Institute on Aging and Brain Disorders, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Neurodegenerative Disorder Research Center, University of Science and Technology of China, Hefei, China.
EMBO Rep. 2022 Sep 5;23(9):e53234. doi: 10.15252/embr.202153234. Epub 2022 Aug 1.
Lysosomes are degradative organelles and play vital roles in a variety of cellular processes. Ion channels on the lysosomal membrane are key regulators of lysosomal function. TMEM175 has been identified as a lysosomal potassium channel, but its modulation and physiological functions remain unclear. Here, we show that the apoptotic regulator Bcl-2 binds to and inhibits TMEM175 activity. Accordingly, Bcl-2 inhibitors activate the channel in a caspase-independent way. Increased TMEM175 function inhibits mitophagy, disrupts mitochondrial homeostasis, and increases production of reactive oxygen species (ROS). ROS further activates TMEM175 and thus forms a positive feedback loop to augment apoptosis. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), knockout (KO) of TMEM175 mitigated motor impairment and dopaminergic (DA) neuron loss, suggesting that TMEM175-mediated apoptosis plays an important role in Parkinson's disease (PD). Overall, 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).
溶酶体是一种降解性细胞器，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溶酶体功能的关键调节剂。TMEM175 已被鉴定为溶酶体钾通道，但它的调节和生理功能仍不清楚。在这里，我们发现凋亡调节剂 Bcl-2 与 TMEM175 结合并抑制其活性。相应地，Bcl-2 抑制剂以 caspase 非依赖性方式激活该通道。TMEM175 功能的增加抑制了线粒体自噬，破坏了线粒体的动态平衡，并增加了活性氧物质 (ROS) 的产生。ROS 进一步激活 TMEM175，从而形成正反馈环以增强细胞凋亡。在帕金森病 (PD) 的 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 小鼠模型中，TMEM175 的敲除 (KO) 减轻了运动障碍和多巴胺能 (DA) 神经元的丧失，表明 TMEM175 介导线粒体凋亡在帕金森病 (PD) 中发挥着重要作用。总的来说，我们的研究揭示了 TMEM175 是细胞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。
