TCF25 serves as a nutrient sensor to orchestrate metabolic adaptation and cell death by enhancing lysosomal acidification under glucose starvation

TCF25 serves as a nutrient sensor to orchestrate metabolic adaptation and cell death by enhancing lysosomal acidification under glucose starvation

Summary: Cells adapt to nutrient limitation by activating catabolic and inhibiting anabolic pathways, yet prolonged stress may lead to cell death. How cells orchestrate metabolic adaptation and cell death to nutrient stress is poorly understood. We conduct a genome-wide CRISPR-Cas9 screen to identif...

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Main Authors: Wenqing Ren, Hui Jiang, Qianqian Song, Yiliang Chen, Chenxiao Tang, Fang Wang, Jing Zhu, Jingming Ren, Yaxing Zhao, Yuan He, Jin Cai, Tianle Zhang, Zhuhong Wang, Chenjie Zhu, Wen Xue, Ai Peng, Xiaona Feng, Yue Liu, Jianqiang Yu, Zheng-gang Liu, Zhenyu Cai
Format: Article
Language:English
Published: Elsevier 2025-09-01
Series:Cell Reports
Subjects:
CP: Cell biology
CP: Metabolism
Online Access:http://www.sciencedirect.com/science/article/pii/S221112472500957X
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Summary:Summary: Cells adapt to nutrient limitation by activating catabolic and inhibiting anabolic pathways, yet prolonged stress may lead to cell death. How cells orchestrate metabolic adaptation and cell death to nutrient stress is poorly understood. We conduct a genome-wide CRISPR-Cas9 screen to identify regulators in glucose-starvation-induced cell death and find a group of genes in lysosomal pathway is enriched following glucose starvation. We focus on one candidate gene, Transcriptional Factor 25 (TCF25). We find TCF25 enhances lysosomal acidification by targeting V-ATPase, promoting autophagy and ATP generation under glucose starvation. However, prolonged glucose starvation constitutively activates ferritinophagy via TCF25, increasing lysosomal membrane permeability (LMP) and leading to lysosome-dependent cell death (LDCD). Knocking out TCF25 or V-ATPase components prevents cell death. Furthermore, TCF25 deficiency protects mice from hepatic ischemia-reperfusion injury. Our findings identify TCF25 as a crucial nutrient sensor that regulates lysosomal activity, offering potential therapeutic targets for metabolic and ischemic disorders.
ISSN:2211-1247

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