The effects of ethionine treatment on the metabolism of liver mitochondria

Abstract

The administration of the methionine analog, ethionine, to female rats lowers the mitochondrial as well as the total intracellular level of ATP in the liver. The mitochondrial ADP/O, state 4 Q 02, i.e., the respiratory rate in the absence of ADP, Ca 2+- and water-activated ATPase remain unchanged up to 4 hr after ethionine treatment. However, the respiratory control index, state 3 Q 02, i.e., the respiratory rate in the presence of ADP, and DNP-activated ATPase are considerably lower than the control values. The preincubation of the mitochondria in a medium favorable to K + transport will partially restore the activity of the DNP-activated ATPase. DNP-stimulated respiration is normal when potassium succinate is the substrate but is inhibited with potassium glutamate as substrate. Ethionine doses of 0.25 mg/g body wt and 0.5 mg/g body wt have little effect on the respiratory control index or state 3 Q 02 of rat liver mitochondria, although the latter dose reduces the hepatic ATP level to approximately 35% of the control value; doses of 0.75 mg/g body wt and 1 mg/g body wt reduce the ATP level to about 20% of the control value and produce inhibition of the respiratory control index and state 3 Q 02. Therefore, it seems that mitochondria can function quite normally in respect to the control and generation of energy via respiration in the presence of a large decrease in intracellular adenine nucleotides. However, when the ATP concentration falls below 35% of the control value, changes in mitochondrial metabolism become apparent and the data suggest that these changes may be due to inhibition of the transphosphorylation reactions.