Effect of 8-azaguanine on oxidative phosphorylation of mouse-liver mitochondria

1. 1. Mitochondria have been prepared from the livers of mice that had been injected with sodium bicarbonate, 8-azaguanine plus sodium bicarbonate, or from mice that had not been injected at all. The particles from the normal (uninjected mice) showed high P:O ratios for the oxidation of α-ketoglutarate. Particles from mice injected with sodium bicarbonate showed lower P:O ratios than those from normal mice, whilst a certain amount of uncoupling was observed with mitochondria isolated from the livers of mice that had been injected with 8-azaguanine plus bicarbonate. 2. 2. The uncoupling of oxidation from phosphorylation observed when animals had been injected with 8-azaguanine was confined to α-ketoglutarate and glutamate. No inhibition was observed when succinate and β-hydroxybutyrate were used as substrates. 3. 3. Mitochondria isolated from the livers of normal mice and mice that had been injected 10 h previously with bicarbonate or 8-azaguanine plus bicarbonate have their oxygen consumption controlled by their ADP levels. Particles from mice injected daily for 6 days with bicarbonate or 8-azaguanine are not under ADP respiratory control. 4. 4. The significance of these results is discussed. It is concluded that 8-azaguanine incorporated into RNA has little effect on oxidative metabolism of isolated mouse-liver mitochondria. Its slight uncoupling effect may result from an antimetabolite action of 8-azaguanosine phosphates.