scholarly journals The Effects of a Ketogenic Diet on Patients with Dihydrolipoamide Dehydrogenase Deficiency

Nutrients ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 3523
Author(s):  
Orna Staretz-Chacham ◽  
Ben Pode-Shakked ◽  
Eyal Kristal ◽  
Smadar Yaala Abraham ◽  
Keren Porper ◽  
...  
Keyword(s):  
Ketogenic Diet ◽  
Treatment Guidelines ◽  
Pyruvate Dehydrogenase Complex ◽  
Early Death ◽  
Tca Cycle ◽  
Dihydrolipoamide Dehydrogenase ◽  
Acetyl Coa ◽  
Historical Cohort ◽  
Improve Patient Survival ◽  
Pathogenic Variants

Background: Dihydrolipoamide dehydrogenase (DLD lipoamide dehydrogenase, the E3 subunit of the pyruvate dehydrogenase complex (PDHC)) is the third catalytic enzyme of the PDHC, which converts pyruvate to acetyl-CoA catalyzed with the introduction of acetyl-CoA to the tricyclic acid (TCA) cycle. In humans, PDHC plays an important role in maintaining glycose homeostasis in an aerobic, energy-generating process. Inherited DLD-E3 deficiency, caused by the pathogenic variants in DLD¸ leads to variable presentations and courses of illness, ranging from myopathy, recurrent episodes of liver disease and vomiting, to Leigh disease and early death. Currently, there is no consensus on treatment guidelines, although one suggested solution is a ketogenic diet (KD). Objective: To describe the use and effects of KD in patients with DLD-E3 deficiency, compared to the standard treatment. Results: Sixteen patients were included. Of these, eight were from a historical cohort, and of the other eight, four were on a partial KD. All patients were homozygous for the D479V (or D444V, which corresponds to the mutated mature protein without the mitochondrial targeting sequence) pathogenic variant in DLD. The treatment with partial KD was found to improve patient survival. However, compared to a historical cohort, the patients’ quality of life (QOL) was not significantly improved. Conclusions: The use of KD offers an advantage regarding survival; however, there is no significant improvement in QOL.

Abstract 280: Cardiac Deletion of the Mitochondrial Pyruvate Carrier Results in Dilated Cardiomyopathy with Preservation of Fatty Acid Catabolism

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Kyle S McCommis ◽  
Carrie M Gierasch ◽  
Attila Kovacs ◽  
Carla J Weinheimer ◽  
Timothy R Koves ◽  
...  
Keyword(s):  
Heart Failure ◽  
Dilated Cardiomyopathy ◽  
Ketogenic Diet ◽  
Contractile Function ◽  
Tca Cycle ◽  
Acetyl Coa ◽  
Gene Markers ◽  
Atp Production ◽  
Mitochondrial Pyruvate Carrier ◽  
Heart Size

Pyruvate is an important metabolic substrate for the heart that is formed in the cytosol by glycolysis or conversion of lactate, and then must be transported into the mitochondrial matrix for further metabolism. The mitochondrial pyruvate carrier (MPC) is composed of MPC1 and MPC2 proteins that are each required for complex stability and transport activity. Indeed, mice with cardiac-specific knockout of MPC2 (CS-MPC2-/- mice) exhibited concomitant MPC1 degradation and marked reduction in pyruvate-stimulated mitochondrial respiration. While cardiac function and heart size was normal in 6 week old CS-MPC2-/- mice, serial echocardiograms demonstrated drastic increases in heart size, chamber dilation, and loss of contractile function at 10 and 16 weeks of age. Gene markers of heart failure, hypoxia, and fibrosis were markedly increased in CS-MPC2-/- hearts. Mitochondria isolated from 16 week old failing CS-MPC2-/- hearts exhibited normal respiration on glutamate/malate, succinate, palmitoylcarnitine, and 3-hydroxybutyrate/malate, indicating preservation of mitochondrial energetics with anaplerotic malate, or substrates to produce acetyl-CoA independent of pyruvate. Expression of genes encoding fat and ketone oxidation enzymes was not down-regulated in failing CS-MPC2-/- hearts as is typically observed in heart failure, suggesting these hearts may rely on fat or ketone body oxidation for ATP production. However, targeted metabolomics of hearts from 6 week old CS-MPC2-/- chow-fed mice suggested TCA cycle dysfunction due to decreased acetyl-CoA levels that are insufficient to condense with oxaloacetate, causing an accumulation of oxaloacetate/aspartate, malate, and fumarate. To determine whether increasing the availability of usable substrates (fatty acids and ketones) would rescue the cardiac dysfunction, CS-MPC2-/- mice were fed a high fat, low carbohydrate (ketogenic) diet. Ketogenic diet strikingly decreased hypertrophy and improved functional parameters in 10 week old mice. In conclusion, loss of mitochondrial pyruvate utilization leads to altered cardiac substrate metabolism and inability to maintain TCA cycle flux, resulting in dilated cardiomyopathy that can be corrected by administration of a ketogenic diet.

