We have studied the role of changes in mitochondrial membrane potential (v v8 8) in two widely-used models of apoptosis, such as dexamethasone-treated rat thymocytes and U937 human cells treated with tumor necrosis factor-K K and cycloheximide. To dissipate v v8 8, we used low concentrations of valinomycin, unable per se to induce apoptosis, and demonstrated that the decline in v v8 8 exerts opposite effects in the two models. Indeed, in U937 cells, depolarization of mitochondria increased apoptosis, which decreased in rat thymocytes. This leads to the suggestion that disruption of v v8 8 plays opposite roles depending on the experimental model. In U937 cells, the drop of v v8 8 is a possible contributory cause for the apoptotic process; in rat thymocytes, it could be a limiting factor. We propose that these opposite effects could be due to the different ATP requirement of each apoptotic pathway.z 2000 Federation of European Biochemical Societies.

The effects on the liver of feeding a diet containing 0.2% dehydroepiandrosterone were studied after short (7 d) and long (100 d) periods of treatment in rats. The short-term treatment caused hypertrophy of the hepatocytes that, at the ultrastructural level, seemed to be due to proliferation of peroxisomes and (to a minor extent) of mitochondria. The mitochondria seemed to have undergone transition from expanded to condensed configuration; accordingly, after isolation, their rate of coupled respiration was greater than that of control mitochondria. After long-term treatment, the structure of the hepatocytes reverted toward normal. In fact, at the ultrastructural level, the number and the size of peroxisomes was not significantly different from those of the controls, but degenerative phenomena were observed in the mitochondria. Attempts are made to explain the above ultrastructural and biochemical findings in view of the effects of dehydroepiandrosterone on the energy metabolism of liver.

The effect of the in vivo thyroid status on mitochondrial membrane potential (v v8 8 m ) in isolated rat hepatocytes was studies by means of a cytofluorimetric technique and the v v8 8 mspecific probe JC-1. It is shown that the v v8 8 m level decreases in the order hypothyroid s euthyroid s hyperthyroid. Polarographic measurement of the hepatocyte respiratory rates revealed an opposite trend of values: the highest respiratory rate in hepatocytes from hyperthyroid animals, the lowest in those from hypothyroid ones. This means that mitochondrial energy coupling is highest in hypothyroid hepatocytes and lowest in hyperthyroid hepatocytes. 6-Ketocholestanol added to hepatocytes failed to counterbalance the uncoupling effect of thyroid hormones on v v8 8 m and respiration rate. Under the same conditions, 6-ketocholestanol appeared to be effective in recoupling of respiration uncoupled by low concentrations of the artificial protonophore FCCP. The mechanism and possible physiological functions of the thyroid hormone-induced decrease in mitochondrial energy coupling are discussed.z 1998 Federation of European Biochemical Societies.

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