Mathematical Modeling of Mitochondrial Adenine Nucleotide Translocase

Metelkin, Eugeniy; Goryanin, Igor; Demin, Oleg

doi:10.1529/biophysj.105.061986

Cited by 41 publications

(61 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Metelkin et al 9 have developed a bi-bi random kinetic model of ANT, which takes into account these electrochemical driving forces and their impact on kinetic binding and rate constants. For ANT flux simulations, we used the data of Glancy et al 25 obtained from isolated skeletal muscle mitochondria respiring at five experimentally maintained levels of ATP free energy (see Table 5).…”

Section: Methodsmentioning

confidence: 99%

Adenine Nucleotide Translocase Is Acetylated in Vivo in Human Muscle: Modeling Predicts a Decreased ADP Affinity and Altered Control of Oxidative Phosphorylation

et al. 2014

View full text Add to dashboard Cite

Proteomics techniques have revealed that lysine acetylation is abundant in mitochondrial proteins. This study was undertaken (1) to determine the relationship between mitochondrial protein acetylation and insulin sensitivity in human skeletal muscle, identifying key acetylated proteins, and (2) to use molecular modeling techniques to understand the functional consequences of acetylation of adenine nucleotide translocase 1 (ANT1), which we found to be abundantly acetylated. Eight lean and eight obese nondiabetic subjects had euglycemic clamps and muscle biopsies for isolation of mitochondrial proteins and proteomics analysis. A number of acetylated mitochondrial proteins were identified in muscle biopsies. Overall, acetylation of mitochondrial proteins was correlated with insulin action (r = 0.60; P < 0.05). Of the acetylated proteins, ANT1, which catalyzes ADP–ATP exchange across the inner mitochondrial membrane, was acetylated at lysines 10, 23, and 92. The extent of acetylation of lysine 23 decreased following exercise, depending on insulin sensitivity. Molecular dynamics modeling and ensemble docking simulations predicted the ADP binding site of ANT1 to be a pocket of positively charged residues, including lysine 23. Calculated ADP–ANT1 binding affinities were physiologically relevant and predicted substantial reductions in affinity upon acetylation of lysine 23. Insertion of these derived binding affinities as parameters into a complete mathematical description of ANT1 kinetics predicted marked reductions in adenine nucleotide flux resulting from acetylation of lysine 23. Therefore, acetylation of ANT1 could have dramatic physiological effects on ADP–ATP exchange. Dysregulation of acetylation of mitochondrial proteins such as ANT1 therefore could be related to changes in mitochondrial function that are associated with insulin resistance.

show abstract

Section: Methodsmentioning

confidence: 99%

Adenine Nucleotide Translocase Is Acetylated in Vivo in Human Muscle: Modeling Predicts a Decreased ADP Affinity and Altered Control of Oxidative Phosphorylation

et al. 2014

View full text Add to dashboard Cite

show abstract

“…The sigmoid kinetics of ADP/ATP exchange by mitochondrial ANT in vivo was proposed to explain this phenomenon [80]. This conclusion is in contradiction with all information known about the kinetics of ADT/ATP exchange by ANT [81–83], for which the mathematical model was developed by Metelkin and Demin on the basis of structural and functional data [84] that quantitatively describes the gated pore mechanism of ANT functioning. In no cases sigmoid kinetics was seen, and it is not seen when respiration is studied as the function of ADP concentration both in isolated mitochondria and in permeabilized fibers, where mitochondria are in the intracellular milieu and their behavior in situ can be studied experimentally (see below).…”

Section: Controversial State Of the Art Of Muscle Bioenergeticsmentioning

confidence: 99%

Application of the Principles of Systems Biology and Wiener's Cybernetics for Analysis of Regulation of Energy Fluxes in Muscle Cells in Vivo

