Ca2+ Requirement in ATP‐Induced Activation of Uncoupled Oxidation of Succinate in Isolated Rat‐Liver Mitochondria

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Abstract
1. Small amounts of Ca2+ cause an ATP‐dependent activation of state 3 oxidation of succinate in rat liver mitochondria in vitro.2. The Ca2+‐induced, ATP‐requiring activation of uncoupled oxidation of succinate (the Ca2+ effect) is blocked by ruthenium red, tetracaine, or high concentrations of K+. It is not blocked by La3+ or Pr3+.3. The Ca2+ effect is demonstrable in mitochondria treated with hyposmotic shock (mitochondria devoid of the outer membrane), freezing‐and‐thawing or aging. Treatment with detergents (sodium deoxycholate and Triton X) causes a loss of the Ca2+ sensitivity.4. For Ca2+ to produce the effect a much longer latent period (several minutes at room temperature) is needed than for ATP or succinate.5. The Ca2+ effect is ATP dose‐related and maximum response is obtained with 0.2 mM ATP.6. The Ca2+ effect is observed in the absence of mitochondrial accumulation of Ca2+ and is Ca2+ dose‐related with external Ca2+ between 0.5 and 50 μM. The half‐maximum response is obtained at about 1 μM.7. The Ca2+ effect is not accompanied by an increase in the penetration of succinate across the mitochondrial membrane as judged from the swelling experiment of Chappell and Crofts, but is accompanied by the activation of succinate dehydrogenase.8. The Ca2+ effect is demonstrable not only in the presence of external oxaloacetate or malonate, but also in conditions where endogenous oxaloacetate accumulation is prevented by the addition of rotenone and glutamate.9. From the above results, a model is proposed in which cytosol Ca2+ alters mitochondrial metabolism by activating succinate dehydrogenase through a change of membrane conformation produced by the Ca2+ interaction with low affinity Ca2+‐binding sites on the outer surface of the inner mitochondrial membrane.

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