Integration of Mitochondrial Targeting for Molecular Cancer Therapeutics

Figure 4

Hypothetical diagram depicting roles of mitochondrial reprogramming in BRAF mutated cells when exposed to BRAF inhibitors (see text for details). Mutated BRAF melanoma mainly relies on aerobic glycolysis. Upon BRAFi exposure, glucose uptake and glycolysis are inhibited leading to ER stress and cell death by apoptosis and consequent energetic collapse (inhibition of both glycolysis and mitochondrial OXPHOS). However, there remains a subpopulation of BRAFi-tolerant cells. These cells reprogram the metabolism towards mitochondrial oxidation in order to survive and consequently this BRAFi-tolerant subpopulation of cells becomes addicted to mitochondria. These surviving cells are prone to accumulating subsequent mutations (potentially induced by mitochondrial ROS overproduction) leading to the onset of a resistant phenotype characterized by aerobic glycolysis associated with high levels of mitochondrial activity (red blot: inhibition, green blot: activation).