Guzun

Saks

2010

IJMS

View full text Add to dashboard Cite

The mechanisms of regulation of respiration and energy fluxes in the cells are analyzed based on the concepts of systems biology, non-equilibrium steady state kinetics and applications of Wiener’s cybernetic principles of feedback regulation. Under physiological conditions cardiac function is governed by the Frank-Starling law and the main metabolic characteristic of cardiac muscle cells is metabolic homeostasis, when both workload and respiration rate can be changed manifold at constant intracellular level of phosphocreatine and ATP in the cells. This is not observed in skeletal muscles. Controversies in theoretical explanations of these observations are analyzed. Experimental studies of permeabilized fibers from human skeletal muscle vastus lateralis and adult rat cardiomyocytes showed that the respiration rate is always an apparent hyperbolic but not a sigmoid function of ADP concentration. It is our conclusion that realistic explanations of regulation of energy fluxes in muscle cells require systemic approaches including application of the feedback theory of Wiener’s cybernetics in combination with detailed experimental research. Such an analysis reveals the importance of limited permeability of mitochondrial outer membrane for ADP due to interactions of mitochondria with cytoskeleton resulting in quasi-linear dependence of respiration rate on amplitude of cyclic changes in cytoplasmic ADP concentrations. The system of compartmentalized creatine kinase (CK) isoenzymes functionally coupled to ANT and ATPases, and mitochondrial-cytoskeletal interactions separate energy fluxes (mass and energy transfer) from signalling (information transfer) within dissipative metabolic structures – intracellular energetic units (ICEU). Due to the non-equilibrium state of CK reactions, intracellular ATP utilization and mitochondrial ATP regeneration are interconnected by the PCr flux from mitochondria. The feedback regulation of respiration occurring via cyclic fluctuations of cytosolic ADP, Pi and Cr/PCr ensures metabolic stability necessary for normal function of cardiac cells.

show abstract

“…The translocation of both ATP and ADP in the Mg 2þ -free forms is related to the conformational changes in pore-forming monomers [125]. This conformational change (''gated pore'') mechanism leads in its simplest version to the ping-pong transport mechanism [126][127][128][129][130][131][132][133][134][135][136][137][138][139], but the kinetics of ATP-ADP exchange conforms to the sequential mechanism with simultaneous binding of nucleotides on both sides [130]. The structural data and the kinetics of ATP-ADP exchange by ANT fit well together by assuming that the dimers with alternatively activated monomers function in a coordinated manner in the tetramers, where the export of ATP from mitochondria by one monomer in a dimer occurs simultaneously with import of ADP by another monomer in another dimer [132,133], or both monomers in the dimmer may be active and transport nucleotides simultaneously in opposite directions [125,131].…”

Section: Functional Coupling Of Mitochondrial Creatine Kinase and Adementioning

confidence: 99%

Integrated and Organized Cellular Energetic Systems: Theories of Cell Energetics, Compartmentation, and Metabolic Channeling

Saks

Monge

Anmann

et al. 2007

Molecular System Bioenergetics

View full text Add to dashboard Cite

Bioenergetics as a part of biophysical chemistry and biophysics is a quantitative science that is based on several fundamental theories. The definition of energy itself is given by the first law of thermodynamics, and application of the second law of thermodynamics shows that living cells can function as open systems only where the internal order (low entropy state) is maintained due to increasing the entropy in the surrounding medium (Schrödinger's principle of negentropy). For this, the exchange of mass is needed, which gives rise to metabolism as the sum of catabolism and anabolism, and the free energy changes during catabolic reactions supply energy for all cellular work -osmotic, mechanical, and biochemical. The free energy changes during metabolic reactions obey the rules of chemical thermodynamics, which deals with Gibbs free energy of chemical reactions and with electrochemical potentials. For application of these theories to the integrated systems in vivo, complex cellular organization should be accounted for: macromolecular crowding; metabolic channeling and functional coupling mechanisms due to close and tight protein-protein interactions; compartmentation of the enzymes due to their attachment to the subcellular membranes or connection to the cytoskeleton; and both macro-and microcompartmentation of substrates and metabolites in the cells. Because of this, almost all processes important for cell life are localized within small areas of the cell, and for their integration effective systems of communication, including compartmentalized energy transfer systems, are required. These are represented in muscle cells by the phosphotransfer networks, mostly by the creatine kinase and adenylate kinase systems, whose alterations under ischemic conditions contribute significantly to acute ischemic contractile failure of the heart. 59 Molecular System Bioenergetics: Energy for Life. Edited by Valdur Saks

show abstract

Mathematical Modeling of Mitochondrial Adenine Nucleotide Translocase

Cited by 41 publications

References 18 publications

Adenine Nucleotide Translocase Is Acetylated in Vivo in Human Muscle: Modeling Predicts a Decreased ADP Affinity and Altered Control of Oxidative Phosphorylation

Adenine Nucleotide Translocase Is Acetylated in Vivo in Human Muscle: Modeling Predicts a Decreased ADP Affinity and Altered Control of Oxidative Phosphorylation

Application of the Principles of Systems Biology and Wiener's Cybernetics for Analysis of Regulation of Energy Fluxes in Muscle Cells in Vivo

Integrated and Organized Cellular Energetic Systems: Theories of Cell Energetics, Compartmentation, and Metabolic Channeling

Contact Info

Product

Resources

About