82 S. S. COHEN 



In 1912, Batelli and Stern and Warburg recognized the insoluble nature of 

 key oxidative systems. Keilin began to study the correlation between 

 respiration and cytoplasmic structure in the late 1920's and, in examining 

 the activity of the cytochromes, observed that certain substrates, e.g., 

 cysteine, capable of interacting with cytochrome c in solution, were incapable 

 of interacting with particle-bound cytochrome c. That the oxidative enzymes 

 are not randomly aggregated in mitochondria and that they are spatially 

 organized and integrated in these structures was a concept developed further 

 by Green (1957) and others in work on the citric acid cycle, fatty acid 

 oxidation, the organization of terminal electron transport, etc. 



Hogeboom et al. (1946) were the first to show that cytochrome oxidase was 

 entirely organized within mitochondria. As noted above. Lardy and Wellman 

 (1952) showed that the rate of respiration of these bodies was tied to oxidative 

 phosphorylation and that the removal of newly formed high energy phosphate 

 by means of glucose and hexokinase was important for the maximal efiiciency 

 of the electron chain. Pressman and Lardy (1952) have also observed an 

 enhancement of mitochondrial respiratory rate by a microsomal component.^ 

 Thus, maximal energy production in the cell requires optimal conditions of 

 interaction of mitochondrion and its surroundmg miheu. 



In the operation of the citric acid cycle, which also funnels electrons to the 

 cytochrome systems, the existence of extramitochondrial enzymes of the 

 cycle, e.g., isocitric dehydrogenase, has been thought to argue against the 

 concept of integration of cycle operations within the organelle. However, the 

 mitochondrion does catalyze all the reactions of the cycle and the largest part 

 of the citrate of the cell is found within this particle. Nevertheless, recent 

 reviewers (Schneider and Hogeboom, 1956) are not convinced of the pre- 

 ponderant role of an integrated organelle in the operation of the cycle, 

 pointing out that cytoplasm as a whole is greatly superior to mitochondria in 

 catalyzing cycle oxidations. To this reviewer, the argument seems mainly 

 one of terminology, since those who consider that mitochondria do embody 

 an integrated array of enzymes do not msist that this system operate in a 

 vacuum and, indeed, will agree that the exigencies of optimal operation will 

 require a host of factors and reactions supplied by an enveloping cytoplasm. 



Energy production and conservation in mitochondria are not entirely a 

 function of the chemical tapping via oxidative phosphorylation of the main 

 electron chain from the reduced pyridine nucleotides through flavoproteins 

 and the cytochromes. The oxidation of a-ketoacids, such as pyruvate and 

 a-ketoglutarate, lead to the formation of thioesters, which represent an 

 additional mechanism for the conservation of the energy derived from 



^ A heat-stable component of the supernatant fluid after removal of mitochondria, 

 which by themselves possess a small ability to glycolyse anaerobically, will markedly 

 stimulate such glycolysis by separated mitochondria (Hochstein, 1957). 



