EFFECTS OF THYROXINE AND RELATED COMPOUNDS ON LIVER MITOCHONDRIA 25 



systems. This lack of reproducibility may perhaps be explained bv assuming 

 that the fla\in-linked electron transport and phosphorylation reactions 

 usually occur in the mitochondria at an excess capacity in comparison to 

 the overall rates of respiration and phosphorylation. Such an assumption 

 would be in line with the repeated findings [69, 83, 113-115] that the rate 

 of P -ATP exchange considerably exceeds the rate of phosphate uptake 

 in mitochondria under conditions of maximal respiration and phosphorv- 

 lation. The possibility that the inconsistent and gradual character of the 

 effects of thyroxine and related compounds on respiration and phosphory- 

 lation could be due to a poor penetration of these compounds through the 

 intact mitochondrial membrane seems improbable, since consistent and 

 instantaneous effects ensued in the case of the P—ATP exchange and 

 dinitrophenol-induced ATPase reactions, both of which were measured 

 in intact mitochondria. Moreover, as has been demonstrated recentlv by 

 Tapley and Basso [116], the uptake of thyroxine and related compounds 

 by mitochondria occurs in an instantaneous manner. 



As outlined in the introduction, mitochondrial swelling and related 

 symptoms seem to be dependent on an active oxidative phosphorvlation ; 

 this is indicated bv the findings that swelling does not occur in the absence 

 of oxidizable substrate, and is prevented by respiratory inhibitors and bv 

 dinitrophenol. This state of affairs raises the question as to how mito- 

 chondria in a state of acti\e phosphorylation are able to maintain their 

 structural integrity. It has been pointed out [29] that the ATP-induced 

 contraction of the mitochondria cannot be due to a simple reversal of the 

 process underlying the swelling, since the contraction is not inhibited by 

 dinitrophenol. However, there are now indications [50-53, 85, 117, 118] 

 that dinitrophenol interferes onlv with the forward reaction, and not the 

 reversal, of electron transport-coupled phosphorylation. It has also been 

 shown [26] that amytal inhibits the ATP-induced contraction of mito- 

 chondria and that this effect is not shared by antiniycin A and cyanide. 

 These facts point thus to the possibilitv that a reversal of the fla\in-linked 

 phosphorylation may play a part in the contraction of the mitochondria. It 

 would not seem inconceivable, therefore, that the great excess capacity of 

 this phosphorvlation in the mitochondria as compared with the overall 

 rate of respiration and phosphorvlation might be endowed with the 

 important function of maintaining the actively phosphorylating mito- 

 chondrion in a structurallv and functionally intact shape. It would be 

 understandable, then, that exposure of mitochondria to toxic concentra- 

 tions of thvroid hormone, therebv depriving them of this excess capacity 

 of the fla\"in-linked phosphorvlation, mav lead to a gradual loss of their 

 integrated properties. 



In summarv, then, the present data seem to pro\'ide a first information 

 about a direct effect of thvroxine and related compounds on the mito- 



