth. Examination of the effect of temperature on ATPase activity showed that at 5 °C the specific activity of ATPase isolated from the CS mutant grown at 5 °C was 15-fold less than the ATPases isolated from wild-type cells grown at either 5 or 20 °C and 10.5-fold lower than ATPase from CS mutant cells grown at 20 °C. The large reduction in CS mutant ATPase activity at 5 °C appears to be at least partly due to an effect on synthesis since citrate did not inhibit preformed ATPase.

scholarly journals Anesthesia management in a patient with very long-chain acyl-Coenzyme A dehydrogenase deficiency

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Haruyuki Yuasa ◽  
Yukio Onoda ◽  
Atsuhiro Kitaura ◽  
Takashi Mino ◽  
Shota Tsukimoto ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Body Temperature ◽  
Alternative Energy ◽  
Coenzyme A ◽  
Case Presentation ◽  
Energy Needs ◽  
Chain Acyl ◽  
Acyl Coenzyme A ◽  
Vlcad Deficiency ◽  
Long Chain

Abstract Background In a patient with very long-chain acyl-Coenzyme A dehydrogenase (VLCAD) deficiency, metabolism of fatty acids is impaired and a supply of alternative energy is limited when glucose level is insufficient on starvation. Case presentation A 37-year-old woman with VLCAD deficiency was diagnosed with an ovarian cyst and was scheduled for laparoscopic ovarian cystectomy. Glucose was administered intravenously with the start of fasting. Anesthesia was induced with remifentanil, midazolam, and thiamylal, maintained with desflurane and remifentanil. Body temperature was maintained at 36.2–36.7 °C. During anesthesia, hypoglycemia did not occur, creatine kinase levels were in the normal range, and myoglobinuria was not detected. No shivering was observed after extubation. Conclusions Glucose was administered to avoid perioperative hypoglycemia. Body temperature was controlled to avoid shivering, which would otherwise increase skeletal muscle energy needs. Blood creatine kinase did not increase, and myoglobinuria was not detected; thus, rhabdomyolysis was unlikely to develop.

Malonate and Krebs Cycle Intermediates Utilization in the Presence of other Carbon Sources by Rhizobium japonicum and Soybean Bacteroids

1982 ◽  
Vol 37 (10) ◽  
pp. 921-926 ◽  
Author(s):  
Dietrich Werner ◽  
Walburga Dittrich ◽  
Heidemarie Thierfelder
Keyword(s):  
Sole Carbon Source ◽  
Carbon Sources ◽  
Krebs Cycle ◽  
Living Cells ◽  
The Other ◽  
Rhizobium Japonicum ◽  
Free Living ◽  
Low Concentrations ◽  
Substrate Saturation ◽  
Krebs Cycle Intermediates

Abstract Free living cells of Rhizobium japonicum 61-A-101 and bacteroids from Glycine max var. Mandarin infected with the same strain utilized malonate with a substrate saturation greater than 10-2 mol/l. At low concentrations of malonate (10-5 mol/1) the free living cells were significantly more active in utilizing malonate than bacteroids. In bacteroids two substrate saturation ranges were found, one between 3 x 10-4mol/l and 10-3 mol/l, the other at more than 10-2 mol/l. Utilization of malonate was not affected by 10 to 100 times larger concentrations of either arabinose or xylose. 10-3 mol/l succinate inhibited the utilization of malonate (10-4 mol/l) completely in bacteroids, and by 90% in free living cells. Succinate utilization (10-4 mol/1) was reduced in those cells exposed to 100 times higher malonate concentration only by 20-30% . Utilization and incorporation of pyruvate and 2-oxoglutarate into bacteroids was also only slightly affected by 100 times larger malonate concentration. Citrate utilization by bacteroids however was reduced by more than 70%. The rate of endoxidation of malonate as sole carbon source (14CO2 production from [2-14C] malonic acid)was about 1.5 μmol · h-1 • mg protein-1 and about half the rate with Pseudomonas putida and 70% o f the rate with Pseudomonas fluorescens under the same conditions (pH 6.0, 28 °C).

