6 OLOV LINDBERG et al. 



effects (cf. [29]). According to one of the visualized mechanisms, the 

 mitochondrial DPN might constitute the target molecule for thyroxine 

 action, the latter causing a displacement of the bound DPN and thereby a 

 disorganization of the structure. The possibility has also been considered 

 that thyroxine might act primarily by activating the "R factor", thus 

 inducing a loose-coupling of phosphorylation from respiration, or alterna- 

 tively by inhibiting the activation of the "M-factor" and thus interfering 

 with the contractile mechanism responsible for the maintenance of a 

 tight mitochondrial structure. 



A marked swelling of liver mitochondria m vivo following treatment 

 of rats with large doses of thyroxine has been described in electron 

 microscopic studies by Schulz et al. [61]. However, when these mito- 

 chondria were isolated they exhibited normal respiration and P/O ratio, 

 and differed from normal mitochondria only with regard to an increased 

 susceptibility to agents eliciting swelling such as calcium ions [62]. 



A state of loose-coupling of the oxidative phosphorylation, of the type 

 earlier described by Hoch and Lipmann [13] in liver mitochondria from 

 thyrotoxic hamsters, was recently reported by Ernster et al. [63] to occur 

 in skeletal muscle mitochondria from patients with thyrotoxicosis. These 

 mitochondria revealed a markedly lowered respiratory control as compared 

 with those from normal subjects, whereas the P/O ratio obtained in the 

 presence of phosphate and phosphate acceptor, as well as the rate of 

 oxidation of DPN-linked substrates, were virtually normal. Interestingly, 

 the same findings were also made with skeletal muscle mitochondria 

 from a patient exhibiting an extremely severe hypermetabolism (BMR 

 around + 200%) of non-thyroid origin which is now being considered 

 to be related to an inborn defect of the mitochondrial structure. 



In summarizing this brief historical survey, it may be said that there 

 exists today a well-established symptomatology of the action of thyroxine 

 on isolated mitochondria in vitro, and that some of the symptoms, though 

 not all, can also be seen in mitochondria exposed to toxic levels of thyroid 

 hormone in vivo. However, some of these effects, such as a decreased 

 P/O ratio, are inconsistent from one case to another, and those which 

 are consistent, such as the enhanced swelling, the loss of bound DPN 

 and the loose-coupling of phosphorylation from respiration, are in their 

 nature connected with a time factor, thus giving the impression of being 

 consequences of some other primary event. 



2. Some instantaneous effects of thyroxine and related compounds 

 on partial reactions of oxidative phosphorylation 



In the present paper, certain effects of thyroxine and some related 

 compounds on various enzyme activities in mitochondria in vitro will 



