TRPML1-/TFEB-Dependent Regulation of Lysosomal Exocytosis

Paola, Simone Di; Medina, Diego L.

doi:10.1007/978-1-4939-9018-4_12

Cited by 18 publications

(16 citation statements)

References 7 publications

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“…Probably, mitochondrial ROS can regulate exocytosis of mast cells by acting on Ca 2+ channels in secretory granules. The main lysosomal Ca 2+ channel mucolipin-1 (MCOLN1/TRPML1) is localized in the secretory lysosomes of NK cells related to secretory granules ( 73 ) and can be directly activated by mitochondrial ROS ( 61 , 74 , 75 ). Ca 2+ release via TRPML1 leads to lysosomal fission ( 76 ) and calcineurin-dependent translocation of the nuclear transcription factor TFEB which stimulates lysosome exocytosis, autophagy, and lysosome biogenesis ( 61 , 74 , 75 ).…”

Section: The Role Played By Mitochondria In the Fcεri-dependent Mast mentioning

confidence: 99%

“…The main lysosomal Ca 2+ channel mucolipin-1 (MCOLN1/TRPML1) is localized in the secretory lysosomes of NK cells related to secretory granules ( 73 ) and can be directly activated by mitochondrial ROS ( 61 , 74 , 75 ). Ca 2+ release via TRPML1 leads to lysosomal fission ( 76 ) and calcineurin-dependent translocation of the nuclear transcription factor TFEB which stimulates lysosome exocytosis, autophagy, and lysosome biogenesis ( 61 , 74 , 75 ). The key role of mucolipin-1 in the regulation of granule exocytosis was demonstrated in experiments in which the pharmacological inhibition of phosphoinositide kinase PIKfyve, which stimulates the opening of the mucolipin-1 channel, inhibited exocytosis in mouse bone marrow-derived mast cells during FcεRI-dependent activation ( 77 ).…”

Section: The Role Played By Mitochondria In the Fcεri-dependent Mast mentioning

confidence: 99%

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The Role Played by Mitochondria in FcεRI-Dependent Mast Cell Activation

et al. 2020

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Mast cells play a key role in the regulation of innate and adaptive immunity and are involved in pathogenesis of many inflammatory and allergic diseases. The most studied mechanism of mast cell activation is mediated by the interaction of antigens with immunoglobulin E (IgE) and a subsequent binding with the high-affinity receptor Fc epsilon RI (FcεRI). Increasing evidences indicated that mitochondria are actively involved in the FcεRI-dependent activation of this type of cells. Here, we discuss changes in energy metabolism and mitochondrial dynamics during IgE-antigen stimulation of mast cells. We reviewed the recent data with regards to the role played by mitochondrial membrane potential, mitochondrial calcium ions (Ca 2+) influx and reactive oxygen species (ROS) in mast cell FcεRI-dependent activation. Additionally, in the present review we have discussed the crucial role played by the pyruvate dehydrogenase (PDH) complex, transcription factors signal transducer and activator of transcription 3 (STAT3) and microphthalmia-associated transcription factor (MITF) in the development and function of mast cells. These two transcription factors besides their nuclear localization were also found to translocate in to the mitochondria and functions as direct modulators of mitochondrial activity. Studying the role played by mast cell mitochondria following their activation is essential for expanding our basic knowledge about mast cell physiological functions and would help to design mitochondria-targeted anti-allergic and anti-inflammatory drugs.

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Section: The Role Played By Mitochondria In the Fcεri-dependent Mast mentioning

confidence: 99%

Section: The Role Played By Mitochondria In the Fcεri-dependent Mast mentioning

confidence: 99%

The Role Played by Mitochondria in FcεRI-Dependent Mast Cell Activation

et al. 2020

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“…Transient release of lysosomal calcium locally by TRPML1 activates calcineurin, a protein phosphatase, which dephosphorylates TFEB sites targeted by mTORC1 and releases from 14-3-3, thereby translocating to the nucleus (Napolitano et al, 2018). Nonetheless, TRPML1 is also regulated by PI3,5 bisphosphate in the lysosomal membrane, which is synthesized by PIKFYVE kinase (Di Paola and Medina, 2019). Therefore, these kinases and phosphatases may also involve in the regulation of lysosomal function, autophagy/mitophagy flux, exocytosis, and mitochondrial biogenesis.…”

Section: Discussionmentioning

confidence: 99%

Auranofin Mediates Mitochondrial Dysregulation and Inflammatory Cell Death in Human Retinal Pigment Epithelial Cells: Implications of Retinal Neurodegenerative Diseases

