TMEM175 Is an Organelle K(+) Channel Regulating Lysosomal Function

Area of Science:

• Cell Biology
• Molecular Biology
• Physiology

Background:

• Potassium ions (K+) are vital for cellular functions, primarily studied at the plasma membrane.
• The role of potassium in organelle function, particularly in lysosomes and endosomes, remains largely unknown.
• Understanding organelle ion transport is critical for cellular homeostasis.

Purpose of the Study:

• To investigate the mechanism of potassium (K+) permeation across organelle membranes.
• To identify the protein responsible for K+ conductance in lysosomes and endosomes.
• To elucidate the functional significance of organelle K+ channels in cellular processes.

Main Methods:

• Direct recording of organelle K+ conductance.
• Genetic deletion of TMEM175 in lysosomes.
• Measurement of lysosomal membrane potential (ΔΨ) and luminal pH.
• Analysis of autophagosome-lysosome fusion dynamics.

Main Results:

• A novel K+-selective channel, KEL, was identified on endosomes and lysosomes, formed by TMEM175.
• TMEM175 lacks canonical K+ channel features (e.g., GYG signature).
• Lysosomes deficient in TMEM175 showed impaired K+ conductance, depolarized membrane potential, unstable pH, and defects in autophagy.

Conclusions:

• TMEM175 functions as a K+ channel, mediating lysosomal and endosomal potassium permeability.
• This discovery provides the molecular basis for organelle K+ transport.
• TMEM175 is essential for maintaining lysosomal function and cellular homeostasis during autophagy.