Effect of Ca2+ on cardiac mitochondrial energy production is modulated by Na+ and H+ dynamics

2007 ◽  
Vol 292 (6) ◽  
pp. C2004-C2020 ◽  
Author(s):  
My-Hanh T. Nguyen ◽  
S. J. Dudycha ◽  
M. Saleet Jafri
Keyword(s):  
Energy Metabolism ◽  
Energy Production ◽  
Hydrogen Exchange ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Calcium Dynamics ◽  
Mitochondrial Energy Metabolism ◽  
Acid Cycle ◽  
Atp Production ◽  
Sodium Hydrogen

The energy production of mitochondria in heart increases during exercise. Several works have suggested that calcium acts at multiple control points to activate net ATP production in what is termed “parallel activation”. To study this, a computational model of mitochondrial energy metabolism in the heart has been developed that integrates the Dudycha-Jafri model for the tricarboxylic acid cycle with the Magnus-Keizer model for mitochondrial energy metabolism and calcium dynamics. The model improves upon the previous formulation by including an updated formulation for calcium dynamics, and new descriptions of sodium, hydrogen, phosphate, and ATP balance. To this end, it incorporates new formulations for the calcium uniporter, sodium-calcium exchange, sodium-hydrogen exchange, the F1F0-ATPase, and potassium-hydrogen exchange. The model simulates a wide range of experimental data, including steady-state and simulated pacing protocols. The model suggests that calcium is a potent activator of net ATP production and that as pacing increases energy production due to calcium goes up almost linearly. Furthermore, it suggests that during an extramitochondrial calcium transient, calcium entry and extrusion cause a transient depolarization that serve to increase NADH production by the tricarboxylic acid cycle and NADH consumption by the respiration driven proton pumps. The model suggests that activation of the F1F0-ATPase by calcium is essential to increase ATP production. In mitochondria very close to the release sites, the depolarization is more severe causing a temporary loss of ATP production. However, due to the short duration of the depolarization the net ATP production is also increased.

scholarly journals Tricarboxylic acid cycle and proton gradient in Pandoravirus massiliensis: Is it still a virus?

2020 ◽  
Author(s):  
Sarah Aherfi ◽  
Djamal Brahim Belhaouari ◽  
Lucile Pinault ◽  
Jean-Pierre Baudoin ◽  
Philippe Decloquement ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Isocitrate Dehydrogenase ◽  
Energy Production ◽  
Citrate Synthase ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Proton Gradient ◽  
Giant Virus ◽  
Acid Cycle ◽  
Key Enzyme

ABSTRACTSince the discovery of Acanthamoeba polyphaga Mimivirus, the first giant virus of amoeba, the historical hallmarks defining a virus have been challenged. Giant virion sizes can reach up to 2.3 µm, making them visible by optical microscopy. They have large genomes of up to 2.5 Mb that encode proteins involved in the translation apparatus. Herein, we investigated possible energy production in Pandoravirus massiliensis, the largest of our giant virus collection. MitoTracker and TMRM mitochondrial membrane markers allowed for the detection of a membrane potential in virions that could be abolished by the use of the depolarizing agent CCCP. An attempt to identify enzymes involved in energy metabolism revealed that 8 predicted proteins of P. massiliensis exhibited low sequence identities with defined proteins involved in the universal tricarboxylic acid cycle (acetyl Co-A synthase; citrate synthase; aconitase; isocitrate dehydrogenase; α-ketoglutarate decarboxylase; succinate dehydrogenase; fumarase). All 8 viral predicted ORFs were transcribed together during viral replication, mainly at the end of the replication cycle. Two of these proteins were detected in mature viral particles by proteomics. The product of the ORF132, a predicted protein of P. massiliensis, cloned and expressed in Escherichia coli, provided a functional isocitrate dehydrogenase, a key enzyme of the tricarboxylic acid cycle, which converts isocitrate to α-ketoglutarate. We observed that membrane potential was enhanced by low concentrations of Acetyl-CoA, a regulator of the tricarboxylic acid cycle. Our findings show for the first time that energy production can occur in viruses, namely, pandoraviruses, and the involved enzymes are related to tricarboxylic acid cycle enzymes. The presence of a proton gradient in P. massiliensis coupled with the observation of genes of the tricarboxylic acid cycle make this virus a form a life for which it is legitimate to question ‘what is a virus?’.