2019

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PurposePhotoreceptor degeneration occurs in various retinal diseases including age-related macular degeneration (AMD), Retinitis pigmentosa (RP), and diabetic retinopathy (DR). However, molecular mechanisms are not fully understood yet. The retinal pigment epithelium (RPE) forms the outer blood retinal barrier (oBRB) and supplies glucose, oxygen and nutrients from the fenestrated choriocapillaris to photoreceptors for visual function. Therefore, RPE dysfunction leads to photoreceptor injury/death and progression of blinding eye diseases. This study aims to understand the role of the thioredoxin (Trx) and its reductase (TrxR) redox signaling in human RPE dysfunction and cell death mechanism(s) in an in vitro system.MethodsA human RPE cell line (APRE-19) was cultured in DMEM/F12 medium and treated with auranofin (AF – 4 μM, an inhibitor of TrxR) for 4 and 24 h. Mitochondrial and lysosomal function, cellular oxidative stress and NLRP3 inflammasome activity were measured using cell assays, Western blotting, and confocal microscopy. Antioxidants and anti-inflammatory compounds were tested for blocking AF effects on RPE damage. Cell death mechanisms (LDH release to culture media) were determined using necroptosis, ferroptosis and pyroptosis inhibitors. P < 0.05 was considered significant in statistical analysis.ResultsAuranofin causes mitochondrial dysfunction (Δψm↓ and ATP↓), oxidative stress (H2O2↑) and mitophagic flux to lysosomes. Furthermore, the lysosomal enzyme (cathepsin L) activity is reduced while that of pro-inflammatory caspase-1 (NLRP3 inflammasome) is enhanced in ARPE-19. These effects of AF on ARPE-19 are inhibited by antioxidant N-acetylcysteine (5 mM, NAC) and significantly by a combination of SS31 (mitochondrial antioxidant) and anti-inflammatory drugs (amlexanox and tranilast). AF also causes cell death as measured by cytosolic LDH release/leakage, which is not inhibited by either ferrostatin-1 or necrostatin-1 (ferroptosis and necroptosis inhibitors, respectively). Conversely, AF-induced LDH release is significantly reduced by MCC950 and Ac-YVAD-cmk (NLRP3 and Caspase-1 inhibitors, respectively), suggesting a pro-inflammatory cell death by pyroptosis.ConclusionThe Trx/TrxR redox system is critical for RPE function and viability. We previously showed that thioredoxin-interacting protein (TXNIP) is strongly induced in DR inhibiting the Trx/TrxR system and RPE dysfunction. Therefore, our results suggest that the TXNIP-Trx-TrxR redox pathway may participate in RPE dysfunction in DR and other retinal neurodegenerative diseases.

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“…Furthermore, lysosomal content is increasingly released into the extracellular compartment, such as cathepsin D and V-ATPase (41,71). Enhanced membrane fusion and subsequent exocytosis could be mediated by lysosomal calcium release via activation of lysosomal cation channels, such as TRPML1 (42). After lysosomal exocytosis, former trapped cytostatics are again abundant in the extracellular compartment, enabling repeated diffusion into the cell.…”

Section: The Lysosome As Drug Safe Housementioning

confidence: 99%

Targeting Lysosomes in Cancer as Promising Strategy to Overcome Chemoresistance—A Mini Review

et al. 2020

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To date, cancer remains a worldwide leading cause of death, with a still rising incidence. This is essentially caused by the fact, that despite the abundance of therapeutic targets and treatment strategies, insufficient response and multidrug resistance frequently occur. Underlying mechanisms are multifaceted and extensively studied. In recent research, it became evident, that the lysosome is of importance in drug resistance phenotypes. While it has long been considered just as cellular waste bag, it is now widely known that lysosomes play an important role in important cellular signaling processes and are in the focus of cancer research. In that regard lysosomes are now considered as so-called "drug safe-houses" in which chemotherapeutics are trapped passively by diffusion or actively by lysosomal P-glycoprotein activity, which prevents them from reaching their intracellular targets. Furthermore, alterations in lysosome to nucleus signaling by the transcription factor EB (TFEB)-mTORC1 axis are implicated in development of chemoresistance. The identification of lysosomes as essential players in drug resistance has introduced novel strategies to overcome chemoresistance and led to innovate therapeutic approaches. This mini review gives an overview of the current state of research on the role of lysosomes in chemoresistance, summarizing underlying mechanisms and treatment strategies and critically discussing open questions and drawbacks.

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TRPML1-/TFEB-Dependent Regulation of Lysosomal Exocytosis

Cited by 18 publications

References 7 publications

The Role Played by Mitochondria in FcεRI-Dependent Mast Cell Activation

The Role Played by Mitochondria in FcεRI-Dependent Mast Cell Activation

Auranofin Mediates Mitochondrial Dysregulation and Inflammatory Cell Death in Human Retinal Pigment Epithelial Cells: Implications of Retinal Neurodegenerative Diseases

Targeting Lysosomes in Cancer as Promising Strategy to Overcome Chemoresistance—A Mini Review

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