5.3.2. Depolarization of the Mitochondrial Membrane Potential

Mitochondria can play an essential role in the indirect killing of the parasite from ROS generation [107,112]. ROS production occurs as a result of membrane depolarization, dissipating its membrane potential, which plays vital roles in maintaining parasite cellular integrity, hence causing death [117,118]. This depolarization can be caused by the direct inhibition of PfATPase6 by artemisinins and other endoperoxides [119]. Artemisinins can also generate ROS at the mitochondrial level by altering the transfer of electrons from complex III to molecular oxygen, forming superoxide radicals [16,38,69,112].

**Figure 9.** Mode of action of artemisinins [109]. (**A**) Primary carbon-centered radical formation; (**B**) heme alkylation and adduct formation of heme–artemisinin; (**C**) ROS generation, especially the most deleterious hydroxy radical, •OH.

**Box 2.** Probable roles of other transition metals as cofactors in endoperoxide activities [15,96].

#### **Transition metals potentiate the artemisinin activity**

Apart from iron, other metals, especially transition metals such as copper, which are essential components of some proteins, also play a crucial role in ROS generation in the malaria parasite by catalyzing redox cycling in their unbound forms. The ROS generation by antimalarials is potentiated through the redox recycling of Fe3+ to Fe2+ with the aid of reduced flavin cofactors and probably NADPH-Fe (flavin reductase). Among the transition metals are copper and zinc.
