Significance of Mitochondrial Binding and Release of Hexokinase in Metabolic Regulation

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Significance of the binding of hexokinase to mitochondria, especially in tissues and cells with high blycolytic activity, was examined with special reference to regulatory mechanism for glucose metabolism.1) Intracellular conditions for cations, especially the concentration of potassium ion in addition to that of magnesium ion, were significantly involved in the intracellular distribution of hexokinase.2) The binding to mitochondria brought about not only the facilitation for the action but also the stabilization of hexokinase.3) Intracellular distridution of hexokinase was also examined for cultured neuroblastoma cells for almost the first time, in reference to that in the brain which has been studied most extenvsively. About 30% of hexokinase activity was found as mitochondria-bound-form in-the neuroblastoma cells. It was also found that hexokinase I was predominant in the cells as was in the brain.4) Throughout the present study, hexokinase I showed much higher affinity to mitochond … More ria than hexokinase II, and the binding hexokinase was almost constant irrespective of the change in extra-cellular concentration of gluose. These properties of hexokinase I may be important for homeo-stasis of glucose metabolism in the brain.5) Almost no hexokinase activity was bound to mitochondria in normal rat liver as well as in the regenerating liver. However, the activity was found to some extent in the mitochondria fraction of some strains of rat ascites hepatoma cells, indicating the change in the intracellular distribution of hexokinase in relation to carcinogenesis.6) Posttranslational processing of hexokinase was investigated on an assumption that the elimination of the binding domain by the processing was responsible for the absence of mitochondria-bound hexokinase in the liver. The binding domain rich in hydrophobic amino acids has been postulated in the n-terminus of hexokinase molecule, since mild chymotrypsin treatment causes loss of the mitochondria-binding ability with little changes in the catalytic activity and molecular weight. Similar activity was found in the liver but not in the brain, and the activity was concentrated in the lysosomal fraction of the liver. From inhibitor and activator studies, thiol protease was found to be responsible for the processing. The processing activity was located in the outer surface of lysosomes to some extent, and possible mechanism for the processing was discussed. Less