Physical training attenuates phosphocreatine and long-chain acyl-CoA alterations in diabetic rat heart

1993 ◽  
Vol 74 (4) ◽  
pp. 1785-1790 ◽  
Author(s):  
N. Mokhtar ◽  
S. Rousseau-Migneron ◽  
G. Tancrede ◽  
A. Nadeau
Keyword(s):  
Exercise Training ◽  
Training Program ◽  
Physical Training ◽  
High Energy ◽  
Heart Tissue ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Sedentary Control ◽  
Chain Acyl ◽  
Long Chain

This study was designed to assess the effect of physical training on high-energy phosphate levels in the heart of diabetic rats. Diabetes was induced with streptozocin (50 mg/kg), and exercise training was carried out on a treadmill with a progressive 10-wk program. Plasma glucose levels at the end of the training program showed only a small improvement of the diabetic state in trained animals (21.7 +/- 1.3 vs. 24.4 +/- 0.8 mmol/l; P < 0.05). The lower heart rate observed in sedentary diabetic rats (279 +/- 6 vs. 356 +/- 5 beats/min; P < 0.001) was improved by physical training (301 +/- 8 beats/min; P < 0.05 vs. sedentary diabetics). Significantly lower phosphocreatine levels were found in sedentary diabetic rats (12.0 +/- 0.7 mumol/g dry wt) than in sedentary control rats (15.0 +/- 0.9 mumol/g dry wt; P < 0.05) but not in trained diabetic rats (13.7 +/- 0.7 mumol/g dry wt). ATP levels were not affected by diabetes but were increased by training. The increased long-chain acyl-CoA levels in sedentary diabetic rats (146 +/- 7 vs. 119 +/- 8 mumol/g dry wt in sedentary control rats; P < 0.05) were improved by training (138 +/- 6 mumol/g dry wt; P > 0.05 vs. sedentary control rats). These data indicate that the diminution in phosphocreatine levels observed in the heart tissue of chronically diabetic rats can be attenuated by an exercise training program.

scholarly journals Characterization of the binding sites for dicarboxylic acids on bovine serum albumin

1991 ◽  
Vol 276 (3) ◽  
pp. 569-575 ◽  
Author(s):  
J H Tonsgard ◽  
S C Meredith
Keyword(s):  
Dicarboxylic Acid ◽  
Binding Site ◽  
Dicarboxylic Acids ◽  
Acid Oxidation ◽  
Affinity Binding ◽  
Reye's Syndrome ◽  
Medium Chain ◽  
High Affinity ◽  
Dodecanedioic Acid ◽  
Long Chain

Dicarboxylic acids are prominent features of several diseases, including Reye's syndrome and inborn errors of mitochondrial and peroxisomal fatty acid oxidation. Moreover, dicarboxylic acids are potentially toxic to cellular processes. Previous studies [Tonsgard, Mendelson & Meredith (1988) J. Clin. Invest. 82, 1567-1573] demonstrated that long-chain dicarboxylic acids have a single high-affinity binding site and between one and three lower-affinity sites on albumin. Medium-chain-length dicarboxylic acids have a single low-affinity site. We further characterized dicarboxylic acid binding to albumin in order to understand the potential effects of drugs and other ligands on dicarboxylic acid binding and toxicity. Progesterone and oleate competitively inhibit octadecanedioic acid binding to the single high-affinity site. Octanoate inhibits binding to the low-affinity sites. Dansylated probes for subdomain 2AB inhibit dodecanedioic acid binding whereas probes for subdomain 3AB do not. In contrast, low concentrations of octadecanedioic acid inhibit the binding of dansylated probes to subdomain 3AB and 2AB. L-Tryptophan, which binds in subdomain 3AB, inhibits hexadecanedioic acid binding but has no effect on dodecanedioic acid. Bilirubin and acetylsalicylic acid, which bind in subdomain 2AB, inhibit the binding of medium-chain and long-chain dicarboxylic acids. Our results suggest that long-chain dicarboxylic acids bind in subdomains 2C, 3AB and 2AB. The single low-affinity binding site for medium-chain dicarboxylic acids is in subdomain 2AB. These studies suggest that dicarboxylic acids are likely to be unbound in disease states and may be potentially toxic.

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