Mitochondria structural modifications, mitochondria-bound hexokinase, glycolysis and oxidative phosphorylation in human gliomas.
文摘
Glioblastoma multiforme, a malignant primary brain tumor, is characterized by an increase in aerobic glycolysis and in nucleic acid metabolism. In highly glycolytic tumors, 60 % of ATP supply is provided by glycolysis. The phosphorylation by ATP of glucose to glucose-6-phosphate is catalyzed by a clue enzyme: hexokinase 1 (HK), whose activity is clearly reduced in gliomas. The increase of HK-dependent ATP supply could be related to defective mitochondria (mt) functions expressed by oxidative respiration alterations and/or reflected by mt ultrastructure re-modelling. We have examined the correlation between morphological mt characteristics, glycolysis metabolism and oxidative phosphorylation, in four human xenografted gliomas expressing different levels of mt-bound HK (mHK) fraction. Glioma samples were highly glycolytic, as shown by the lactate/pyruvate ratio, by comparison with rat brain tissue taken as control. The four gliomas, according to their mHK fraction, could be separated into two distinct low and high mHK fraction groups. Biochemical results showed that human glioma xenografts did not present major impairements in mt electron transfer system and respiratory capacities. Glioma mt were examined for their ultrastructural morphometry, relative number, organite relationships, matrix density and cristea distribution. The mt averaged surface of gliomas was not statistically different from that of rat brain mt. Less mt were in close contacts with the nuclear membrane in gliomas from the low mHK fraction group. In addition, the length of the contact zones was reduced in gliomas compared with rat brain. The mt fraction in contact with the rough endoplasmic reticulum was independent of the corresponding glioma group. The optical density of matrix electron opaque material was higher in the low mHK fraction group than in the high one, where values were very similar to those obtained with rat brain mt. Mean cristae distance was constantly higher in gliomas.
