Fig. 3.

Schematic overview of the effect of iron depletion on the AMPK-dependent energy homeostasis pathway. The chelator, desferrioxamine (DFO), binds iron, which results in the inhibition of cellular energy generation due to the requirement for this metal for key enzymes required for electron transport (e.g., cytochromes and iron-sulfur proteins) and the activation of AMPK via LKB1. Activated AMPK leads to inhibition of raptor and acetyl CoA carboxylase 1 (ACC1) by their phosphorylation, which results in suppression of protein and fatty acid synthesis, respectively. The inhibition of these anabolic processes is important in the face of the cytotoxic insult that activates catabolism (e.g., via autophagy) to mobilize essential nutrients (such as iron) that are crucial for metabolic repair and function. As an integral part of this response, iron depletion also results in activation of ULK1 which leads to the activation of autophagy, which aims to recycle nutrients via catabolism of proteins such as the iron storage protein, ferritin [205]. This initial metabolic response of the cancer cell attempts to rescue the loss of metal ions and the repair of cytotoxic damage mediated through cellular metal ion chelation and the subsequent redox cycling of Dp44mT-metal ion complexes, respectively.