Quantitative Analysis of Integrated Energy Metabolism of Muscle Cells: Experimental and Theoretical Studies

Abstract

Quantitative analysis, in combination with detailed experimental studies, is the basis of Molecular System Bioenergetics (MSB) which takes into account specific interactions between cellular components, formation of metabolic dissipative structures and resulting system level properties such as metabolic compartmentation. There are several experimental and theoretical approaches used: studies in vivo kinetics of mitochondrial respiration regulation; Metabolic Control Analysis of integrated energy metabolism; mathematical modeling. Cardiac cells are characterized by high level of structural organization with very regular arrangement of mitochondria and their interaction with cytoskeleton. Heterodimeric tubulin containing beta II isoform is connected to mitochondrial outer membrane, specifically controls VDAC permeability and is coexpressed with mitochondrial creatine kinase. These proteins form with ATP Synthasome a supercomplex Mitochondrial Interactosome (MI) in which the kinetics of regulation of respiration by MtCK is significantly altered in comparison with mitochondria in vitro affinity for extramitochondrial ATP is strongly decreased due to limited permeability of VDAC but for creatine increased. Metabolic Control Analysis of reactions in MI showed that flux control coefficients are significantly increased for reactions of ADP/ATP recycling coupled with phosphocreatine production by MtCK. These experimental data are the basis of the mathematical model of compartmentalized energy transfer and show that about 90 % of energy is carried out of mitochondria by phosphocreatine due to specific structure of MI. This model explains well the metabolic aspects of Frank -Starling law of the heart. In cancerous HL −1 cells of cardiac phenotype MtCK and beta II tubulin are not expressed. Mathematical models based on the theory of homogenous intracellular medium and CK equilibrium do not explain adequately the experimental observations. In future development, application of single-molecule enzyme kinetics and theory of nonlinear biochemical reaction networks is necessary.