Figure 7
From: Identification of ML-9 as a lysosomotropic agent targeting autophagy and cell death
A model for ML-9’s mode of action. ML-9 as a lipophilic weak base enters the cell by simple diffusion. ML-9 downregulates Akt/mTOR pathway and as such stimulates autophagosome formation. ML-9 induces calcium release from ER and provokes ER stress. ER stress is a well-known autophagy inducer. At neutral pH, ML-9 is in its non-protonated form. When ML-9 enters acidic vacuoles (such as lysosomes, late endosomes, amphisomes and autolysosomes) it becomes positively charged through protonation and trapped in these vacuoles. Then, the increased osmotic pressure in these vacuoles stimulates water influx and vacuoles enlargement. All these events result in the increased intravacuolar pH, subsequent inhibition of lysosomal enzymes and block in degradation of the autolysosomal content as well as accumulation of autophagic vacuoles