scholarly journals Succinate Dehydrogenase Loss in Familial Paraganglioma: Biochemistry, Genetics, and Epigenetics

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Yeng F. Her ◽  
L. James Maher
Keyword(s):  
Succinate Dehydrogenase ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Acid Cycle ◽  
Atp Production ◽  
Metabolic Defects ◽  
Biochemical Genetic

It is counterintuitive that metabolic defects reducing ATP production can cause, rather than protect from, cancer. Yet this is precisely the case for familial paraganglioma, a form of neuroendocrine malignancy caused by loss of succinate dehydrogenase in the tricarboxylic acid cycle. Here we review biochemical, genetic, and epigenetic considerations in succinate dehydrogenase loss and present leading models and mysteries associated with this fascinating and important tumor.

scholarly journals Role of Energy Metabolism in the Progression of Neuroblastoma

2021 ◽  
Vol 22 (21) ◽  
pp. 11421
Author(s):  
Monika Sakowicz-Burkiewicz ◽  
Tadeusz Pawełczyk ◽  
Marlena Zyśk
Keyword(s):  
Energy Metabolism ◽  
Extracellular Vesicles ◽  
Tricarboxylic Acid Cycle ◽  
Significant Risk ◽  
Metabolic Enzymes ◽  
Genetic Alterations ◽  
Tricarboxylic Acid ◽  
Primary Role ◽  
Acid Cycle ◽  
Risk Of Death

Neuroblastoma is a common childhood cancer possessing a significant risk of death. This solid tumor manifests variable clinical behaviors ranging from spontaneous regression to widespread metastatic disease. The lack of promising treatments calls for new research approaches which can enhance the understanding of the molecular background of neuroblastoma. The high proliferation of malignant neuroblastoma cells requires efficient energy metabolism. Thus, we focus our attention on energy pathways and their role in neuroblastoma tumorigenesis. Recent studies suggest that neuroblastoma-driven extracellular vesicles stimulate tumorigenesis inside the recipient cells. Furthermore, proteomic studies have demonstrated extracellular vesicles (EVs) to cargo metabolic enzymes needed to build up a fully operative energy metabolism network. The majority of EV-derived enzymes comes from glycolysis, while other metabolic enzymes have a fatty acid β-oxidation and tricarboxylic acid cycle origin. The previously mentioned glycolysis has been shown to play a primary role in neuroblastoma energy metabolism. Therefore, another way to modify the energy metabolism in neuroblastoma is linked with genetic alterations resulting in the decreased activity of some tricarboxylic acid cycle enzymes and enhanced glycolysis. This metabolic shift enables malignant cells to cope with increasing metabolic stress, nutrition breakdown and an upregulated proliferation ratio.

scholarly journals Bioenergetic Analysis of Single Pancreatic β-Cells Indicates an Impaired Metabolic Signature in Type 2 Diabetic Subjects

Endocrinology ◽  
2015 ◽  
Vol 156 (10) ◽  
pp. 3496-3503 ◽  
Author(s):  
Akos A. Gerencser
Keyword(s):  
Insulin Secretion ◽  
Membrane Potential ◽  
Energy Metabolism ◽  
Tricarboxylic Acid Cycle ◽  
Atp Synthesis ◽  
Tricarboxylic Acid ◽  
Β Cells ◽  
Acid Cycle ◽  
Type 2 Diabetic

Impaired activation of mitochondrial energy metabolism by glucose has been demonstrated in type 2 diabetic β-cells. The cause of this dysfunction is unknown. The aim of this study was to identify segments of energy metabolism with normal or with altered function in human type 2 diabetes mellitus. The mitochondrial membrane potential (ΔψM), and its response to glucose, is the main driver of mitochondrial ATP synthesis and is hence a central mediator of glucose-induced insulin secretion, but its quantitative determination in β-cells from human donors has not been attempted, due to limitations in assay technology. Here, novel fluorescence microscopic assays are exploited to quantify ΔψM and its response to glucose and other secretagogues in β-cells of dispersed pancreatic islet cells from 4 normal and 3 type 2 diabetic organ donors. Mitochondrial volume densities and the magnitude of ΔψM in low glucose were not consistently altered in diabetic β-cells. However, ΔψM was consistently less responsive to elevation of glucose concentration, whereas the decreased response was not observed with metabolizable secretagogue mixtures that feed directly into the tricarboxylic acid cycle. Single-cell analysis of the heterogeneous responses to metabolizable secretagogues indicated no dysfunction in relaying ΔψM hyperpolarization to plasma membrane potential depolarization in diabetic β-cells. ΔψM of diabetic β-cells was distinctly responsive to acute inhibition of ATP synthesis during glucose stimulation. It is concluded that the mechanistic deficit in glucose-induced insulin secretion and mitochondrial hyperpolarization of diabetic human β-cells is located upstream of the tricarboxylic acid cycle and manifests in dampening the control of ΔψM by glucose metabolism.

