title: Structure-function relationships in feedback regulation of energy fluxes in vivo in health and disease: mitochondrial interactosome.
abstract: The aim of this review is to analyze the results of experimental research of mechanisms of regulation of mitochondrial respiration in cardiac and skeletal muscle cells in vivo obtained by using the permeabilized cell technique. Such an analysis in the framework of Molecular Systems Bioenergetics shows that the mechanisms of regulation of energy fluxes depend on the structural organization of the cells and interaction of mitochondria with cytoskeletal elements. Two types of cells of cardiac phenotype with very different structures were analyzed: adult cardiomyocytes and continuously dividing cancerous HL-1 cells. In cardiomyocytes mitochondria are arranged very regularly, and show rapid configuration changes of inner membrane but no fusion or fission, diffusion of ADP and ATP is restricted mostly at the level of mitochondrial outer membrane due to an interaction of heterodimeric tubulin with voltage dependent anion channel, VDAC. VDAC with associated tubulin forms a supercomplex, Mitochondrial Interactosome, with mitochondrial creatine kinase, MtCK, which is structurally and functionally coupled to ATP synthasome. Due to selectively limited permeability of VDAC for adenine nucleotides, mitochondrial respiration rate depends almost linearly upon the changes of cytoplasmic ADP concentration in their physiological range. Functional coupling of MtCK with ATP synthasome amplifies this signal by recycling adenine nucleotides in mitochondria coupled to effective phosphocreatine synthesis. In cancerous HL-1 cells this complex is significantly modified: tubulin is replaced by hexokinase and MtCK is lacking, resulting in direct utilization of mitochondrial ATP for glycolytic lactate production and in this way contributing in the mechanism of the Warburg effect. Systemic analysis of changes in the integrated system of energy metabolism is also helpful for better understanding of pathogenesis of many other diseases.
authors.affiliation: Laboratory of Fundamental and Applied Bioenergetics, INSERM U884, Joseph Fourier University, Grenoble, France. Valdur.Saks@ujf-grenoble.fr
authors.forename: Valdur
authors.initials: V
authors.lastname: Saks
authors.forename: Rita
authors.initials: R
authors.lastname: Guzun
authors.forename: Natalja
authors.initials: N
authors.lastname: Timohhina
authors.forename: Kersti
authors.initials: K
authors.lastname: Tepp
authors.forename: Minna
authors.initials: M
authors.lastname: Varikmaa
authors.forename: Claire
authors.initials: C
authors.lastname: Monge
authors.forename: Nathalie
authors.initials: N
authors.lastname: Beraud
authors.forename: Tuuli
authors.initials: T
authors.lastname: Kaambre
authors.forename: Andrey
authors.initials: A
authors.lastname: Kuznetsov
authors.forename: Lumme
authors.initials: L
authors.lastname: Kadaja
authors.forename: Margus
authors.initials: M
authors.lastname: Eimre
authors.forename: Enn
authors.initials: E
authors.lastname: Seppet
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D019069:Cell Respiration; D052281:Creatine Kinase, Mitochondrial Form / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004734:Energy Metabolism; D025461:Feedback, Physiological; D006801:Humans; D007700:Kinetics; D008928:Mitochondria / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000378:metabolism; D008954:Models, Biological; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D010725:Phosphocreatine / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism
chemical_list: D000227:Adenine Nucleotides; D014404:Tubulin; D050994:Voltage-Dependent Anion Channels; D010725:Phosphocreatine; D052281:Creatine Kinase, Mitochondrial Form