Autophagy is essential for eliminating aging and organelle damage that maintaining cellular homeostasis. However, the dysfunction of autophagy has been proven in hair loss such as AGA. Despite the crucial role of TRPML channels in regulating autophagy, their specific function in hair growth remains unclarified. To investigate the biological functions and associated molecular mechanisms of TRPMLs in hair growth, Animal experiments were conducted to confirm the function of TRLMLs activation in promoting hair growth. Subsequently, we analyzed molecular mechanisms in human dermal papilla cells (hDPCs) activated by TRPMLs through transcriptome sequencing analysis. MLSA1(a TRPML agonist) promoted hair regeneration and accelerated hair cycle transition in mice. The activation of TRPMLs upregulated calcium signaling inducing hDPCs to secrete hair growth promoting factors and decrease hair growth inhibiting factors. In addition, activation of TRPMLs triggered autophagy and reduced the generation of ROS, thereby delaying the senescence of hDPCs. All these findings suggested that TRPMLs activation could promote hair growth by regulating hDPCs secretion of hair growth-related factors. Moreover, it may play a prominent role in preventing hDPCs from ROS damage induced by H₂O₂ or DHT. Targeting TRPMLs may represent a promising therapeutic strategy for treating hair loss.

01 Jun 2024·Skin Research and Technology

Transient receptor potential mucolipin 1 circumvents oxidative stress in primary human melanocytes

Article

Author: Hu, Yebei ; Shen, Yuqing ; Xu, Jinhui ; Chen, Yi ; Xie, Bo ; Sun, Jiayi ; Zhu, Yuqi ; Song, Xiuzu

AbstractBackgroundTransient Receptor Potential Mucolipin 1 (TRPML1) serves as a pivotal reactive oxygen species (ROS) sensor in cells, which is implicated in the regulation of autophagy. However, its function in melanocyte autophagy under oxidative stress remains elusive.MethodsThe expression and ion channel function of TRPML1 were investigated using immunofluorescence and calcium imaging in primary human melanocytes (MCs). After activating TRPML1 with MLSA1 (TRPML1 agonist), autophagy‐related molecules were investigated via western blot. ROS level, apoptosis‐ and autophagy‐related molecules were investigated after pretreatment with MLSA1. After interference with TRPML1 expression, mitochondrial structures were visualized by electron microscopy with hydrogen peroxide (H2O2）treatment.ResultsTRPML1 was expressed and functionally active in primary human MCs, and its activation promotes elevated expression of LC3‐II and reduced apoptosis and ROS levels under oxidative stress. TRPML1 downregulation caused mitochondrial swelling and disruption of cristae structures under oxidative stress in primary human MCs.ConclusionsTRPML1 might mediate lysosomal autophagy in primary human MCs under oxidative stress, participating in mechanisms that maintain the oxidative and antioxidant systems in balance.

19 Mar 2024·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

Molecular and structural basis of the dual regulation of the polycystin-2 ion channel by small-molecule ligands

Q1 · CROSS-FIELD

Article

Author: Wang, Zhifei ; Wang, Yan ; Yu, Yong ; Chen, Mengying ; Shi, Yigong ; Pillai, Akhilraj R. ; Nazginov, Elianna ; Qian, Feng ; Su, Qiang ; Morais, Tiago D. C.

Mutations in thePKD2gene, which encodes the polycystin-2 (PC2, also called TRPP2) protein, lead to autosomal dominant polycystic kidney disease (ADPKD). As a member of the transient receptor potential (TRP) channel superfamily, PC2 functions as a non-selective cation channel. The activation and regulation of the PC2 channel are largely unknown, and direct binding of small-molecule ligands to this channel has not been reported. In this work, we found that most known small-molecule agonists of the mucolipin TRP (TRPML) channels inhibit the activity of the PC2_F604P, a gain-of-function mutant of the PC2 channel. However, two of them, ML-SA1 and SF-51, have dual regulatory effects, with low concentration further activating PC2_F604P, and high concentration leading to inactivation of the channel. With two cryo-electron microscopy (cryo-EM) structures, a molecular docking model, and mutagenesis results, we identified two distinct binding sites of ML-SA1 in PC2_F604P that are responsible for activation and inactivation, respectively. These results provide structural and functional insights into how ligands regulate PC2 channel function through unusual mechanisms and may help design compounds that are more efficient and specific in regulating the PC2 channel and potentially also for ADPKD treatment.

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Indication	Highest Phase	Country/Location	Organization	Date
Lysosomal Storage Diseases	Preclinical	US	Calporta Therapeutics, Inc.Startup	-
Neurodegenerative Diseases	Preclinical	US	Calporta Therapeutics, Inc.Startup	-

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