Mitochondrial energetic metabolism: A simplified model of TCA cycle with ATP production

Nazaret, Christine; Heiske, Margit; Thurley, Kevin; Mazat, Jean‐Pierre

doi:10.1016/j.jtbi.2008.09.037

Cited by 69 publications

(60 citation statements)

References 48 publications

(34 reference statements)

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“…As initial values, we used the parameters reported in [33],[46]. Note that the fitting has been carried out on only 9 of the 10 observations since the model is intended to simulate production following input with D-glucose or L-alanine and not the basal production/consumption of the cell.…”

Section: Resultsmentioning

confidence: 99%

Mathematical Model of Metabolism and Electrophysiology of Amino Acid and Glucose Stimulated Insulin Secretion: In Vitro Validation Using a β-Cell Line

2013

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We integrated biological experimental data with mathematical modelling to gain insights into the role played by L-alanine in amino acid-stimulated insulin secretion (AASIS) and in D-glucose-stimulated insulin secretion (GSIS), details important to the understanding of complex β-cell metabolic coupling relationships. We present an ordinary differential equations (ODEs) based simplified kinetic model of core metabolic processes leading to ATP production (glycolysis, TCA cycle, L-alanine-specific reactions, respiratory chain, ATPase and proton leak) and Ca2+ handling (essential channels and pumps in the plasma membrane) in pancreatic β-cells and relate these to insulin secretion. Experimental work was performed using a clonal rat insulin-secreting cell line (BRIN-BD11) to measure the consumption or production of a range of important biochemical parameters (D-glucose, L-alanine, ATP, insulin secretion) and Ca2+ levels. These measurements were then used to validate the theoretical model and fine-tune the parameters. Mathematical modelling was used to predict L-lactate and L-glutamate concentrations following D-glucose and/or L-alanine challenge and Ca2+ levels upon stimulation with a non metabolizable L-alanine analogue. Experimental data and mathematical model simulations combined suggest that L-alanine produces a potent insulinotropic effect via both a stimulatory impact on β-cell metabolism and as a direct result of the membrane depolarization due to Ca2+ influx triggered by L-alanine/Na+ co-transport. Our simulations indicate that both high intracellular ATP and Ca2+ concentrations are required in order to develop full insulin secretory responses. The model confirmed that K+ ATP channel independent mechanisms of stimulation of intracellular Ca2+ levels, via generation of mitochondrial coupling messengers, are essential for promotion of the full and sustained insulin secretion response in β-cells.

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Section: Resultsmentioning

confidence: 99%

Mathematical Model of Metabolism and Electrophysiology of Amino Acid and Glucose Stimulated Insulin Secretion: In Vitro Validation Using a β-Cell Line

2013

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“…This most likely indicates a lower glycolytic rate in treated males. Glycolysis and TCA cycle are main pathways for ATP production in insect and play an important role in embryo development (Chen 1966, Werner et al 1999, Fernie et al 2004, Nazaret et al 2009). Based on the aforementioned information, it was speculated that radiation-damaged genes regulated glycolysis and TCA cycle.…”

Section: Discussionmentioning

confidence: 99%

Effect of Irradiation on Mating Ability in the Male Sweetpotato Weevil (Coleoptera: Curculionidae)

Kumano

Haraguchi

Kohama

2008

Journal of Economic Entomology

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“…The confirmation of the presence of AOX in animals indicates that some animals probably possess a branched ETC. This also has direct implications for theoretical models of mitochondrial bioenergetics, which assume a linear ETC (Nazaret et al, 2008). Future models and experiments should be designed with this in mind.…”

Section: Future Directionsmentioning

confidence: 99%

Alternative oxidase in animals: unique characteristics and taxonomic distribution

McDonald

Vanlerberghe

Staples

2009

Journal of Experimental Biology

118

109

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SUMMARYAlternative oxidase (AOX), a ubiquinol oxidase, introduces a branch point into the respiratory electron transport chain, bypassing complexes III and IV and resulting in cyanide-resistant respiration. Previously, AOX was thought to be limited to plants and some fungi and protists but recent work has demonstrated the presence of AOX in most kingdoms of life, including animals. In the present study we identified AOX in 28 animal species representing nine phyla. This expands the known taxonomic distribution of AOX in animals by 10 species and two phyla. Using bioinformatics we found AOX gene sequences in members of the animal phyla Porifera, Placozoa, Cnidaria, Mollusca, Annelida, Nematoda, Echinodermata, Hemichordata and Chordata. Using reversetranscriptase polymerase chain reaction (RT-PCR) with degenerate primers designed to recognize conserved regions of animal AOX, we demonstrated that AOX genes are transcribed in several animals from different phyla. An analysis of full-length AOX sequences revealed an amino acid motif in the C-terminal region of the protein that is unique to animal AOXs. Animal AOX also lacks an N-terminal cysteine residue that is known to be important for AOX enzyme regulation in plants. We conclude that the presence of AOX is the ancestral state in animals and hypothesize that its absence in some lineages, including vertebrates, is due to gene loss events. Supplementary material available online at

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Mitochondrial energetic metabolism: A simplified model of TCA cycle with ATP production

Cited by 69 publications

References 48 publications

Mathematical Model of Metabolism and Electrophysiology of Amino Acid and Glucose Stimulated Insulin Secretion: In Vitro Validation Using a β-Cell Line

Mathematical Model of Metabolism and Electrophysiology of Amino Acid and Glucose Stimulated Insulin Secretion: In Vitro Validation Using a β-Cell Line

Effect of Irradiation on Mating Ability in the Male Sweetpotato Weevil (Coleoptera: Curculionidae)

Alternative oxidase in animals: unique characteristics and taxonomic distribution

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