In the 1930s, Otto Warburg hypothesized that when an “injury” occurs to the mitochondrial respiratory machinery in malignant cells, these cells meet the demand of energy needs through increased glycolytic ATP production, as opposed to normal, efficient oxidative phosphorylation; conclusively, he theorized that this change proliferates carcinogenesis in a process aptly titled the “Warburg effect”. Further research has identified three impacts of the alterations to respiratory machinery that directly affect cancer development: 1) reduced oxidation of NADH-linked substrates, 2) variation in glycolytic enzyme activity and expression, and 3) mitochondrial DNA (mtDNA) mutations. However, contrary to Warburg’s assumption that the Warburg effect is a consequence of mitochondrial damage, recent insight has shown that aerobic glycolysis actually supports various metabolisms, notably the metabolic requirements for tumor proliferation. Essentially, cancer suppresses normal mitochondrial function and stimulates metabolic reprogramming within cells. Carcinogenesis relies much more heavily on the glycolysis portion of cellular respiration, despite the fact that it is much less efficient in producing ATP than oxidative phosphorylation. Thus, even in the presence of normal oxygen levels, cancer cells do not metabolize glucose to create energy and instead convert glucose into lactate; therefore, high rates of glucose uptake are required to meet energy demands for tumor progression. Without being able to regulate glucose uptake, mitochondria can refuel cancer cells to such an extent that they have unrestrained growth capabilities.
Secondly, mitochondrial DNA mutations also affect cancer development. mtDNA is inherently more susceptible to mutations than nuclear DNA due not only to its lack of histone protection and inadequate repair capabilities, but to its lack of introns, which allow mutations to occur in the coding sequences. Since mitochondria play a key role in ATP metabolism and apoptosis regulation, mutations in mtDNA are likely to affect energy capabilities and cellular responses to apoptosis initiation by growth-regulating inhibitors. Moreover, mtDNA mutations cause alterations to the electron transport chain that compromise normal electron flow; from this, increased bifurcation of electrons from the electron transport chain, and consequentially the generation of superoxide radicals, yield mitochondrial reactive oxygen species (ROS), which pose a risk of cancer. Glucose and oxygen deficiency (hypoxia) contribute largely to an elevation in ROS production, which enables cells to eventually adapt to and sustain elevated ROS. Though few cells survive DNA damage from increased mitochondrial ROS production, those that do undergo malignant cell transformation, wherein the newly-developed oncogenic mutations immortalize them as tumors.