1. Academic Validation
  2. Lysosomal K+ channel TMEM175 promotes apoptosis and aggravates symptoms of Parkinson's disease

Lysosomal K+ channel TMEM175 promotes apoptosis and aggravates symptoms of Parkinson's disease

  • EMBO Rep. 2022 Sep 5;23(9):e53234. doi: 10.15252/embr.202153234.
Lili Qu  # 1 2 Bingqian Lin  # 1 2 Wenping Zeng 1 2 Chunhong Fan 1 2 Haotian Wu 1 2 Yushu Ge 1 Qianqian Li 1 2 Canjun Li 1 2 Yanan Wei 1 2 Jing Xin 1 Xingbing Wang 3 Dan Liu 1 Chunlei Cang 1 2
Affiliations

Affiliations

  • 1 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.
  • 2 Neurodegenerative Disorder Research Center, University of Science and Technology of China, Hefei, China.
  • 3 Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • # Contributed equally.
Abstract

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).

Keywords

Parkinson's disease; TMEM175; apoptosis; lysosome; potassium channel.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15534
    99.0%, 线粒体膜电位探针