Abstract:
:We have established that a preferential export of pyruvate-generated citrate occurs from cholesterol-rich tumor mitochondria, with both isolated mitochondrial systems as well as with viable tumor tissue slices (i.e., with whole tumors cells). Furthermore, we have demonstrated that the more rapid citrate efflux kinetics (catalyzed by the tricarboxylate exchange carrier) of isolated tumor mitochondria is completely inhibited upon addition of 1,2,3-benzenetricarboxylate (BTC) and have shown that this inhibition is apparently also obtained in viable tumor tissue when the inhibitor is added to the tissue incubation. Upon BTC inhibition of tumor mitochondrial citrate export in viable tumor tissue incubations, the incorporation of [14C]pyruvate into newly synthesized cholesterol is severely inhibited as well. Among the most interesting conclusions drawn from our results, we catalog the following. The preferential export of citrate from isolated tumor mitochondria appears to be coupled, functionally, to a high linear rate of incorporation of 14C from pyruvate to cholesterol in viable tumor tissue slices, simultaneously supporting the postulate of a truncated Krebs cycle and corroborating the well-established deregulated and continuous cholesterogenesis pathway in tumors, especially hepatomas. The extent of [14C]pyruvate flux to newly generated cholesterol in either tumor or normal liver tissue is inversely related to the extent of 14CO2 production. Despite the evolution of some CO2 during cholesterogenesis, the predominant portion presumably arises via metabolic processing of pyruvate-generated citrate during Krebs cycle-linked respiration. Isolated tumor mitochondrial systems, as well as viable tumor tissue incubations, can manifest a reversal in the pattern of enhanced mitochondrial citrate efflux coupled to increased cholesterogenesis, when BTC is added to the system. This implies that BTC, a hydrophobic but negatively charged moiety at pH 7, can indeed penetrate the plasma membrane of cells. Upon entry into the cell, BTC apparently blocks the tricarboxylate carrier of tumor tissue mitochondria, thus forcing the mitochondrial citrate into Krebs cycle-linked respiration rather than permitting it to serve as the predominant provider of an increased supply of cytosolic acetyl CoA precursor required for deregulated cholesterogenesis during the development of the tumor.
journal_name
Ann N Y Acad Scijournal_title
Annals of the New York Academy of Sciencesauthors
Coleman PSdoi
10.1111/j.1749-6632.1986.tb46578.xsubject
Has Abstractpub_date
1986-01-01 00:00:00pages
451-67eissn
0077-8923issn
1749-6632journal_volume
488pub_type
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