Optogenetic manipulation of lysosomal physiology and autophagic activity

Lysosomes are essential degradative organelles and signaling hubs within cells, playing a crucial role in the regulation of macroautophagy/autophagy. Dysfunction of lysosomes and impaired autophagy are closely associated with the development of various neurodegenerative diseases. Enhancing lysosomal activity and boosting autophagy levels holds great promise as effective strategies for treating these diseases. However, there remains a lack of methods to dynamically regulate lysosomal activity and autophagy levels in living cells or animals. In our recent work, we applied optogenetics to manipulate lysosomal physiology and function, developing three lysosome-targeted optogenetic tools: lyso-NpHR3.0, lyso-ArchT, and lyso-ChR2. These new actuators enable light-dependent regulation of key aspects such as lysosomal membrane potential, lumenal pH, hydrolase activity, degradation processes, and Ca