Fig. 3

General summary of altered mitochondrial functions in cancer cell life and death. a In normal non-transformed cells glucose is mainly metabolized through the glycolysis pathway and the resulting pyruvate enters the mitochondrial TCA cycle, producing reduced equivalents that are fed into the ETC to generate ATP with high efficiency through the OXPHOS. Antioxidant defenses and coupled respiration through OXPHOS maintain low levels of mitochondrial ROS. b Normal cells are sensitive to apoptotic stimuli triggered by different stresses that finally converge in BAK/BAX activation and MOMP with subsequent release of cytochrome c into the cytosol, stimulating the formation of the apoptosome and apoptotic cell death. c In cancer cells gain-of-function of oncogenes and loss-of-function of tumor suppressor genes (such as MYC, HIF1α and TP53) results in altered metabolism, exemplified by the Warburg effect, characterized by high glucose consumption rates. Glucose is degraded through glycolysis to obtain biosynthetic intermediates and the resulting pyruvate is reduced to lactate to generate ATP. In this scenario, mitochondrial TCA is diverted to generate biosynthetic intermediates, which is accompanied by low OXPHOS activity and increased mitochondrial ROS production. NRF2 is upregulated in cancer cells to counteract ROS and permits cancer cells to withstand its deleterious effects. d Cancer cells, through the overexpression of anti-apoptotic proteins or inactivation of pro-apoptotic proteins, counteract the action of BAX/BAK and evade MOMP formation. Besides this effect, mitochondrial cholesterol loading shields mitochondrial membrane, impairing BAK/BAX oligomerization in MOM and subsequent MOMP formation and represents an additional mechanism of cell death resistance in tumor cells