A molecular switch in cytochrome C oxidase turns on thermogenesis in heart at low work load.

We describe a new mechanism of respiratory control by ATP on cytochrome c oxidase, which contrasts with the well known respiratory control of the electron transfer chain in mitochondria by ADP/ATP ratios. It is well established that high ADP/ATP ratios stimulate respiration and thus the synthesis of ATP in mitochondria, according to the energy requirements of the cell. Herein we describe the direct stimulation by high ATP/ADP-ratios of bovine heart (but not liver) cytochrome c oxidase activity in reconstituted vesicles. Under these same conditions it has already been shown that ATP decreases the H+/e- stoichiometry of cytochrome oxidase. Thus the observed effect of high ATP on cytochrome c oxidase would be expected to lead to partial uncoupling of energy transduction in mitochondria and to stimulation of thermogenesis.