2. Academic Validation
  3. TRPML1 ameliorates seizures-related neuronal injury by regulating autophagy and lysosomal biogenesis via Ca2+/TFEB signaling pathway

TRPML1 ameliorates seizures-related neuronal injury by regulating autophagy and lysosomal biogenesis via Ca2+/TFEB signaling pathway

  • Biochim Biophys Acta Mol Basis Dis. 2024 Dec;1870(8):167477. doi: 10.1016/j.bbadis.2024.167477.
Tingting Peng 1,  Yinyin Xie 1,  Senfeng Zhao 2,  Xiaoyi Wang 3,  Wanwan Zhang 4,  Yi Xie 4,  Cui Wang 5,  Nanchang Xie 6
Affiliations

Affiliations

  • 1 Department of Neurology, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou 450052, Henan Province, PR China; Academy of Medical Sciences of Zhengzhou University, Zhengzhou 450052, Henan Province, PR China.
  • 2 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou 450052, Henan Province, PR China; Academy of Medical Sciences of Zhengzhou University, Zhengzhou 450052, Henan Province, PR China.
  • 3 Institutes of Biological and Medical Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, Jiangsu Province, PR China.
  • 4 Department of Neurology, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou 450052, Henan Province, PR China.
  • 5 Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Key Clinical Laboratory of Henan Province, 1 East Jianshe Road, Zhengzhou 450052, Henan Province, PR China. Electronic address: snowy_cui@126.com.
  • 6 Department of Neurology, The First Affiliated Hospital of Zhengzhou University, 1 East Jianshe Road, Zhengzhou 450052, Henan Province, PR China. Electronic address: xienanchang2001@163.com.
PMID: 39173889 DOI: 10.1016/j.bbadis.2024.167477
Abstract

Alterations in Autophagy have been observed in epilepsy, although their exact etiopathogenesis remains elusive. Transient Receptor Potential Mucolipin Protein 1 (TRPML1) is an ion channel protein that regulates Autophagy and lysosome biogenesis. To explore the role of TRPML1 in seizures-induced neuronal injury and the potential mechanisms involved, an hyperexcitable neuronal model induced by Mg2+-free solution was used for the study. Our results revealed that TRPML1 expression was upregulated after seizures, which was accompanied by intracellular ROS accumulation, mitochondrial damage, and neuronal Apoptosis. Activation of TRPML1 by ML-SA1 diminished intracellular ROS, restored mitochondrial function, and subsequently alleviated neuronal Apoptosis. Conversely, inhibition of TRPML1 had the opposite effect. Further examination revealed that the accumulation of ROS and damaged mitochondria was associated with interrupted Mitophagy flux and enlarged defective lysosomes, which were attenuated by TRPML1 activation. Mechanistically, TRPML1 activation allows more CA2+ to permeate from the lysosome into the cytoplasm, resulting in the dephosphorylation of TFEB and its nuclear translocation. This process further enhances Autophagy initiation and lysosomal biogenesis. Additionally, the expression of TRPML1 is positively regulated by WTAP-mediated m6A modification. Our findings highlighted crucial roles of TRPML1 and Autophagy in seizures-induced neuronal injury, which provides a new target for epilepsy treatment.

Keywords

Autophagy; Epilepsy; Lysosome; TFEB; TRPML1.

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