(S)-ML-SA1 Activates Autophagy via TRPML1-TFEB Pathway

Area of Science:

• Cell Biology
• Biochemistry
• Pharmacology

Background:

• Autophagic flux is critical in disease pathogenesis.
• The lysosomal ion channel TRPML1 is a key target for lysosomal storage diseases.
• Mucolipin synthetic agonist-1 (ML-SA1) is a known TRPML1 agonist but has limitations.

Purpose of the Study:

• To synthesize and separate ML-SA1 enantiomers.
• To determine the absolute configuration of ML-SA1 enantiomers.
• To investigate the differential effects of ML-SA1 enantiomers on the TRPML1-TFEB pathway.

Main Methods:

• Chiral liquid chromatography for enantiomer separation.
• Vibrational circular dichroism (VCD) for absolute configuration determination.
• Live-cell imaging to assess TFEB translocation and autophagic flux.

Main Results:

• (S)-ML-SA1 was identified as the active enantiomer.
• (S)-ML-SA1 dose-dependently activates TRPML1 at the lysosomal membrane.
• Activation of TRPML1 by (S)-ML-SA1 leads to TFEB nuclear translocation, increased CLEAR gene expression, and enhanced autophagic flux.

Conclusions:

• (S)-ML-SA1 is a potent TRPML1 agonist with therapeutic potential.
• Targeting the TRPML1-TFEB axis with (S)-ML-SA1 may offer new treatment strategies for lysosomal storage diseases.
• This study elucidates the specific role of (S)-ML-SA1 in modulating lysosomal function and autophagy.