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Cited by 558Calcium signaling and nucleotide metabolismAutophagy in Disease and TherapyRedox biology and oxidative stress

MCOLN1 is a ROS sensor in lysosomes that regulates autophagy

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Zhang, Xiaoli, Cheng, Xiping, Yu, Lu, Yang, Junsheng, Calvo, Raul, Patnaik, Samarjit, Hu, Xin, Gao, Qiong +6 more·2016·Nature Communications
DOI 10.1038/ncomms12109PMC PMC4931332
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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.

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Cited by

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Authors
Zhang, X., Cheng, X., Yu, L., Yang, J., Calvo, R., Patnaik, S., Hu, X., Gao, Q., Yang, M., Lawas, M., Delling, M., Marugan, J., Ferrer, M., & Xu, H.
Affiliations
  • University of Michigan (US)
  • National Institutes of Health (US)
  • Boston Children's Hospital (US)
Corresponding author
Xu, Haoxing
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2016-06-30
Volume
7
Issue
1
Pages
12109-12109
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms12109
PMC
PMC4931332
OpenAlex
W2464503524
Cited by
558
References
9
Citations by year
2026: 39 · 2025: 62 · 2024: 78 · 2023: 59 · 2022: 61 · 2021: 75 · 2020: 62 · 2019: 47 · 2018: 31 · 2017: 34 · 2016: 10
FWCI
37.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (AR060837, NS062792)
  • National Institute of Mental Health (R03MH096595)
  • National Institute of Neurological Disorders and Stroke (R21NS091928, R01NS062792)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR060837)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
MCOLN1, TRPML1, reactive oxygen species, lysosomes, autophagy, TFEB, lysosomal calcium release, calcineurin, mitochondrial damage, lysosomal biogenesis, oxidative stress, autophagosome formation
MeSH terms
Animals, Autophagy, Organelle Biogenesis, Calcium, Chlorocebus aethiops, HeLa Cells, Humans, Lysosomes, Microtubule-Associated Proteins, Mitochondria, Reactive Oxygen Species, Patch-Clamp Techniques, COS Cells, Transient Receptor Potential Channels, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, HEK293 Cells

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