New Roles of Mitochondrial Transcription Factor A in Cancer

Mitochondria generate cellular energy in the form of adenosine triphosphate (ATP) by the process of oxidative phosphorylation. The organelle contains a small genome that, in animals, encodes 13 essential subunits of the respiratory chain complexes as well as all the rRNAs and tRNAs necessary for their translation. The mitochondrial genome is more vulnerable tooxidative damage and undergoes a higher rate of mutation than the nucleargenome. Otto Warburg observed that tumor slices have elevated levels of glucose consumption and lactate production in the presence of ample oxygen (termed the Warburg effect). He later postulated that cancer originates from irreversible injury to respiration followed by an increase in glycolysis to replace ATP loss due to defective oxidative phosphorylation. 

According to Warburg, this metabolic shift from oxidative phosphorylation to glycolysis converts differentiated cells into undifferentiated cells that proliferate as cancer cells. Although the observation that tumor cells exhibit high levels of aerobic glycolysis has been corroborated, the role of mitochondria in tumor cells has been contentious. While multiple investigators have demonstrated that mitochondria are indeed functional in most tumor cells, some argue that decreases in mitochondrialmetabolism and respiratory rate are essential for tumor cell proliferation. However, the only tumor cells shown to exhibit mitochondrial dysfunction are those that have mutations in the tricarboxylic acid cycle enzymes succinate dehydrogenase or fumarate hydratase. Furthermore, oncogene activation increases mitochondrial metabolism, correlating with metastatic potential.