Programming and regulation of metabolic homeostasis

Abstract

Wilson DF. Programming and regulation of metabolic homeostasis. Am J Physiol Endocrinol Metab 308: E506 -E517, 2015. First published January 20, 2015 doi:10.1152 doi:10. /ajpendo.00544.2014dence is presented that the rate and equilibrium constants in mitochondrial oxidative phosphorylation set and maintain metabolic homeostasis in eukaryotic cells. These internal constants determine the energy state ([ATP]/[ADP][P i]), and the energy state maintains homeostasis through a bidirectional sensory/signaling control network that reaches every aspect of cellular metabolism. The energy state is maintained with high precision (to ϳ1 part in 10 10 ), and the control system can respond to transient changes in energy demand (ATP utilization) of more than 100 times the resting rate. Epigenetic and environmental factors are able to "fine-tune" the programmed set point over a narrow range to meet the special needs associated with cell differentiation and chronic changes in metabolic requirements. The result is robust across-platform control of metabolism, which is essential to cellular differentiation and the evolution of complex organisms. A model of oxidative phosphorylation is presented, for which the steady-state rate expression has been derived and computer programmed. The behavior of oxidative phosphorylation predicted by the model is shown to fit the experimental data available for isolated mitochondria as well as for cells and tissues. This includes measurements from several different mammalian tissues as well as from insect flight muscle and plants. The respiratory chain and oxidative phosphorylation is remarkably similar for all higher plants and animals. This is consistent with the efficient synthesis of ATP and precise control of metabolic homeostasis provided by oxidative phosphorylation being a key to cellular differentiation and the evolution of structures with specialized function. oxygen; oxidative phosphorylation; energy metabolism; oxygen pressure; metabolic control; mitochondria; respiratory control THOUSANDS OF DIFFERENT METABOLITES AND ENZYMES must work together if a cell is to survive and grow. In addition to the complex ensemble of reactions within individual cells, in organisms with extensive cellular differentiation, metabolism must support the robust cell-to-cell communication needed for different cell types to contribute to integrated function of the organism. DNA contains the blueprint needed to construct the parts of the ensemble, but in living cells metabolism has to constantly and rapidly respond to changes in the environment. These metabolic responses often occur in seconds, far faster than information encoded in the DNA can be read and implemented. Real-time control of metabolism requires a metabolic unit with intrinsic properties that drive it toward a particular metabolic condition (set point) and is connected to the rest of metabolism through a network of regulatory pathways that maintain that set point (65). To control the ensemble, this central control unit needs to have sensory input fr...

Regulation of metabolism: the rest-to-work transition in skeletal muscle

“…The fit retained the basic chemical and thermodynamic properties of the mechanism of oxygen reduction by cytochrome c oxidase, and the values for the rate and equilibrium constants are consistent with independent measurements of those parameters, where measurements are available. The rate expression was fitted to the behavior of cytochrome c oxidase in suspensions of rat liver mitochondria, but it is also consistent with the behavior of other types of mitochondria (49,50) as well as for paracoccus denitrificans (8).…”

“…The rate expression for cytochrome c oxidase can then be extended to overall oxidative phosphorylation, with the first two sites of oxidative phosphorylation added (without the pH dependence of ATP hydrolysis): NADH ϩ 2 P i ϩ 2 ADP ϩ2 cyt c 3ϩ ϭ NAD ϩ ϩ H ϩ ϩ 2 ATP ϩ 2 cyt c 2ϩ (1). The reactions of the first two sites are readily reversible and near equilibrium (8 -11, 16, 20, 39, 49, 50, 54), and the result is the steady-state rate expression for all of oxidative phosphorylation (49,50,55). This rate expression has been shown to predict metabolic energy states very similar to those observed experimentally in several types of cells and tissues (49,50).…”

“…The concentrations of ATP, ADP, and P i and of the many other small metabolites that are coupled to their concentrations (notably AMP) transmit, in real time and to all parts of the cell, the information used to maintain metabolic homeostasis. The intrinsic program of oxidative phosphorylation sets the energy state near 10 5 M Ϫ1 (49,50,55), about 5 ϫ 10 10 greater than the equilibrium value of 2 ϫ 10 Ϫ6 M Ϫ1 (17,34), and maintains that value (average over time) within narrow limits.…”

“…Integrated metabolism, however, counters these metabolic displacements and on a time average basis operates near a particular set point (metabolic homeostasis), and this set point is very similar for all eukaryotic cells. Real-time control of metabolism and maintaining metabolic homeostasis requires a metabolic unit that is programmed with that set point and is connected to the rest of metabolism through a network of regulatory pathways through which the set point is maintained (49,50,55). In eukaryotic cells, mitochondrial oxidative phosphorylation is programmed with a set point for the energy state To better understand how oxidative phosphorylation is able to set and maintain metabolic homeostasis, it is necessary to understand the mechanism(s) by which oxidative phosphorylation is regulated and to construct a model that quantifies the dependence on each of the regulatory parameters.…”

“…The reactions of the first two sites are readily reversible and near equilibrium (8 -11, 16, 20, 39, 49, 50, 54), and the result is the steady-state rate expression for all of oxidative phosphorylation (49,50,55). This rate expression has been shown to predict metabolic energy states very similar to those observed experimentally in several types of cells and tissues (49,50). In addition, the predicted rates of respiration agree with those observed experimentally for tissues in which the data are available.…”