Lysosomal K+ Channel TMEM175 Promotes Apoptosis and Aggravates Symptoms of Parkinson's Disease

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 an MPTP mouse model of Parkinson's disease, knockout of TMEM175 mitigated motor impairment and

SUBMITTER: Lili Qu 

PROVIDER: S-SCDT-EMBOR-2021-53234-T | biostudies-other |

REPOSITORIES: biostudies-other