2. Academic Validation
  3. Repair of damaged lysosomes by TECPR1-mediated membrane tubulation during energy crisis

Repair of damaged lysosomes by TECPR1-mediated membrane tubulation during energy crisis

  • Cell Res. 2026 Jan;36(1):51-71. doi: 10.1038/s41422-025-01193-6.
Hanmo Chen # 1,  Chaojun Zhang # 2 3,  Yuhui Fu 1,  Linsen Li 1,  Xiaoyu Qiao 1,  Shen Zhang 1,  Hanyan Luo 1,  She Chen 4,  Xiaoxia Liu 5,  Qing Zhong 6
Affiliations

Affiliations

  • 1 Institute for Translational Medicine on Cell Fate and Disease, Shanghai Ninth People's Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Department of Oral Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, Shanghai, China.
  • 4 National Institute of Biological Sciences, Beijing, China.
  • 5 Institute for Translational Medicine on Cell Fate and Disease, Shanghai Ninth People's Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • 6 Institute for Translational Medicine on Cell Fate and Disease, Shanghai Ninth People's Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41478856 DOI: 10.1038/s41422-025-01193-6
Abstract

Lysosomes are essential for cellular homeostasis, serving as degradative organelles that recycle nutrients. Whether and how lysosomes maintain membrane integrity under energy stress is poorly understood. Here, we found that the uptake of lipid droplets by lysosomes during glucose starvation provokes disruption of lysosomal membranes. We identified tectonin beta-propeller repeat-containing protein 1 (TECPR1) as a critical mediator of lysosomal repair during glucose starvation or LLOMe-induced lysosomal membrane permeabilization. TECPR1 is recruited to damaged lysosomes via interaction with PI4P on damaged lysosomal membranes. It interacts with KIF1A to facilitate tubule formation from damaged lysosomes, enabling the removal of damaged membrane components and promoting lysosomal repair. Our in vitro reconstituted tubulation process provided further evidence that TECPR1 coordinates with KIF1A to drive tubulation from PI4P-enriched giant unilamellar vesicles. TECPR1-mediated lysosomal repair is essential for maintaining lipid metabolism and cellular survival during an energy crisis, as TECPR1 deficiency exacerbates starvation-induced liver damage in a high-fat diet-induced MAFLD mouse model. Our findings demonstrate a previously unrecognized role of TECPR1 in lysosomal repair, revealing its critical contributions to energy stress adaptation and liver protection. This work provides new insight into mechanisms of lysosomal repair and their implications for metabolic and lysosome-related disorders.

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