Cortisone-induced Alterations in Mitochondrial Function

The effects of cortisone treatment on oxygen consumption, oxidative phosphorylation, and fine structure of rat liver mitochondria have been studied. Male rats weighing 125 g were treated for 6 days with 5 mg of cortisone acetate or isotonic saline. On the 7th day, sections of liver were excised and processed for light and electron microscopy. Mitochondrial respiration and oxidative phosphorylation were studied with mitochondria isolated from these livers. Cortisone treatment is responsible for a 14-40% decrease in the amount of oxygen consumed per mg of mitochondrial protein when succinate, a-ketoglutarate, or j-hydroxybutyrate are used as substrates, or with ascorbate and N ,N, N ,NI-tetramethyl p-phenylenediamine as electron donors. In addition, oxidative phosphorylation is uncoupled with a lowering of the P :O ratios. Randomly selected liver cells have been analyzed by quantitative morphometric techniques. The average mitochondrial volume is increased fourfold in the peripheral and midzonal regions with a commensurate decrease in the number of mitochondria per cell. These alterations are present throughout the hepatic lobule, but are most marked in midzonal cells. The total mitochondrial volume per cell and the per cent of the total cytoplasmic volume occupied by mitochondria remains relatively unaltered, as does the total amount of cristae surface per cell. While the mitochondria are enlarged, they are not "swollen." The relationships between the steroid hormone treatment and the alterations in mitochondrial function and structure are discussed. It has long been recognized that cortisone administration produces a multitude of physiological and biochemical alterations. Cortisone has, for example, been shown to alter the activity in the liver of certain enzymes involved in carbohydrate metabolism (1), and, in addition, may affect the rate of synthesis of nucleic acids, certain enzymes, and other proteins (2, 3). The mechanisms underlying these diverse hormonal effects are still poorly understood. Mitochondrial respiration, oxidative phosphorylation, and ion translocation are of obvious importance in cell metabolism, and a number of studies have been concerned with the influence of glucocorticoid treatment on these aspects of mitochondrial function (4-10). While these earlier reports suggested that cortisone treatment in the rat may alter the number, size, and biochemical function of liver mitochondria, there has been uncertainty about the precise nature of these steroid hormone effects. The present studies were undertaken in an effort to define more clearly the effects of cortisone treatment on rat liver mitochondrial oxygen consumption, oxidative phosphorylation, and fine structure. The results demonstrate that treatment with cortisone causes multiple defects in the mitochondrial respiratory chain and uncouples oxidative phos63 on Jne 7, 2017 D ow nladed fom Published April 1, 1968