A mathematical model of the mitochondrial NADH shuttles and anaplerosis in the pancreatic β-cell

Westermark, Pål O.; Kotaleski, Jeanette Hellgren; Björklund, Anneli; Grill, Valdemar; Lansner, Anders

doi:10.1152/ajpendo.00589.2005

Cited by 16 publications

(28 citation statements)

References 108 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Overall, these experimental studies support the hypothesis that activation NADH/NAD ϩ shuttling occurs in exercising skeletal muscle. This conclusion is also supported by other in silico studies (99). 6, C-F) and cytosolic redox state (Fig.…”

Section: Activation Of Transport Activity For Reducing Equivalentssupporting

confidence: 88%

Role of NADH/NAD⁺ transport activity and glycogen store on skeletal muscle energy metabolism during exercise: in silico studies

Li¹,

Dash²,

Kim³

et al. 2009

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

Skeletal muscle can maintain ATP concentration constant during the transition from rest to exercise, whereas metabolic reaction rates may increase substantially. Among the key regulatory factors of skeletal muscle energy metabolism during exercise, the dynamics of cytosolic and mitochondrial NADH and NAD+ have not been characterized. To quantify these regulatory factors, we have developed a physiologically based computational model of skeletal muscle energy metabolism. This model integrates transport and reaction fluxes in distinct capillary, cytosolic, and mitochondrial domains and investigates the roles of mitochondrial NADH/NAD+ transport (shuttling) activity and muscle glycogen concentration (stores) during moderate intensity exercise (60% maximal O2 consumption). The underlying hypothesis is that the cytosolic redox state (NADH/NAD+) is much more sensitive to a metabolic disturbance in contracting skeletal muscle than the mitochondrial redox state. This hypothesis was tested by simulating the dynamic metabolic responses of skeletal muscle to exercise while altering the transport rate of reducing equivalents (NADH and NAD+) between cytosol and mitochondria and muscle glycogen stores. Simulations with optimal parameter estimates showed good agreement with the available experimental data from muscle biopsies in human subjects. Compared with these simulations, a 20% increase (or approximately 20% decrease) in mitochondrial NADH/NAD+ shuttling activity led to an approximately 70% decrease (or approximately 3-fold increase) in cytosolic redox state and an approximately 35% decrease (or approximately 25% increase) in muscle lactate level. Doubling (or halving) muscle glycogen concentration resulted in an approximately 50% increase (or approximately 35% decrease) in cytosolic redox state and an approximately 30% increase (or approximately 25% decrease) in muscle lactate concentration. In both cases, changes in mitochondrial redox state were minimal. In conclusion, the model simulations of exercise response are consistent with the hypothesis that mitochondrial NADH/NAD+ shuttling activity and muscle glycogen stores affect primarily the cytosolic redox state. Furthermore, muscle lactate production is regulated primarily by the cytosolic redox state.

show abstract

Section: Activation Of Transport Activity For Reducing Equivalentssupporting

confidence: 88%

Role of NADH/NAD⁺ transport activity and glycogen store on skeletal muscle energy metabolism during exercise: in silico studies

Li¹,

Dash²,

Kim³

et al. 2009

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

show abstract

“…This model could reproduce oscillations in glycolytic metabolites and predict a dose-response curve for ATP for increasing concentrations of D-glucose. Other pancreatic β-cell-specific models have been developed for specific parts of the pathway, such as NADH shuttles [35] and the initial section of glycolysis [35],[36]. This glycolytic model underlines the dependency of the occurrence of oscillations as a function of glucokinase, aldolase, phosphofructokinase and GAPD activities.…”

Section: Introductionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…This is accomplished in ␤-cells partly via mitochondrial malate/aspartate and glycerolphosphate shuttles (12), and via PMET, as we suggest here and by an earlier study which demonstrated that NADH could be reoxidized despite blockage of mitochondrial shuttles in pancreatic ␤-cells. The "presence of an unknown cytosolic factor re-oxidizing cytosolic NADH," was suggested (12,45) based on the observation that, despite blockage of mitochondrial shuttles, glycolytic flux remained unchanged (12).…”

mentioning

confidence: 99%

Plasma membrane electron transport in pancreatic β-cells is mediated in part by NQO1

Gray

Eisen

Cline

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Plasma membrane electron transport (PMET), a cytosolic/plasma membrane analog of mitochondrial electron transport, is a ubiquitous system of cytosolic and plasma membrane oxidoreductases that oxidizes cytosolic NADH and NADPH and passes electrons to extracellular targets. While PMET has been shown to play an important role in a variety of cell types, no studies exist to evaluate its function in insulin-secreting cells. Here we demonstrate the presence of robust PMET activity in primary islets and clonal β-cells, as assessed by the reduction of the plasma membrane-impermeable dyes WST-1 and ferricyanide. Because the degree of metabolic function of β-cells (reflected by the level of insulin output) increases in a glucose-dependent manner between 4 and 10 mM glucose, PMET was evaluated under these conditions. PMET activity was present at 4 mM glucose and was further stimulated at 10 mM glucose. PMET activity at 10 mM glucose was inhibited by the application of the flavoprotein inhibitor diphenylene iodonium and various antioxidants. Overexpression of cytosolic NAD(P)H-quinone oxidoreductase (NQO1) increased PMET activity in the presence of 10 mM glucose while inhibition of NQO1 by its inhibitor dicoumarol abolished this activity. Mitochondrial inhibitors rotenone, antimycin A, and potassium cyanide elevated PMET activity. Regardless of glucose levels, PMET activity was greatly enhanced by the application of aminooxyacetate, an inhibitor of the malate-aspartate shuttle. We propose a model for the role of PMET as a regulator of glycolytic flux and an important component of the metabolic machinery in β-cells.

show abstract

A mathematical model of the mitochondrial NADH shuttles and anaplerosis in the pancreatic β-cell

Cited by 16 publications

References 108 publications

Role of NADH/NAD⁺ transport activity and glycogen store on skeletal muscle energy metabolism during exercise: in silico studies

Role of NADH/NAD⁺ transport activity and glycogen store on skeletal muscle energy metabolism during exercise: in silico studies

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

Plasma membrane electron transport in pancreatic β-cells is mediated in part by NQO1

Contact Info

Product

Resources

About

A mathematical model of the mitochondrial NADH shuttles and anaplerosis in the pancreatic β-cell

Cited by 16 publications

References 108 publications

Role of NADH/NAD+ transport activity and glycogen store on skeletal muscle energy metabolism during exercise: in silico studies

Role of NADH/NAD+ transport activity and glycogen store on skeletal muscle energy metabolism during exercise: in silico studies

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

Plasma membrane electron transport in pancreatic β-cells is mediated in part by NQO1

Contact Info

Product

Resources

About

Role of NADH/NAD⁺ transport activity and glycogen store on skeletal muscle energy metabolism during exercise: in silico studies

Role of NADH/NAD⁺ transport activity and glycogen store on skeletal muscle energy metabolism during exercise: in silico studies