Potential mechanisms of action for angiostatin. (A) Angiostatin binds to cell surface ATP synthase, inhibiting proton transport coupled to ATP synthesis/hydrolysis by this enzyme. Interference with intracellular pH and purinergic signaling may account for some effects of angiostatin. (B) Lee et al demonstrate internalization of angiostatin via ATP synthase and binding to mitochondrial MDH2 and ATP synthase. They propose that angiostatin targeting of these enzymes regulates several downstream effects of this antitumorigenic protein.²