title: Intracellular Energetic Units regulate metabolism in cardiac cells.
abstract: This review describes developments in historical perspective as well as recent results of investigations of cellular mechanisms of regulation of energy fluxes and mitochondrial respiration by cardiac work - the metabolic aspect of the Frank-Starling law of the heart. A Systems Biology solution to this problem needs the integration of physiological and biochemical mechanisms that take into account intracellular interactions of mitochondria with other cellular systems, in particular with cytoskeleton components. Recent data show that different tubulin isotypes are involved in the regular arrangement exhibited by mitochondria and ATP-consuming systems into Intracellular Energetic Units (ICEUs). Beta II tubulin association with the mitochondrial outer membrane, when co-expressed with mitochondrial creatine kinase (MtCK) specifically limits the permeability of voltage-dependent anion channel for adenine nucleotides. In the MtCK reaction this interaction changes the regulatory kinetics of respiration through a decrease in the affinity for adenine nucleotides and an increase in the affinity for creatine. Metabolic Control Analysis of the coupled MtCK-ATP Synthasome in permeabilized cardiomyocytes showed a significant increase in flux control by steps involved in ADP recycling. Mathematical modeling of compartmentalized energy transfer represented by ICEUs shows that cyclic changes in local ADP, Pi, phosphocreatine and creatine concentrations during contraction cycle represent effective metabolic feedback signals when amplified in the coupled non-equilibrium MtCK-ATP Synthasome reactions in mitochondria. This mechanism explains the regulation of respiration on beat to beat basis during workload changes under conditions of metabolic stability. This article is part of a Special Issue entitled "Local Signaling in Myocytes."
authors.affiliation: Laboratory of Bioenergetics, National Institute of Chemical Physics and Biophysics, Tallinn, Estonia. Valdur.Saks@ujf-grenoble.fr
authors.forename: Valdur
authors.initials: V
authors.lastname: Saks
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Kuznetsov
authors.forename: Marcela
authors.initials: M
authors.lastname: Gonzalez-Granillo
authors.forename: Kersti
authors.initials: K
authors.lastname: Tepp
authors.forename: Natalja
authors.initials: N
authors.lastname: Timohhina
authors.forename: Minna
authors.initials: M
authors.lastname: Karu-Varikmaa
authors.forename: Tuuli
authors.initials: T
authors.lastname: Kaambre
authors.forename: Pierre
authors.initials: P
authors.lastname: Dos Santos
authors.forename: François
authors.initials: F
authors.lastname: Boucher
authors.forename: Rita
authors.initials: R
authors.lastname: Guzun
mesh_terms: D000818:Animals; D002463:Cell Membrane Permeability; D003599:Cytoskeleton / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology*; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008929:Mitochondria, Heart / Q000378:metabolism; D008962:Models, Theoretical; D032383:Myocytes, Cardiac / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism
chemical_list: D014404:Tubulin