In early studies on energy metabolism of tumor cells, it was proposed that the enhanced glycolysis was induced by a decreased oxidative phosphorylation. Since then it has been indiscriminately applied to all types of tumor cells that the ATP supply is mainly or only provided by glycolysis, without an appropriate experimental evaluation. In this review, the different genetic and biochemical mechanisms by which tumor cells achieve an enhanced glycolytic flux are analyzed. Furthermore, the proposed mechanisms that arguably lead to a decreased oxidative phosphorylation in tumor cells are discussed. As the O(2) concentration in hypoxic regions of tumors seems not to be limiting for the functioning of oxidative phosphorylation, this pathway is re-evaluated regarding oxidizable substrate utilization and its contribution to ATP supply versus glycolysis. In the tumor cell lines where the oxidative metabolism prevails over the glycolytic metabolism for ATP supply, the flux control distribution of both pathways is described. The effect of glycolytic and mitochondrial drugs on tumor energy metabolism and cellular proliferation is described and discussed. Similarly, the energy metabolic changes associated with inherent and acquired resistance to radiotherapy and chemotherapy of tumor cells, and those determined by positron emission tomography, are revised. It is proposed that energy metabolism may be an alternative therapeutic target for both hypoxic (glycolytic) and oxidative tumors.

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1742-4658.2007.05686.x

Energy metabolism in tumor cells

Hypoxia-inducible Factor 1 Activation by Aerobic Glycolysis Implicates the Warburg Effect in Carcinogenesis

The Warburg and Crabtree effects: On the origin of cancer cell energy metabolism and of yeast glucose repression.

Publisher Summary This chapter describes the behavior of mitochondria in the living cell. The dynamics of mitochondria during fusion and fission and in intracellular displacement have important implications for understanding the supramolecular organization of cytoplasm. The physiological significance of the formation of mitochondrial reticula and the location of mitochondria close to energy-consuming structures is clear, and active locomotion establishes and maintains these important associations. Fusion and fission is of genetic significance, allowing the rapid exchange of alleles among different strands of DNA and thus accelerating the spreading of new mutations through a population of mitochondria. It also stabilizes the mitochondrial genome by facilitating recombinations and eliminating mutations. Fusion and fission of mitochondria also provide a structural control mechanism within the cell, allowing adaptation to varying energy demands during differentiation processes. A mitochondrial reticulum forms a pathway for energy transduction, which is equivalent to other transport systems such as cytoplasmic streaming or electrotonic signal transduction in some nerve cells. The role of supramolecular organization within the cytoplasm and the resulting microcompartmentation of the cell are necessary to elucidate these mechanisms.

Behavior of Mitochondria in the Living Cell

A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth.

A comparative study of the transport of pyruvate in mitochondria isolated from normal rat liver and from three tumors has been carried out. The Km for net pyruvate uptake in mitochondria isolated from Ehrlich ascites tumor cells is practically equal to that measured in normal rat liver mitochondria while, on the other hand, it is higher in Morris hepatomas 44 and 3924A. The Vmax of pyruvate uptake is depressed in all three types of tumor mitochondria as compared to that in the rat liver mitochondria, with the depression being higher in Morris hepatoma 3924A mitochondria. The lower activity of pyruvate translocator in mitochondria isolated from tumor cells as compared to that in rat liver mitochondria is also shown by depression of the rate of pyruvate-supported oxygen uptake. The results document a decreased activity of the pyruvate translocator in tumor mitochondria which seems to be correlated with the growth rate of the tumor cells.

/pdf/transport-of-pyruvate-in-mitochondria-from-different-tumor-21qdimzgg5.pdf

G Palombini

Papers

Transport of Pyruvate in Mitochondria from Different Tumor Cells