CONTROL OF ELECTRON FLUX THROUGH THE RESPIRATORY CHAIN IN MITOCHONDRIA AND CELLS

Abstract

Summary: To answer the question ‘What controls the rate of respiration?’ requires a clear definition of control and an explicit description of the limits of the system to be considered. In this review we use a neutral definition of control in which A controls B if changes in A cause changes in B. A useful system to define when discussing the control of respiration consists of the electron transport chain, the H+‐ATPase, the adenine nucleotide carrier, the intramitochondrial adenine nucleotide and phosphate pools, δ p and the proton leak across the mitochondrial inner membrane. Controls operating within this system are designated internal controls and many of them are fairly well characterized. Several models have been advanced to describe the rates of these internal processes in isolated mitochondria, including control of respiration rate by cytochrome oxidase with all other steps near to equilibrium, control by the adenine nucleotide carrier or control by the extent of displacement of individual reactions from equilibrium. More recently, analysis using control theory has shown that in the resting state (state 4) most control over flux is exerted by the leak of protons through the inner membrane, whereas in more active, phosphorylating states (up to state 3) control is distributed between a number of steps, including the proton leak, the adenine nucleotide carrier and cytochrome oxidase. This approach seems a very useful framework within which to pose further questions. This system may be treated as a ‘black box’ interacting with its environment (the rest of the mitochondrion and the experimental cuvette or living cell) through the redox states of NAD, Q and O 2 and through the phosphorylation state of the extramitochondrial adenine nucleotides. Very few external effectors cross the system boundary; the only well‐characterized ones are long‐chain fatty acyl‐CoA, which inhibits the adenine nucleotide carrier, and fatty acids, which activate a specific uncoupling protein found only in the inner membrane of mitochondria from brown adipose tissue. At this level respiration rate is determined only by the internal properties of the ‘black box’, by the redox states of NAD, Q and O 2, and by the phosphorylation status of the extramitochondrial adenine nucleotide pool. Within a cell the rate of respiration is controlled primarily by the rates of reactions feeding electrons to the electron transport chain (through their effects on NADH/NAD and QH 2/Q ratios) and by the rates of reactions consuming or producing ATP (through the cytosolic phosphorylation potential or ATP/ADP ratio). Control of reducing equivalent supply occurs through availability of oxidizable substrates (determined by diet and hormonal status), through regulation of pathways such as glycolysis or fatty acid catabolism and, importantly, through Ca 2+ activation of intramitochondrial dehydrogenases. Hormonal control over respiration can occur at all the levels mentioned. Hormones may alter the kinetic properties of the oxidative phosphorylation system by altering the concentrations of individual proteins or by altering their kinetic properties either by affecting the lipid environment or, possibly, more directly. Important controls by hormones occur through changes in ATP demand altering the cytoplasmic adenine nucleotide pool and by changes in free Ca 2+ concentration in the mitochondrial matrix, altering the activity of dehydrogenases and the supply of electrons to NAD and Q. Hormones also affect the supply of reducing equivalents to the mitochondria by their catabolic or anabolic effects on other pathways.