Mechanisms of autophagy and lysosomal dysfunction toxicity. The initiators of autophagy and lysosomal dysfunction toxicity, displayed in light blue text in the figure, include blockade of vesicle trafficking, lysosomal membrane permeabilization (LMP), and autophagy dysregulation. Nanoparticles could potentially cause autophagy dysfunction by overloading or directly damaging the lysosomal compartment, or altering the cell cytoskeleton, resulting in blockade of autophagosome-lysosome fusion. Nanoparticles could also directly affect lysosomal stability by inducing lysosomal oxidative stress, alkalization, osmotic swelling, or causing detergent-like disruption of the lysosomal membrane itself, resulting in LMP. Toxic effectors (lysosomal iron, cytosolic acidification, hydrolytic enzymes, reactive oxygen species, and the NLRP3 inflammasome) are displayed in dark blue. Conditions resulting from effector-mediated loss of homeostasis (oxidative stress, inflammation, ER stress, disrupted mitophagy, accumulation of ubiquitinated protein aggregates, and mitochondrial perturbation) are displayed in green. Finally, this loss of homeostasis can result in the cell death pathways necrosis, and Apoptotic (type I) and autophagic (type II) cell death; displayed in red (see text for details).