Optogenetic manipulation of lysosomal physiology and autophagic activity.

1. Autophagy. 2024 Nov;20(11):2591-2592. doi: 10.1080/15548627.2024.2392464. Epub 2024 Aug 28.

Optogenetic manipulation of lysosomal physiology and autophagic activity.

Zeng W(1)(2), Li C(1)(3), Qu L(1)(2), Cang C(1)(3)(4).

Author information: (1)Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Neurodegenerative Disease Research Center, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. (2)Hefei National Research Center for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, China. (3)Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui, China. (4)Department of Rheumatology and Immunology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.

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 Ca2+ dynamics in living cells. Notably, lyso-ChR2 activation induces autophagy via the MTOR pathway while it promotes Aβ clearance through autophagy induction i