scholarly journals Integrative Analysis of Multiomics Data Identified Acetylation as Key Variable of Excessive Energy Metabolism in Hyperthyroidism-induced Osteoporosis Rats

2021 ◽  
Author(s):  
Jiaxin Bei ◽  
Shaoping Zhu ◽  
Minqun Du ◽  
Zheng Tang ◽  
Cailing Chen ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Bone Loss ◽  
Previous Experiment ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Creb Binding Protein ◽  
Acid Cycle ◽  
Metabolism Enzymes ◽  
Close Relationship

Abstract Background The results from the previous experiment have demonstrated that there were occurrence of bone loss and excess metabolism in Hyperthyroidism-induced rats. Thus, there was speculation that there may be an underlying relationship between metabolism and bone loss. In addition, there were past studies showing acetylation influencing metabolism in tissues and diseases. The hypothesis from this case study stated that excessive metabolism was induced upon acetylated vital metabolism enzymes. Results In the case study, a HYP-induced osteoporosis rats model was used and the glucose metabolite was tested through the acetylation of proteins by the mass spectrometer. The results showed that pivotal enzymes of Glycolysis-Tricarboxylic acid cycle-Oxidative phosphorylation were acetyled along with upregulated metabolites. All the acetyly-lysine sites of related enzymes were listed in this article.Our results showed that bone loss in HYP rats accompanied by upregulation of CREB-binding protein (Crebbp, CBP). Furthermore, our result indicated that CBP has a close relationship with enhancement of LDHa that promote glucose metabolism. Conclusions Acetylation is the key variable of energy metabolism in hyperthyroid osteoporosis rats, therein, we showed a representation relationship between CBP and LDHa.

Intermediary carbohydrate metabolism in protoscoleces ofEchinococcus granulosus(horse and sheep strains) andE. multilocularis

Parasitology ◽  
1982 ◽  
Vol 84 (2) ◽  
pp. 351-366 ◽  
Author(s):  
D. P. McManus ◽  
J. D. Smyth
Keyword(s):  
Steady State ◽  
Carbohydrate Metabolism ◽  
Pyruvate Kinase ◽  
Energy Production ◽  
Alternative Energy ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Acid Cycle ◽  
State Content

SUMMARYWith few exceptions, the specific activities of the glycolytic enzymes and the steady-state content of glycolytic and associated intermediates in protoscoleces of the horse (E.g.H) and sheep (E.g.S) strains ofEchinococcus granulosusand the closely relatedE. multilocularis(E.m.) are very similar. Phosphorylase, hexokinase, phosphofructokinase and pyruvate kinase catalyse non-equilibrium reactions and the patterns of activity for pyruvate kinase, phosphoenolpyruvate carboxykinase and malic enzyme are similar in the three organisms. The levels of tricarboxylic acid cycle intermediates inE.g.H., E.g.S. andE.m. are of the same order as those reported in tissues with an active cycle. Each has a complete sequence of cycle enzymes but there are substantial differences between the three parasites with regard to the activity of individual enzymes, The activities of NAD and NADP-linked isocitrate dehydrogenases are significantly lower inE.g.H. than inE.g.S. and particularly inE.m. which suggests that the tricarboxylic acid cycle may play a more important role in carbohydrate metabolism and energy production in the latter parasites. Nevertheless, the three organisms utilize fermentative pathways for alternative energy production, fix carbon dioxide via phosphoenolpyruvate carboxykinase and have a partial reversed tricarboxylic acid cycle. It is speculated thatin vivomore carbon will be channelled towards oxaloacetate than pyruvate at the phosphoenolpyruvate branch point. The steady state content of ATP and the ATP/AMP ratios are low in the three organisms, suggesting a low rate of ATP utilization in each.