Acetyl-CoA provision and the acetyl group deficit at the onset of contraction in ischemic canine skeletal muscle

2005 ◽  
Vol 288 (2) ◽  
pp. E327-E334 ◽  
Author(s):  
Paul A. Roberts ◽  
Susan J. G. Loxham ◽  
Simon M. Poucher ◽  
Dumitru Constantin-Teodosiu ◽  
Paul L. Greenhaff
Keyword(s):  
Skeletal Muscle ◽  
Energy Production ◽  
Pyruvate Dehydrogenase Complex ◽  
Tca Cycle ◽  
Treated Group ◽  
Acetyl Coa ◽  
Tension Development ◽  
The Tca Cycle ◽  
Work Transition ◽  
Acetyl Group

We examined the effects of increasing acetylcarnitine and acetyl-CoA availability at rest, independent of pyruvate dehydrogenase complex (PDC) activation, on energy production and tension development during the rest-to-work transition in canine skeletal muscle. We aimed to elucidate whether the lag in PDC-derived acetyl-CoA delivery toward the TCA cycle at the onset of exercise can be overcome by increasing acetyl group availability independently of PDC activation or is intimately dependent on PDC-derived acetyl-CoA. Gracilis muscle pretreated with saline or sodium acetate (360 mg/kg body mass) (both n = 6) was sampled repeatedly during 5 min of ischemic contraction. Acetate increased acetylcarnitine and acetyl-CoA availability (both P < 0.01) above control at rest and throughout contraction ( P < 0.05), independently of differences in resting PDC activation between treatments. Acetate reduced oxygen-independent ATP resynthesis ∼40% ( P < 0.05) during the first minute of contraction. No difference in oxygen-independent ATP resynthesis existed between treatments from 1 to 3 min of contraction; however, energy production via this route increased ∼25% ( P < 0.05) above control in the acetate-treated group during the final 2 min of contraction. Tension development was ∼20% greater after 5-min contraction after acetate treatment than in control ( P < 0.05). In conclusion, at the immediate onset of contraction, when PDC was largely inactive, increasing cellular acetyl group availability overcame inertia in mitochondrial ATP regeneration. However, after the first minute, when PDC was near maximally activated in both groups, it appears that PDC-derived acetyl-CoA, rather than increased cellular acetyl group availability per se, dictated mitochondrial ATP resynthesis.

scholarly journals The Metabolic Fates of Pyruvate in Normal and Neoplastic Cells

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 762
Author(s):  
Edward V. Prochownik ◽  
Huabo Wang
Keyword(s):  
Metabolic Pathways ◽  
Redox State ◽  
Pyruvate Dehydrogenase Complex ◽  
Tca Cycle ◽  
Vascular Supply ◽  
Extrinsic Factors ◽  
The Tca Cycle ◽  
Initial Substrate ◽  
Numerous Cell ◽  
Bio Synthesis

Pyruvate occupies a central metabolic node by virtue of its position at the crossroads of glycolysis and the tricarboxylic acid (TCA) cycle and its production and fate being governed by numerous cell-intrinsic and extrinsic factors. The former includes the cell’s type, redox state, ATP content, metabolic requirements and the activities of other metabolic pathways. The latter include the extracellular oxygen concentration, pH and nutrient levels, which are in turn governed by the vascular supply. Within this context, we discuss the six pathways that influence pyruvate content and utilization: 1. The lactate dehydrogenase pathway that either converts excess pyruvate to lactate or that regenerates pyruvate from lactate for use as a fuel or biosynthetic substrate; 2. The alanine pathway that generates alanine and other amino acids; 3. The pyruvate dehydrogenase complex pathway that provides acetyl-CoA, the TCA cycle’s initial substrate; 4. The pyruvate carboxylase reaction that anaplerotically supplies oxaloacetate; 5. The malic enzyme pathway that also links glycolysis and the TCA cycle and generates NADPH to support lipid bio-synthesis; and 6. The acetate bio-synthetic pathway that converts pyruvate directly to acetate. The review discusses the mechanisms controlling these pathways, how they cross-talk and how they cooperate and are regulated to maximize growth and achieve metabolic and energetic harmony.

