Figure 3.

Schematic representation of rotenone’s direct and indirect mechanisms of action at different subcellular levels. Direct effects of rotenone are considered as the ATP production decrease and the increase in ROS generation. Indirect effects stem from those direct. A decrease in energy charge affects many aspects of structure/function maintenance such as cell and organellar volume control (cell swelling), vesicle formation, transport and secretion, and cytoskeletal functions. Increased ROS generation affects mitochondrial components (such membranes, VDAC, enzymes, and proteins), and then, after diffusing into the cytosol through aquaporins, may target a large number of elements, among them the Golgi and endoplasmic reticulum (contributing to ER-stress), lysosomes and peroxisomes, and cytoskeletal elements (microtubule and actin filament fragmentation) leading to cell movement and architecture changes. A combined indirect catastrophic effect is the cell death through different pathways leading to apoptosis (VDAC opening with release of cytC, APAF, mtDNA), pyroptosis [45], ferroptosis [46], and lithic/autophagocytic death (with increased autophagocytosis) [47].