Naturally occurring alkaloids trigger a biphasic cellular response

Tsukuba, Japan—Autophagy is a mechanism whereby unnecessary proteins and organelles within cells are removed, often called a "cellular cleaning crew." Lysosomes, small organelles within cells, play a key role in this process. Tetrandrine, a nitrogen-containing alkaloid primarily found in Stephania tetrandra, a plant native to China and Taiwan, can modulate autophagy and has various pharmacological activities, including anticancer and neuroprotective effects. However, the detailed mechanism underlying these functions, particularly its role in autophagy, remains unclear.

In this study, researchers investigated the subcellular tetrandrine localization using a fluorescently tagged compound, Probe 2. They found that Probe 2 specifically accumulated in lysosomes. Furthermore, tetrandrine temporarily increased the pH in lysosomes, which are normally acidic, thereby inhibiting their function. Furthermore, the researchers discovered that tetrandrine triggers a two-step cellular response wherein damaged lysosomes are selectively removed by autophagy (lysophagy) while promoting formation of new lysosomes.

Unlike existing modulators that target lysosomes by blocking membrane channels or inhibiting intralysosomal hydrolases, tetrandrine triggers a unique cellular response, highlighting its therapeutic potential in autophagy-lysosome dysfunction diseases such as neurodegeneration.

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This study was partially supported by Grants-in-Aid for Scientific Research (B) [KAKENHI, GRANT no. 25K01910 to Y.M. and no. 23K23547 to H.S. and Y.M.] from the Japan Society for the Promotion of Science, JST SPRING Grant number JPMJSP2124 (Z.Y.).

_{Original Paper}

Title of original paper:
Biphasic Cellular Response Triggered by Tetrandrine-Mediated Dysfunction and Lysophagic Clearance of Lysosomes

Journal:
ACS Chemical Biology

DOI:
10.1021/acschembio.5c00220

_{Correspondence}

Associate Professor MIYAMAE, Yusaku
Institute of Life and Environmental Sciences, University of Tsukuba

Zhe Yang
Doctoral Program in Life Science Innovation, Degree Programs in Life and Earth Sciences, Graduate School of Science and Technology, University of Tsukuba

_{Related Link}

Institute of Life and Environmental Sciences