scholarly journals Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex

1998 ◽  
Vol 329 (1) ◽  
pp. 191-196 ◽  
Author(s):  
Melissa M. BOWKER-KINLEY ◽  
I. Wilhelmina DAVIS ◽  
Pengfei WU ◽  
A. Robert HARRIS ◽  
M. Kirill POPOV
Keyword(s):  
Tissue Distribution ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Synthetic Analogue ◽  
Complex Activity ◽  
Acetyl Coa ◽  
Tissue Specific ◽  
Specific Regulation ◽  
Dehydrogenase Complex

Tissue distribution and kinetic parameters for the four isoenzymes of pyruvate dehydrogenase kinase (PDK1, PDK2, PDK3 and PDK4) identified thus far in mammals were analysed. It appeared that expression of these isoenzymes occurs in a tissue-specific manner. The mRNA for isoenzyme PDK1 was found almost exclusively in rat heart. The mRNA for PDK3 was most abundantly expressed in rat testis. The message for PDK2 was present in all tissues tested but the level was low in spleen and lung. The mRNA for PDK4 was predominantly expressed in skeletal muscle and heart. The specific activities of the isoenzymes varied 25-fold, from 50 nmol/min per mg for PDK2 to 1250 nmol/min per mg for PDK3. Apparent Ki values of the isoenzymes for the synthetic analogue of pyruvate, dichloroacetate, varied 40-fold, from 0.2 mM for PDK2 to 8 mM for PDK3. The isoenzymes were also different with respect to their ability to respond to NADH and NADH plus acetyl-CoA. NADH alone stimulated the activities of PDK1 and PDK2 by 20 and 30% respectively. NADH plus acetyl-CoA activated these isoenzymes nearly 200 and 300%. Under comparable conditions, isoenzyme PDK3 was almost completely unresponsive to NADH, and NADH plus acetyl-CoA caused inhibition rather than activation. Isoenzyme PDK4 was activated almost 2-fold by NADH, but NADH plus acetyl-CoA did not activate above the level seen with NADH alone. These results provide the first evidence that the unique tissue distribution and kinetic characteristics of the isoenzymes of PDK are among the major factors responsible for tissue-specific regulation of the pyruvate dehydrogenase complex activity.

Gluconeogenesis from labeled carbon: estimating isotope dilution

1986 ◽  
Vol 250 (3) ◽  
pp. E296-E305 ◽  
Author(s):  
J. K. Kelleher
Keyword(s):  
Steady State ◽  
Isotope Dilution ◽  
Experimental Tests ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Complex Model ◽  
Acetyl Coa ◽  
The Tca Cycle ◽  
Carbon Compounds ◽  
Mathematical Techniques

To estimate the rate of gluconeogenesis from steady-state incorporation of labeled 3-carbon precursors into glucose, isotope dilution must be considered so that the rate of labeling of glucose can be quantitatively converted to the rate of gluconeogenesis. An expression for the value of this isotope dilution can be derived using mathematical techniques and a model of the tricarboxylic acid (TCA) cycle. The present investigation employs a more complex model than that used in previous studies. This model includes the following pathways that may affect the correction for isotope dilution: 1) flux of 3-carbon precursor to the oxaloacetate pool via acetyl-CoA and the TCA cycle; 2) flux of 4- or 5-carbon compounds into the TCA cycle; 3) reversible flux between oxaloacetate (OAA) and pyruvate and between OAA and fumarate; 4) incomplete equilibrium between OAA pools; and 5) isotope dilution of 3-carbon tracers between the experimentally measured pool and the precursor for the TCA-cycle OAA pool. Experimental tests are outlined which investigators can use to determine whether these pathways are significant in a specific steady-state system. The study indicated that flux through these five pathways can significantly affect the correction for isotope dilution. To correct for the effects of these pathways an alternative method for calculating isotope dilution is proposed using citrate to relate the specific activities of acetyl-CoA and OAA.

scholarly journals Association of the malate dehydrogenase-citrate synthase metabolon is modulated by intermediates of the Krebs tricarboxylic acid cycle

2021 ◽  
Author(s):  
Joy Omini ◽  
Izabela Wojciechowska ◽  
Aleksandra Skirycz ◽  
Hideaki Moriyama ◽  
Toshihiro Obata
Keyword(s):  
Malate Dehydrogenase ◽  
Metabolic Flux ◽  
Citrate Synthase ◽  
Tricarboxylic Acid Cycle ◽  
Feedback Regulation ◽  
Dynamic Structure ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Enzyme Complex ◽  
Acetyl Coa

