Parathyroid Hormone and Mitochondrial Metabolism

The effects of parathyroid hormone upon substrate decarboxylation and ion uptake and release in isolated mitochondria in terms of specificity, sensitivity, and the correlation between action in vivo and in vitro were studied. Parathyroid hormone added to isolated liver or kidney mitochondria in vitro stimulated the decarboxylation of a variety of Krebs' cycle intermediates. This decarboxylation required specific ion environments and in particular was not seen if chloride was the only anion present. In contrast, polylysine, histone, dinitrophenol, Zn++, and a basic nonhormonal peptide from the parathyroid glands all stimulated decarboxylation in a chloride medium. The effects of these basic polypeptides were inhibited completely by polyglutamic acid which did not greatly alter the effect of parathyroid hormone. The actions of these basic polypeptides were partially blocked by bovine serum albumin or by serum from parathyroidectomized animals, both of which enhanced the effect of parathyroid hormone. Specificity was also examined by comparing the effect of four different chemical modifications of the parathyroid hormone molecule upon succinate decarboxylation in vitro with their effects in a standard rat assay in vivo. There was a comparable loss of potency in the two assays with each derivative examined. Under optimum conditions in vitro, 2 x 10-8 m hormone produced a 2-fold increase in rate of succinate decarboxylation. This is well above the concentration found in normal plasma, but approaches that found in the plasma of patients with chronic secondary hyperparathyroidism. Conditions were defined under which the addition of parathyroid hormone to rat kidney mitochondria in vitro led to either enhanced or decreased uptake of calcium. The factor determining which of these effects was produced appeared to be the ionic composition of the medium. These data led to the following conclusions: (a) the effect of parathyroid hormone upon mitochondrial metabolism is highly specific; (b) concentrations of hormone which approach those seen in vivo are effective; and (c) there is a significant correlation between the effects that the hormone produces in vivo and those that it induces in vitro.