Mitochondria And Cancer: The Warburg Fact

Abstract

Mitochondria play a key role in the energy generation of cells. Here, we reassess the opportunities to fight cancer by manipulating the expression of mitochondrial DNA (mtDNA). The mtDNA encodes 13 polypeptides that are all critical for oxidative phosphorylation. Most cancers, if not all, use glycolysis as main bioenergetic pathway, despite the presence of oxygen. This is known as the Warburg effect and leads to disturbance of the mitocytoplasmic energy balance. Cytosolic ATP levels are kept high by the increased glycolysis, limiting the demand for ATP from mitochondria. The restricted ADP-ATP exchange across the mitochondrial membranes results in a high ATP/ADP ratio within the organelles and a high mitochondrial membrane potential. Together, these increase the cancer cell’s resistance to apoptosis. Although the increased glycolysis may enhance the survival of cancer cells, several lines of evidence suggest that mitochondrial activity remains indispensable for proliferation. Specific inhibition of mitochondrial protein synthesis, e.g. with doxycycline, results in a mitonuclear protein imbalance, decreasing the apoptotic threshold and preventing proliferation of various cancer types in vivo . The anti-cancer effects are achieved at serum levels that are present in patients treated with the antibiotic to combat infections. There is good evidence to consider further clinical investigations with doxycycline to substantiate its beneficial effects on cancer.