Mitochondrial malate dehydrogenase (MDH)-citrate synthase (CS) multi-enzyme complex is a part of the Krebs tricarboxylic acid (TCA) cycle 'metabolon' which is enzyme machinery catalyzing sequential reactions without diffusion of reaction intermediates into a bulk matrix. This complex is assumed to be a dynamic structure involved in the regulation of the cycle by enhancing metabolic flux. Microscale Thermophoresis analysis of the porcine heart MDH-CS complex revealed that substrates of the MDH and CS reactions, NAD+ and acetyl-CoA, enhance complex association while products of the reactions, NADH and citrate, weaken the affinity of the complex. Oxaloacetate enhanced the interaction only when it was presented together with acetyl-CoA. Structural modeling using published CS structures suggested that the binding of these substrates can stabilize the closed format of CS which favors the MDH-CS association. Two other TCA cycle intermediates, ATP, and low pH also enhanced the association of the complex. These results suggest that dynamic formation of the MDH-CS multi-enzyme complex is modulated by metabolic factors responding to respiratory metabolism, and it may function in the feedback regulation of the cycle and adjacent metabolic pathways.

scholarly journals E. coli hypoxia-inducible factor ArcA mediates lifespan extension in a lipoic acid synthase mutant by suppressing acetyl-CoA synthetase

2010 ◽  
Vol 391 (10) ◽  
Author(s):  
Stavros Gonidakis ◽  
Steven E. Finkel ◽  
Valter D. Longo
Keyword(s):  
Heat Shock ◽  
Carbon Source ◽  
Pyruvate Dehydrogenase Complex ◽  
Hypoxia Inducible Factor ◽  
Acetyl Coa ◽  
E Coli ◽  
Extended Lifespan ◽  
Shock Resistance ◽  
Survival Extension

Abstract We have previously shown that both the hypoxia-inducible transcription factor ArcA and the PoxB/Acs bypass of the pyruvate dehydrogenase complex contribute to extended lifespan in Escherichia coli. In agreement with studies in higher eukaryotes, we also demonstrated that long-lived E. coli mutants, including LipA-deficient cells, are stress resistant. Here, we show that ArcA contributes to the enhanced lifespan and heat shock resistance of the lipA mutant by suppressing expression of the acetyl-CoA synthetase (acs) gene. The deletion of acs reversed the reduced lifespan of the lipA arcA mutant and promoted the accumulation of extracellular acetate, indicating that inhibition of carbon source uptake contributes to survival extension. However, Acs also sensitized cells lacking ArcA to heat shock, in the absence of extracellular acetate. These results provide evidence for the role of Acs in regulating lifespan and/or stress resistance by both carbon source uptake-dependent and -independent mechanisms.

scholarly journals Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1731 ◽  
Author(s):  
Carina Neitzel ◽  
Philipp Demuth ◽  
Simon Wittmann ◽  
Jörg Fahrer
Keyword(s):  
Colorectal Cancer ◽  
Energy Metabolism ◽  
Pyruvate Dehydrogenase ◽  
Pyruvate Dehydrogenase Complex ◽  
Tca Cycle ◽  
Dietary Factors ◽  
Pyruvate Dehydrogenase Kinase ◽  
Driver Mutations ◽  
The Tca Cycle

Colorectal cancer (CRC) is among the most frequent cancer entities worldwide. Multiple factors are causally associated with CRC development, such as genetic and epigenetic alterations, inflammatory bowel disease, lifestyle and dietary factors. During malignant transformation, the cellular energy metabolism is reprogrammed in order to promote cancer cell growth and proliferation. In this review, we first describe the main alterations of the energy metabolism found in CRC, revealing the critical impact of oncogenic signaling and driver mutations in key metabolic enzymes. Then, the central role of mitochondria and the tricarboxylic acid (TCA) cycle in this process is highlighted, also considering the metabolic crosstalk between tumor and stromal cells in the tumor microenvironment. The identified cancer-specific metabolic transformations provided new therapeutic targets for the development of small molecule inhibitors. Promising agents are in clinical trials and are directed against enzymes of the TCA cycle, including isocitrate dehydrogenase, pyruvate dehydrogenase kinase, pyruvate dehydrogenase complex (PDC) and α-ketoglutarate dehydrogenase (KGDH). Finally, we focus on the α-lipoic acid derivative CPI-613, an inhibitor of both PDC and KGDH, and delineate its anti-tumor effects for targeted therapy.

