Integrated and Organized Cellular Energetic Systems

Abstract

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 the living cells can only function as open systems in which internal order (low entropy state) is maintained by increasing the entropy in surrounding medium (Schrödinger's principle of negentropy). For this mechanism, exchange of mass is needed that yields metabolism as the sum of catabolism and anabolism. The free‐energy changes taking place during metabolic reactions obey 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 caused by close and tight protein–protein interactions, compartmentation of enzymes, as well as both macrocompartmentation and microcompartmentation of substrates and metabolites in cells should be considered. For integration of these system components, effective methods of communication, including compartmentalized energy transfer systems, are required. These systems are represented in muscle cells by phosphotransfer networks, mostly by creatine kinase and adenylate kinase systems. System analysis of these networks shows their central role both in energy transfer and metabolic feedback regulation of mitochondrial function, in regulation of ion fluxes and cellular energetics during increased workload by synchronizing the cellular electrical and mechanical activities with energy supply and substrate oxidation.

Adenylate Kinase and AMP Signaling Networks: Metabolic Monitoring, Signal Communication and Body Energy Sensing

“…Phosphotransfer reactions have emerged as principle signal generators and coupling relays between cellular metabolism and metabolic sensors [ 5 , 29 , 30 , 44 , 218 ]. In particular, adenylate kinase as generator and modulator of metabolic signals is a critical player integrating complex AMPK and KATP channel signaling cascades in regulation of hormone secretion, blood flow, stress response, muscle and brain functional activity [ 1 , 4 , 5 , 30 , 33 , 34 , 37 , 47 ].…”

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

“…In spite of intensive experimental and theoretical research, the mechanisms of intracellular regulation of energy fluxes and mitochondrial respiration in muscles in vivo , including heart and skeletal muscle, are still highly debated and not clear [ 8 , 11 , 23 – 32 ]. Controversies in this important area of physiological research is even increasing because of principal differences in points of views of authors to the nature of intracellular medium and to the state of the phosphotransfer reactions.…”

“…These results, however, validate the third theory of regulation of energy metabolism in vivo which meets the requirements listed above and takes into account the cellular organization and multiple intracellular interactions. This is the theory of phosphotransfer networks [ 11 , 12 , 17 , 18 , 22 ]. We have shown in our previous reviews that this theory, based on experimental results from many laboratories, adequately explains the metabolic aspects of Frank-Starling’s law of the heart [ 8 ].…”

“…However many studies have proved, that the high efficiency of creatine control on the rate of oxidative phosphorylation is due to the functional coupling of mitochondrial creatine kinase (MtCK) with adenine nucleotide translocase (ANT) [ 6 , 10 , 17 , 18 , 98 , 99 , 102 , 119 , 120 ]. In functionally coupled systems the CK always functions in the non-equilibrium state catalyzing only one direction depending on the partners: in mitochondria ANT drives MtCK reaction in direction of PCr synthesis; in myofibrils and at cellular membranes MgATPases drive MMCK reaction in muscle cells (BBCK reaction in brain cells) in direction of local ATP regeneration at the expense of PCr [ 4 , 10 , 11 , 121 ]. In all cases the functional coupling includes direct metabolic channeling of adenine nucleotides or their microcompartmentation within multienzyme complexes.…”

“…This approach has been successfully used in cardiac physiology [ 1 ] and is at the center of international research programs [ 7 ]. It is also a useful tool for studies of cellular mechanisms of metabolic regulation [ 4 , 6 , 8 – 11 ]. In our two previous reviews in the International Journal of Molecular Sciences [ 4 , 6 ] we have shown that one of these important system level properties is metabolic compartmentation, resulting from structural interactions between cellular structures and local restrictions of diffusion within organized intracellular structures.…”