title: MCOLN1 is a ROS sensor in lysosomes that regulates autophagy.
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.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, Michigan 48109, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, Michigan 48109, USA.
authors.forename: Xiping
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, Michigan 48109, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, Michigan 48109, USA.|Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China.
authors.forename: Junsheng
authors.initials: J
authors.lastname: Yang
authors.affiliation: National Center for Advancing Translational Sciences, National Institute of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Calvo
authors.affiliation: National Center for Advancing Translational Sciences, National Institute of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA.
authors.forename: Samarjit
authors.initials: S
authors.lastname: Patnaik
authors.affiliation: National Center for Advancing Translational Sciences, National Institute of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, Michigan 48109, USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, Michigan 48109, USA.
authors.forename: Meimei
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, Michigan 48109, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Lawas
authors.affiliation: The Department of Cardiology, Children's Hospital Boston, Enders 1350, 320 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Delling
authors.affiliation: National Center for Advancing Translational Sciences, National Institute of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Marugan
authors.affiliation: National Center for Advancing Translational Sciences, National Institute of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Ferrer
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, Michigan 48109, USA.
authors.forename: Haoxing
authors.initials: H
authors.lastname: Xu
mesh_terms: D000818:Animals; D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D001678:Organelle Biogenesis; D018408:Patch-Clamp Techniques; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C502070:MAP1LC3B protein, human; C416674:MCOLN1 protein, human; D008869:Microtubule-Associated Proteins; D017382:Reactive Oxygen Species; C064972:TFEB protein, human; D050051:Transient Receptor Potential Channels; D002118:Calcium