The Inhibition of Mitochondrial Adenosine Triphosphatase

Previous studies reported from this and other Laboratories have shown that isolated mitochondria are able to maintain concentration gradients of Na+ and K+ ions. When incubated in media containing an oxidizable substrate and ATP, mitochondria from liver (Macfarlane & Spencer, 1953; Spector, 1953; Price, Fonnesu & Davies, 1956), kidney (Bartley & Davies, 1954; Ulrich, 1961), heart and skeletal muscle (Ulrich, 1959, 1960) accumulate K+ ions against a concentration gradient. Whether this also holds for Na+ ions is uncertain, since some investigators have reported an increased uptake of Na+ ions during metabolic activity (Macfarlane & Spencer, 1953; Bartley & Davies, 1954; Price et al. 1956), but others have been unable to demonstrate this (Spector, 1953; Jackson & Pace, 1956; Ulrich, 1959, 1961). So far, however, no conclusive evidence has been obtained that either Na+ or K+ ions are transported by mitochondria against both a chemical and an electrical gradient. Recent studies of the activation of membrane adenosine triphosphatase by Na+ and K+ ions indicate that this enzyme may play a role in the transport of these cations across cell membranes. It has been demonstrated that Na+ and K+ ions can increase adenosine-triphosphatase activity in microsomes from peripheral nerve (Skou, 1957, 1960) and brain (Jarnefelt, 1961), and from membrane preparations of erythrocytes (Post, Merritt, Kinsolving & Albright, 1960; Dunham & Glynn, 1961), kidney cortex (Whittam & Wheeler, 1961), and E8cherichia coli (Solomon, 1962). These studies have shown (see, for example, Post et al. 1960) that there is a good correlation between the active transport of Na+ and K+ ions, increased adenosine-triphosphatase activity, and the inhibition by ouabain of both active transport and the activation of adenosine triphosphatase. Further, Glynn (1962) and Whittam (1962a, b) have demonstrated that the adenosine triphosphatase of erythrocyte stroma is stimulated asymmetrically by Na+ and K+ ions: Na+ ions stimulate the enzyme from the inside and K+ ions stimulate it from the outside, but only in the presence of the other ion on the opposite side of the membrane. Since mitochondrial adenosine triphosphatase is concentrated in the membrane (Kielley & Kielley,