scholarly journals Genome-Scale Metabolic Network Reconstruction and In Silico Analysis of Hexanoic acid Producing Megasphaera elsdenii

2020 ◽  
Vol 8 (4) ◽  
pp. 539 ◽  
Author(s):  
Na-Rae Lee ◽  
Choong Hwan Lee ◽  
Dong-Yup Lee ◽  
Jin-Byung Park
Keyword(s):  
Cell Growth ◽  
Acid Production ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Flux Ratio ◽  
Value Added ◽  
Tca Cycle ◽  
Hexanoic Acid ◽  
Acetyl Coa ◽  
Megasphaera Elsdenii ◽  
Genome Scale

Hexanoic acid and its derivatives have been recently recognized as value-added materials and can be synthesized by several microbes. Of them, Megasphaera elsdenii has been considered as an interesting hexanoic acid producer because of its capability to utilize a variety of carbons sources. However, the cellular metabolism and physiology of M. elsdenii still remain uncharacterized. Therefore, in order to better understand hexanoic acid synthetic metabolism in M. elsdenii, we newly reconstructed its genome-scale metabolic model, iME375, which accounts for 375 genes, 521 reactions, and 443 metabolites. A constraint-based analysis was then employed to evaluate cell growth under various conditions. Subsequently, a flux ratio analysis was conducted to understand the mechanism of bifurcated hexanoic acid synthetic pathways, including the typical fatty acid synthetic pathway via acetyl-CoA and the TCA cycle in a counterclockwise direction through succinate. The resultant metabolic states showed that the highest hexanoic acid production could be achieved when the balanced fractional contribution via acetyl-CoA and succinate in reductive TCA cycle was formed in various cell growth rates. The highest hexanoic acid production was maintained in the most perturbed flux ratio, as phosphoenolpyruvate carboxykinase (pck) enables the bifurcated pathway to form consistent fluxes. Finally, organic acid consuming simulations suggested that succinate can increase both biomass formation and hexanoic acid production.

scholarly journals Dihydrolipoamide Dehydrogenase Mutation Alters the NADH Sensitivity of Pyruvate Dehydrogenase Complex of Escherichia coli K-12

2008 ◽  
Vol 190 (11) ◽  
pp. 3851-3858 ◽  
Author(s):  
Youngnyun Kim ◽  
L. O. Ingram ◽  
K. T. Shanmugam
Keyword(s):  
Escherichia Coli ◽  
Pyruvate Dehydrogenase ◽  
Double Mutant ◽  
Pyruvate Dehydrogenase Complex ◽  
Anaerobic Growth ◽  
Lower Sensitivity ◽  
Dihydrolipoamide Dehydrogenase ◽  
Fermentation Products ◽  
E Coli ◽  
K 12

ABSTRACT Under anaerobic growth conditions, an active pyruvate dehydrogenase (PDH) is expected to create a redox imbalance in wild-type Escherichia coli due to increased production of NADH (>2 NADH molecules/glucose molecule) that could lead to growth inhibition. However, the additional NADH produced by PDH can be used for conversion of acetyl coenzyme A into reduced fermentation products, like alcohols, during metabolic engineering of the bacterium. E. coli mutants that produced ethanol as the main fermentation product were recently isolated as derivatives of an ldhA pflB double mutant. In all six mutants tested, the mutation was in the lpd gene encoding dihydrolipoamide dehydrogenase (LPD), a component of PDH. Three of the LPD mutants carried an H322Y mutation (lpd102), while the other mutants carried an E354K mutation (lpd101). Genetic and physiological analysis revealed that the mutation in either allele supported anaerobic growth and homoethanol fermentation in an ldhA pflB double mutant. Enzyme kinetic studies revealed that the LPD(E354K) enzyme was significantly less sensitive to NADH inhibition than the native LPD. This reduced NADH sensitivity of the mutated LPD was translated into lower sensitivity of the appropriate PDH complex to NADH inhibition. The mutated forms of the PDH had a 10-fold-higher Ki for NADH than the native PDH. The lower sensitivity of PDH to NADH inhibition apparently increased PDH activity in anaerobic E. coli cultures and created the new ethanologenic fermentation pathway in this bacterium. Analogous mutations in the LPD of other bacteria may also significantly influence the growth and physiology of the organisms in a similar fashion.

Sign in / Sign up

Export Citation Format

Share Document