Oxidative Phosphorylation in Mitochondria From Livers Showing Cloudy Swelling

Abstract

Changes in the morphology of mitochondria have been observed by several authors during the so-called "cloudy swelling" (1-6) which is a peculiar type of cell degeneration well known to pathologists. In view of the close correlation between the morphology and the enzymatic activity of mitochondria (7-9 and others), some metabolic disturbances occurring during cloudy swelling have been related to the changes in mitochondria (6,10, 11).Previous work has shown that phosphorylation of glucose is reduced in diphtheria toxin-treated animals, whose organs show a typical cloudy swelling (10). In these organs, easily hydrolyzable phosphate has been found to be decreased as compared with normal (11). Furthermore, it has been shown that the histological picture of cloudy swelling can be reproduced experimentally by injecting the animals with some compounds which uncouple oxidative phosphorylation, such as 2,4-dinitrophenol (12) and thyroxine (13).It appeared therefore reasonable to suppose that changes in oxidative phosphorylation could be implicated in the pathogenesis of the aforementioned cellular changes. The present paper concerns the oxidative phosphorylation in mitochondria isolated from livers showing cloudy swelling. Materials and MethodsAdult albino rats and guinea pigs, bred in the Institute of General Pathology, were used. In order to produce cloudy swelling of the liver, rats were injected intraperitoneally with the smallest dose of S. typhi murium toxin that was lethal within 4 days, and guinea pigs were injected subcutaneously with diphtheria toxin (1 ~.LD./250 gin. body weight). S. typld murlum toxin was prepared as described previously (6); a commercial preparation of diphtheria toxin was used. The animals were fasted for the 12 hours immediately before killing at 24 hours after the toxin injection.Preparation of Mitochondria.--All manipulations were performed in a cold room at 0°C. using chilled materials.The animals were stunned by a blow on the head, bled at the neck, and the liver was quickly excised. A small sample was taken for histological examination and the remainder

Ultrastructural and Biochemical Aspects of the Myocardium in Guinea-Pigs Treated with Diphteria Toxin

“…These data exclude a primary lesion of the mitochondria by diphtheria toxin, in contrast to other suppositions (12,13).…”

Biochemical Lesion of Diphtheria Toxin in the Heart*

“…Previous investigations have suggested that diphtheria toxin interferes with the synthesis of cytochrome b (21), or with the formation of ATP (22)(23)(24). A defect in either of these could have explained the depressed rate of long-chain fatty acid oxidation.…”

Experimental Study of Diphtheritic Polyneuritis in the Rabbit and Guinea Pig

“…A new and fruitful avenue of investigation was opened with the finding of abnormalities in the formation of high energy phosphate bonds in liver, kidney and skeletal muscle of guinea pigs which had received toxin (68,69). Fonnesu and Severi have recently demonstrated uncoupling of oxidative phosphorylation in the livers of such animals (70) and have speculated that "cloudy swelling represents the morphological equivalent of the uncoupling between oxidation and phosphorylation." No direct effect of toxin on any tissue in vitro has yet been demonstrated, however.…”