Figure 1.

Polyphenols targeting mitochondria in cancer. (A) Polyphenols alters oxidative stress through the generation of intracellular reactive oxygen species (ROS) by different pathways: autoxidation, inhibiting antioxidant pathways and downregulating the modulate electron transport chain (ETC) function both directly or indirectly (e.g., by inhibiting aerobic glycolysis). They also inhibit ATP synthase, HK-II activity, and blocks the voltage-dependent anion channel (VDAC). (B) HK-II/VDAC complex uncoupling causing a drop in glycolysis and in the amount of ADP in the mitochondrial matrix. To compensate the lack of ATP availability, a metabolic switching occurs and metabolism changes towards fatty acid oxidation, inducing (more) ROS generation, membrane permeabilization, inner membrane depolarization and apoptosis. Furthermore, polyphenols inhibit the anti-apoptotic proteins of the bcl-2 family, allowing the exit of Cyt-c from the mitochondria triggering intrinsic apoptosis. This scheme does not include the anti-oxidant mechanisms of polyphenols. (+) positive charge in mitochondrial intermembrane space; (−) negative charge on the matrix side of the inner mitochondrial membrane; red arrows: ROS synthesis increases; inhibitory red lines: inhibitory effects of polyphenols; ↑ increases; ↓ decreases; Ø complex III inhibition.