Abstract
The mitochondrial electron transport chain transforms energy satisfying cellular demand and generates reactive oxygen species (ROS) that act as metabolic signals or destructive factors. Therefore, knowledge of the possible modes and bifurcations of electron transport that affect ROS signaling provides insight into the interrelationship of mitochondrial respiration with cellular metabolism. Here, a bifurcation analysis of a sequence of the electron transport chain models of increasing complexity was used to analyze the contribution of individual components to the modes of respiratory chain behavior. Our algorithm constructed models as large systems of ordinary differential equations describing the time evolution of the distribution of redox states of the respiratory complexes. The most complete model of the respiratory chain and linked metabolic reactions predicted that condensed mitochondria produce more ROS at low succinate concentration and less ROS at high succinate levels than swelled mitochondria. This prediction was validated by measuring ROS production under various swelling conditions. A numerical bifurcation analysis revealed qualitatively different types of multistationary behavior and sustained oscillations in the parameter space near a region that was previously found to describe the behavior of isolated mitochondria. The oscillations in transmembrane potential and ROS generation, observed in living cells were reproduced in the model that includes interaction of respiratory complexes with the reactions of TCA cycle. Whereas multistationarity is an internal characteristic of the respiratory chain, the functional link of respiration with central metabolism creates oscillations, which can be understood as a means of auto-regulation of cell metabolism.
Highlights
IntroductionThe electron transport chain links the central carbohydrate energy metabolism with ATP synthesis (see Fig. 1)
The electron transport chain links the central carbohydrate energy metabolism with ATP synthesis. It transforms the free energy released by the oxidation of NADH and succinate into a form of transmembrane electrochemical potential (DY), which is used for ATP synthesis [1]
We have reported elsewhere that the Q-cycle mechanism of electron transport in respiratory complex III exhibits bistability [10], i.e. two stable steady states may exist under the same microenvironmental conditions (corresponding to two stable steady state solutions of a system of ordinary differential equations (ODEs) at the same parameter values)
Summary
The electron transport chain links the central carbohydrate energy metabolism with ATP synthesis (see Fig. 1). Reactive oxygen species (ROS) are byproducts of electron transport [2] They play the roles of both metabolic signals and destructive agents [3,4,5,6,7,8]. Many interesting dynamical properties of the electron transport and linked ROS production are determined by the intrinsic properties of the electron transport chain, such as the structural and functional links between carriers (topology of the system) and values of parameters, e.g. reaction rate constants. Such intrinsic properties can determine physiologically important modes of respiratory chain operation and how transitions between these modes occur.
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