A Biophysical Model of the Mitochondrial Respiratory System and Oxidative Phosphorylation

Abstract

A computational model for the mitochondrial respiratory chain that appropriately balances mass, charge, and free energy transduction is introduced and analyzed based on a previously published set of data measured on isolated cardiac mitochondria. The basic components included in the model are the reactions at complexes I, III, and IV of the electron transport system, ATP synthesis at F ₁F ₀ ATPase, substrate transporters including adenine nucleotide translocase and the phosphate–hydrogen co-transporter, and cation fluxes across the inner membrane including fluxes through the K ⁺/H ⁺ antiporter and passive H ⁺ and K ⁺ permeation. Estimation of 16 adjustable parameter values is based on fitting model simulations to nine independent data curves. The identified model is further validated by comparison to additional datasets measured from mitochondria isolated from rat heart and liver and observed at low oxygen concentration. To obtain reasonable fits to the available data, it is necessary to incorporate inorganic-phosphate-dependent activation of the dehydrogenase activity and the electron transport system. Specifically, it is shown that a model incorporating phosphate-dependent activation of complex III is able to reasonably reproduce the observed data. The resulting validated and verified model provides a foundation for building larger and more complex systems models and investigating complex physiological and pathophysiological interactions in cardiac energetics.

Abstract

Synopsis

Cells are able to perform tasks that consume energy (such as producing mechanical force in muscle contraction) by using chemical energy delivered in the form of a chemical compound called adenosine triphosphate, or ATP. Two Nobel Prizes were awarded (in 1978 to Peter D. Mitchell and in 1997 to Paul D. Boyer and John E. Walker) for the determination of how ATP is synthesized from the components adenosine diphosphate (ADP) and inorganic phosphate in a subcellular body called the mitochondrion. The operating theory, called the chemiosmotic theory, describes how a driving force called the proton motive force, which arises from the sum of contributions from the electrical potential and the hydrogen ion concentration difference across the mitochondrial inner membrane, is developed by reactions catalyzed by certain enzymes and consumed in generating ATP. Yet, to date, no computer model has successfully described the development and consumption of both the chemical and electrical components of the proton motive force in a thermodynamically balanced simulation. Beard introduces such a model, which is extensively validated based on previously published sets of data obtained on isolated mitochondria. The model is used to test hypotheses about how intracellular respiration is regulated; this model could serve as a foundation for investigating the control of mitochondrial function and for developing larger integrated simulations of cellular metabolism.