Figure 1.

Effects of DOX and of mitochondria-targeted drugs on mitochondrial function and metabolism. DOX preferentially accumulates within mitochondria thanks to its ability to specifically bind to the phospholipid cardiolipin, causing membrane perturbation and ETC disruption that can be limited by Elamipretide, a tetrapeptide that improves the efficiency of electron transport and restores cellular bioenergetics. ETC dysfunction mainly induces ROS production that can be though limited by the usage of the mitochondria-targeted antioxidant, Mito-Tempo, a specific scavenger of mitochondrial superoxide. Moreover, DOX can directly interact with iron to form reactive ANT-iron complexes resulting in an iron cycling between Fe³⁺ and Fe²⁺ which is associated with ROS production and altered iron homeostasis. Dexrazoxane, as an iron-chelator, can inhibit the production of ROS ensuing from the interaction between ANT and non-heme iron, ultimately alleviating DOX-induced mitochondrial oxidative stress. Moreover, Dexrazoxane can prevent DOX from binding to the Top 2β-DNA complex. For AIC treatment, FAO inhibitors can also be used for their ability to enhance glucose oxidation and prevent a decrease in intracellular ATP levels, thereby ensuring the proper maintenance of cellular homeostasis.