TMEM175 Is an Organelle K+ Channel Regulating Lysosomal Function

Potassium is the most abundant ion to face both plasma and organelle membranes. Extensive research over the past seven decades has characterized how K+ permeates the plasma membrane to control fundamental processes such as secretion, neuronal communication, and heartbeat. However, how K+ permeates organelles such as lysosomes and endosomes is unknown. Here, we directly recorded organelle K+ conductance and discovered a major K+-selective channel K-EL on endosomes and lysosomes. K-EL is formed by TMEM175, a protein with unknown function. Unlike any of the similar to 80 plasma membrane K+ channels, TMEM175 has two repeats of 6-transmembrane-spanning segments and has no GYG K+ channel sequence signature-containing, pore-forming P loop. Lysosomes lacking TMEM175 exhibit no K+ conductance, have a markedly depolarized Delta Psi and little sensitivity to changes in [K+], and have compromised luminal pH stability and abnormal fusion with autophagosomes during autophagy. Thus, TMEM175 comprises a K+ channel that underlies the molecular mechanism of lysosomal K+ permeability.