MCOLN1 is a ROS sensor in lysosomes that regulates autophagy

Xiaoli Zhang, Xiping Cheng, Lu Yu, Junsheng Yang, Raul Calvo, Samarjit Patnaik, Xin Hu, Qiong Gao, Meimei Yang, Maria Lawas, Markus Delling, Juan Marugan, Marc Ferrer and Haoxing Xu ()
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Xiaoli Zhang: Cellular, and Developmental Biology, University of Michigan
Xiping Cheng: Cellular, and Developmental Biology, University of Michigan
Lu Yu: Cellular, and Developmental Biology, University of Michigan
Junsheng Yang: Cellular, and Developmental Biology, University of Michigan
Raul Calvo: National Center for Advancing Translational Sciences, National Institute of Health
Samarjit Patnaik: National Center for Advancing Translational Sciences, National Institute of Health
Xin Hu: National Center for Advancing Translational Sciences, National Institute of Health
Qiong Gao: Cellular, and Developmental Biology, University of Michigan
Meimei Yang: Cellular, and Developmental Biology, University of Michigan
Maria Lawas: Cellular, and Developmental Biology, University of Michigan
Markus Delling: Children’s Hospital Boston
Juan Marugan: National Center for Advancing Translational Sciences, National Institute of Health
Marc Ferrer: National Center for Advancing Translational Sciences, National Institute of Health
Haoxing Xu: Cellular, and Developmental Biology, University of Michigan

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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 Ca2+-dependent mechanism independent of mTOR. Exogenous oxidants or increasing mitochondrial ROS levels directly and specifically activate lysosomal TRPML1 channels, inducing lysosomal Ca2+ 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.

Date: 2016
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DOI: 10.1038/ncomms12109

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