MCOLN1 is a ROS sensor in lysosomes that regulates autophagy

Zhang, Xiaoli; Cheng, Xiping; Yu, Lu; Yang, Junsheng; Calvo, Raul; Patnaik, Samarjit; Hu, Xin; Gao, Qiong; Yang, Meimei; Lawas, Maria; Delling, Markus; Marugán, Juan; Ferrer, Marc; Xu, Haoxing

doi:10.1038/ncomms12109

Cited by 387 publications

(403 citation statements)

References 44 publications

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“…The recent evidence of TRPML1 activation by ROS [41] raised the possibility that TRPML1-dependent processes are regulated by ROS as well. The initial evidence for the role of TRPML1 in lysosomal exocytosis comes from resting unstimulated human skin fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, TRPML1 has been proposed to facilitate the expulsion of the copper-filled lysosomes [28], a process that is crucial for limiting oxidative stress [26, 40]. The recent evidence of TRPML1 activation by oxidative stress [41] raises the possibility that lysosomal, exocytosis responds to oxidative stress as well. Such a response would modulate the cellular clearance pathways in a manner integrating signals from oxidative stress and cellular energy sending pathway due to the regulation of TRPML1 expression via mTORC1 and TFEB/TFE3.…”

Section: Introductionmentioning

confidence: 99%

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Biphasic regulation of lysosomal exocytosis by oxidative stress

et al. 2016

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Oxidative stress drives cell death in a number of diseases including ischemic stroke and neurodegenerative diseases. A better understanding of how cells recover from oxidative stress is likely to lead to better treatments for stroke and other diseases. The recent evidence obtained in several models ties the process of lysosomal exocytosis to the clearance of protein aggregates and toxic metals. The mechanisms that regulate lysosomal exocytosis, under normal or pathological conditions, are only beginning to emerge. Here we provide evidence for the biphasic effect of oxidative stress on lysosomal exocytosis. Lysosomal exocytosis was measured using the extracellular levels of the lysosomal enzyme beta-hexosaminidase (β-hex). Low levels or oxidative stress stimulated lysosomal exocytosis, but inhibited it at high levels. Deletion of the lysosomal ion channel TRPML1 eliminated the stimulatory effect of low levels of oxidative stress. The inhibitory effects of oxidative stress appear to target the component of lysosomal exocytosis that is driven by extracellular Ca2+. We propose that while moderate oxidative stress promotes cellular repair by stimulating lysosomal exocytosis, at high levels oxidative stress has a dual pathological effect: it directly causes cell damage and impairs damage repair by inhibiting lysosomal exocytosis. Harnessing these adaptive mechanisms may point to pharmacological interventions for diseases involving oxidative proteotoxicity or metal toxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Biphasic regulation of lysosomal exocytosis by oxidative stress

et al. 2016

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“…TRPC5, TRPA1, TRPV1, TRPV3, and TRPV4 channels are modulated by covalent modification of cysteine residues by ROS and/or RNS 42, 43 . TRPML1, a Ca 2+ -permeable non-selective cation channel that localizes to late endosomes and lysosomes 44, 45 is also activated by ROS in vitro to regulate autophagy 46 . TRPML1 appears to be ubiquitously expressed but is not known to be specifically involved in endothelial function.…”

Section: Redox-sensitive Trp Channels In the Endotheliummentioning

confidence: 99%

Redox regulation of transient receptor potential channels in the endothelium

Pires

Earley

2017

Microcirculation

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Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are important mediators of signaling pathways in the endothelium. Specific members of the transient receptor potential (TRP) superfamily of cation channels act as important Ca2+ influx pathways in endothelial cells, and are involved in endothelium-dependent vasodilation, regulation of barrier permeability, and angiogenesis. ROS and RNS can modulate the activity of certain TRP channels mainly by modifying specific cysteine residues or by stimulating the production of second messengers. In this review we highlight the recent literature describing in redox regulation of TRP channel activity in endothelial cells as well as the physiological importance of these pathways and implication for cardiovascular diseases.

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“…Accumulation of H 2 O 2 can oxidize the activity of the ATG4 [40]. Oxidized ATG4 promotes lipidation of LC3/ATG8 for autophagy initiation [41]. The ROS-dependent of LC3-PE accumulates on the autophagosomal membranes, followed by promoting the first steps in autophagosome formation.…”

Section: Ros Induce Autophagymentioning

confidence: 99%

Antioxidants Maintain Cellular Redox Homeostasis by Elimination of Reactive Oxygen Species

Farrar

et al. 2017

Cell Physiol Biochem

1,286

689

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Reactive oxygen species (ROS) are produced by living cells as normal cellular metabolic byproduct. Under excessive stress conditions, cells will produce numerous ROS, and the living organisms eventually evolve series of response mechanisms to adapt to the ROS exposure as well as utilize it as the signaling molecules. ROS molecules would trigger oxidative stress in a feedback mechanism involving many biological processes, such as apoptosis, necrosis and autophagy. Growing evidences have suggested that ROS play a critical role as the signaling molecules throughout the entire cell death pathway. Overwhelming production of ROS can destroy organelles structure and bio-molecules, which lead to inflammatory response that is a known underpinning mechanism for the development of diabetes and cancer. Cytochrome P450 enzymes (CYP) are regarded as the markers of oxidative stress, can transform toxic metabolites into ROS, such as superoxide anion, hydrogen peroxide and hydroxyl radical which might cause injury of cells. Accordingly, cells have evolved a balanced system to neutralize the extra ROS, namely antioxidant systems that consist of enzymatic antioxidants such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidases (GPxs), thioredoxin (Trx) as well as the non-enzymatic antioxidants which collectively reduce oxidative state. Herein, we review the recent novel findings of cellular processes induced by ROS, and summarize the roles of cellular endogenous antioxidant systems as well as natural anti-oxidative compounds in several human diseases caused by ROS in order to illustrate the vital role of antioxidants in prevention against oxidative stress.

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MCOLN1 is a ROS sensor in lysosomes that regulates autophagy

Cited by 387 publications

References 44 publications

Biphasic regulation of lysosomal exocytosis by oxidative stress

Biphasic regulation of lysosomal exocytosis by oxidative stress

Redox regulation of transient receptor potential channels in the endothelium

Antioxidants Maintain Cellular Redox Homeostasis by Elimination of Reactive Oxygen Species

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