Cooperative effects of Mn(2+) and V(5+) on the energy transfer reaction of rat liver mitochondria were investigated. Mn(2+) (0.10-0.05mM) increased State 4 resperation and decreased State 3 respiration, indicating an uncoupling action on the mitochondria. V(5+) alone at the concentration of 0.1-0.8 mM had no noticeable effect on mitochondrial respiration. In the presence of V(5+), Mn decreased both State 3 and State 4 respiration. The degree of the inhibition was extreme in State 3 respiration at a low concentration of Mn. The change from the accelation of State 4 respiration by Mn(2+) alone to its inhibition by Mn(2+) and V(5+) suggests an incease of cleteriovation in mitochondrial function by the cooperative action of Mn(2+) and V(5+). Cooperative effects of Mn(2+) and Mg(2+) on the energy transfer reaction have been described. In the presence of Mg(2+), the uncoupling action of Mn(2+) was not observed, suggesting that the injurious effect of Mn(2+) on mitochondrial membrane was depressed by Mg(2+). However, phosphorylation activity was more strongly inhibited with Mn(2+) and Mg(2+) together than with Mn(2+) alone.