Figure 4.

Schematic representation of the lysosome dysfunction mediated by pH alteration. Increased lysosomal pH leads to reduced lysosomal degradation of lipid or toxic protein followed by down regulation of lysosomal enzyme (i.e. cathepsin) maturation as well as activity (Lee et al., 2010). The accumulations of lipid or ROS generation result in lysosome membrane damage and release lysosomal protease to the cytosol (Zdolsek et al., 1993). Abnormal lysosome permeabilization results in apoptosis or necrosis (Guicciardi et al., 2004). Altered lysosomal degradation induces massive accumulation of autolysosome and turn result in axonal transport impairment (Lee et al., 2011). Also, impairment of the nutrients (i.e. amino acid) recycle followed by delayed lysosomal proteolysis suppresses mTOR and keeps autophagy induction constitutive (Zoncu et al., 2011). Increases in lysosomal pH also decrease lysosomal calcium efflux, also increasing cytosolic calcium levels (Christensen et al., 2002).