溶酶体钾离子通道 TMEM175 促进细胞凋亡并加重帕金森疾病症状

溶酶体是细胞内行使降解功能的细胞器，在多种细胞过程中发挥着重要作用。溶酶体膜上的离子通道是调节溶酶体功能的关键因子。其中TMEM175已被鉴定为溶酶体钾通道，但其调控机制和生理功能仍不清楚。在本文中，我们发现凋亡调节因子Bcl-2可与TMEM175结合并抑制其活性。相应的，Bcl-2抑制剂能以一种与Caspase无关的方式激活该通道。实验发现增强TMEM175的功能会抑制有丝分裂，破坏线粒体的平衡，并增加活性氧（ROS）的产生。ROS会进一步激活TMEM175，从而形成一个正反馈回路，促进细胞凋亡。在1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）帕金森病（PD）小鼠模型中，TMEM175的基因敲除（KO）减轻了运动障碍和多巴胺能（DA）神经元的缺失，这表明TMEM175介导的细胞凋亡在帕金森病（PD）中发挥了重要作用。总之，我们的研究揭示了TMEM175是凋亡信号通路中的一个重要调节位点，也是帕金森病（PD）的一个潜在治疗靶点。Lysosomes are intracellular organelles responsible for degradation, which play critical roles in various cellular processes. Ion channels on the lysosomal membrane are key regulators of lysosomal function. Among them, TMEM175 has been identified as a lysosomal potassium channel, but its regulatory mechanism and physiological functions remain unclear. In this study, we found that the apoptosis regulator Bcl-2 can bind to TMEM175 and inhibit its activity. Correspondingly, Bcl-2 inhibitors can activate this channel in a Caspase-independent manner. Experiments show that enhancing the function of TMEM175 inhibits mitosis, disrupts mitochondrial homeostasis, and increases the production of reactive oxygen species (ROS). ROS can further activate TMEM175, thereby forming a positive feedback loop that promotes apoptosis. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinson's disease (PD) mouse model, genetic knockout (KO) of TMEM175 alleviated motor deficits and the loss of dopaminergic (DA) neurons, indicating that TMEM175-mediated apoptosis plays an important role in PD. Collectively, our study reveals that TMEM175 is an important regulatory site in the apoptotic signaling pathway and a potential therapeutic target for Parkinson's disease (PD).