MCOLN1 is a ROS sensor in lysosomes that regulates autophagy

Nat Commun. 2016 Jun 30;7:12109. doi: 10.1038/ncomms12109.

Abstract

Cellular stresses trigger autophagy to remove damaged macromolecules and organelles. Lysosomes 'host' multiple stress-sensing mechanisms that trigger the coordinated biogenesis of autophagosomes and lysosomes. For example, transcription factor (TF)EB, which regulates autophagy and lysosome biogenesis, is activated following the inhibition of mTOR, a lysosome-localized nutrient sensor. Here we show that reactive oxygen species (ROS) activate TFEB via a lysosomal Ca(2+)-dependent mechanism independent of mTOR. Exogenous oxidants or increasing mitochondrial ROS levels directly and specifically activate lysosomal TRPML1 channels, inducing lysosomal Ca(2+) release. This activation triggers calcineurin-dependent TFEB-nuclear translocation, autophagy induction and lysosome biogenesis. When TRPML1 is genetically inactivated or pharmacologically inhibited, clearance of damaged mitochondria and removal of excess ROS are blocked. Furthermore, TRPML1's ROS sensitivity is specifically required for lysosome adaptation to mitochondrial damage. Hence, TRPML1 is a ROS sensor localized on the lysosomal membrane that orchestrates an autophagy-dependent negative-feedback programme to mitigate oxidative stress in the cell.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Autophagy*
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
  • COS Cells
  • Calcium / metabolism
  • Chlorocebus aethiops
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Lysosomes / metabolism*
  • Mice
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / metabolism
  • Organelle Biogenesis
  • Patch-Clamp Techniques
  • Reactive Oxygen Species / metabolism*
  • Transient Receptor Potential Channels / metabolism*

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • MAP1LC3B protein, human
  • MCOLN1 protein, human
  • Microtubule-Associated Proteins
  • Reactive Oxygen Species
  • TFEB protein, human
  • Transient Receptor Potential Channels
  • Calcium