Energy metabolism in the developing larval stages of Ancylostoma tubaeforme and Haemonchus contortus: glycolytic and tncarboxylic acid cycle enzymes

Parasitology ◽  
1985 ◽  
Vol 90 (1) ◽  
pp. 169-177 ◽  
Author(s):  
C. O. E. Onwuliri
Keyword(s):  
Energy Metabolism ◽  
Pyruvate Kinase ◽  
Metabolic Pathway ◽  
Haemonchus Contortus ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Aconitate Hydratase ◽  
Acid Cycle ◽  
Infective Larvae

The activities of glycolytic and related enzymes and the tricarboxylic acid cycle enzymes were measured in freshly isolated 1st- (Li), 2nd- (L2) and 3rd-stage (L3) larvae of both Ancylostoma tubaeforme and Haemonchus contortus. All enzymes of the glycolytic pathway were present in all developmental stages of both strongylid nematodes although higher levels of activities were obtained in the pre-infective 1st- and 2nd-stage larvae than in the infective 3rd stage. However, the pre-infective larvae contained lower levels of pyruvate kinase (PK) than the infective larvae. Consequently, the pyruvate kinase to phosphoenolpyruvate carboxykinase (PEPCK) ratios were 0·23 and 0·26 for the L1s and L2s for A. tubaeforme and 0·36 and 0·21 for those of H. contortus respectively. High levels of activity of glucose-6-phosphate dehydrogenase obtained in the bacteriophagous pre-infective larvae were consistent with high rates of morphogenesis and substrate synthesis characteristic of the pre-infective stages. All the tricarboxylic acid cycle enzymes were present in the infective larvae of both nematodes while in the pre-infective Li and L2 stages, the enzymes at the beginning of the cycle, namely aconitate hydratase and NAD-linked isocitrate dehydrogenase, were not detected. A scheme was proposed for the energy metabolism of these developing larvae. In this scheme, the pre-infective larvae were shown to operate an anaerobic metabolic pathway involving the carboxylation of phosphoenolpyruvate (PEP) by phosphoenolpyru vate carboxykinase (PEPCK) to form oxaloacetate (OAA), whereas in the infective larvae the metabolic pathway favouring the direct dephosphorylation of PEP, as in vertebrate tissues, was followed.

Allosteric, transcriptional and post-translational control of mitochondrial energy metabolism

2019 ◽  
Vol 476 (12) ◽  
pp. 1695-1712 ◽  
Author(s):  
Qutuba G. Karwi ◽  
Alice R. Jörg ◽  
Gary D. Lopaschuk
Keyword(s):  
Amino Acids ◽  
Fatty Acids ◽  
Energy Metabolism ◽  
Energy Production ◽  
Energy Regulation ◽  
Energy Substrates ◽  
Mitochondrial Energy Metabolism ◽  
Atp Production ◽  
Cardiac Energy Metabolism ◽  
Cardiac Energy

AbstractThe heart is the organ with highest energy turnover rate (per unit weight) in our body. The heart relies on its flexible and powerful catabolic capacity to continuously generate large amounts of ATP utilizing many energy substrates including fatty acids, carbohydrates (glucose and lactate), ketones and amino acids. The normal health mainly utilizes fatty acids (40–60%) and glucose (20–40%) for ATP production while ketones and amino acids have a minor contribution (10–15% and 1–2%, respectively). Mitochondrial oxidative phosphorylation is the major contributor to cardiac energy production (95%) while cytosolic glycolysis has a marginal contribution (5%). The heart can dramatically and swiftly switch between energy-producing pathways and/or alter the share from each of the energy substrates based on cardiac workload, availability of each energy substrate and neuronal and hormonal activity. The heart is equipped with a highly sophisticated and powerful mitochondrial machinery which synchronizes cardiac energy production from different substrates and orchestrates the rate of ATP production to accommodate its contractility demands. This review discusses mitochondrial cardiac energy metabolism and how it is regulated. This includes a discussion on the allosteric control of cardiac energy metabolism by short-chain coenzyme A esters, including malonyl CoA and its effect on cardiac metabolic preference. We also discuss the transcriptional level of energy regulation and its role in the maturation of cardiac metabolism after birth and cardiac adaptability for different metabolic conditions and energy demands. The role post-translational modifications, namely phosphorylation, acetylation, malonylation, succinylation and glutarylation, play in regulating mitochondrial energy metabolism is also discussed.

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