Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice

Spix, Barbara; Butz, Elisabeth; Chen, Cheng‐Chang; Rosato, Anna Scotto; Tang, Rachel; Jeridi, Aicha; Kudrina, Veronika; Plesch, Eva; Wartenberg, Philipp; Arlt, Elisabeth; Briukhovetska, Daria; Ansari, Meshal; Günsel, Gizem Günes; Conlon, Thomas M.; Wyatt, Amanda; Wetzel, S.; Teupser, Daniel; Holdt, Lesca M.; Ectors, Fabien; Boekhoff, Ingrid; Boehm, Ulrich; Garcı́a-Añoveros, Jaime; Säftig, Paul; Giera, Martin; Kobold, Sebastian; Schiller, Herbert B.; Zierler, Susanna; Gudermann, Thomas; Wahl‐Schott, Christian; Bracher, Franz; Yildirim, Ali Önder; Biel, Martin; Grimm, Christian

doi:10.1038/s41467-021-27860-x

Cited by 47 publications

(28 citation statements)

References 75 publications

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“…Therefore, activation of TRPV2 channels may protect from cigarette smoke-induced COPD in alveoli. A similar mechanism was observed in TRPML3-deficient mice, which showed emphysema-like changes that were further exacerbated by exposure to tobacco smoke [ 127 ]. These changes were linked to an impaired early endolysosomal trafficking as well as defects in endocytosis in TRPML3−/− mice [ 127 ].…”

Section: Trp Expression and Function In Alveolimentioning

confidence: 52%

Transient Receptor Potential (TRP) Channels in Airway Toxicity and Disease: An Update

Müller¹,

Alt²,

Rajan³

et al. 2022

Cells

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Our respiratory system is exposed to toxicants and pathogens from both sides: the airways and the vasculature. While tracheal, bronchial and alveolar epithelial cells form a natural barrier in the airways, endothelial cells protect the lung from perfused toxic compounds, particulate matter and invading microorganism in the vascular system. Damages induce inflammation by our immune response and wound healing by (myo)fibroblast proliferation. Members of the transient receptor potential (TRP) superfamily of ion channel are expressed in many cells of the respiratory tract and serve multiple functions in physiology and pathophysiology. TRP expression patterns in non-neuronal cells with a focus on TRPA1, TRPC6, TRPM2, TRPM5, TRPM7, TRPV2, TRPV4 and TRPV6 channels are presented, and their roles in barrier function, immune regulation and phagocytosis are summarized. Moreover, TRP channels as future pharmacological targets in chronic obstructive pulmonary disease (COPD), asthma, cystic and pulmonary fibrosis as well as lung edema are discussed.

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Section: Trp Expression and Function In Alveolimentioning

confidence: 52%

Transient Receptor Potential (TRP) Channels in Airway Toxicity and Disease: An Update

Müller¹,

Alt²,

Rajan³

et al. 2022

Cells

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“…However, these activators lack specificity for TRPML channel subtypes ( Grimm, 2016 ; Plesch et al, 2018 ; Shen et al, 2012 ). Recently, an isoform-selective activator for TRPML1, based on the structure of MLSA-1, called ML1-SA-1, has been developed by introduction of four additional chlorine substituents in the phthalimide subunit as characterized in Spix et al (2022) ( Fig. 1 A).…”

Section: Resultsmentioning

confidence: 99%

Lysosomal TRPML1 regulates mitochondrial function in hepatocellular carcinoma cells

Siow

Kabiri

Tang

et al. 2022

Journal of Cell Science

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Liver cancers, including hepatocellular carcinoma (HCC), are the second most lethal cancers worldwide and novel therapeutic strategies are still highly needed. Recently, the endolysosomal cation channel TRPML1 has gained focus in cancer research representing an interesting novel target. We utilized the recently developed isoform-selective TRPML1 activator ML1-SA1 and the CRISPR/Cas9 system to generate tools for over-activation and loss-of-function studies on TRPML1 in HCC. After verification of our tools, we investigated the role of TRPML1 in HCC by studying proliferation, apoptosis, and proteomic alterations. Further, we analyzed mitochondrial function in detail, facilitating confocal and transmission electron microscopy, combined with SeahorseTM and Oroboros® functional analysis. We report that TRPML1 over-activation by a novel, isoform-selective, low-molecular activator induces apoptosis by impairing mitochondrial function calcium dependently. Additionally, TRPML1 loss-of-function deregulates mitochondrial renewal, which leads to proliferation impairment. Thus, our study reveals a novel role for TRPML1 as regulator of mitochondrial function and its modulators as promising molecules for novel therapeutic options in HCC therapy.

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“…Only P2X4 and its role in surfactant release from lamellar bodies, lysosome-related organelles is well proven; likewise, the recent study of TRPML3 and its role for emphysema formation is strongly linked to its expression in endolysosomes. Plasma membrane expression of TRPML3 in endogenous cell systems including alveolar macrophages could not be confirmed [ 1 ]. By contrast, while the patch-clamp evidence for BK in endolysosomes is very convincing, potential roles in lung function seem not connected to endolysosomes.…”

Section: Discussionmentioning

confidence: 99%

“…Spix et al recently reported the first bona fide single TRPML3 knockout disease phenotype [ 1 ]. In two independently generated Trpml3 knockout mouse models, lung function measurements revealed an emphysema-like phenotype under basal conditions which strongly exacerbated under elastase treatment or tobacco smoke exposure.…”

Section: Trpml3—regulator Of Mmp-12 Levels In Bronchoalveolar Fluid: Early Endosomes Of Alveolar Macrophagesmentioning

confidence: 99%

“…We will discuss here the recent discovery that a non-selective Ca 2+ permeable cation channel of the TRP (transient receptor potential) superfamily, TRPML3, which is mainly expressed in alveolar macrophages in the lung and which is residing in intracellular compartments, so called endosomes and lysosomes, results in exacerbation of lung tissue injury and emphysema formation under basal, elastase or cigarette smoke exposure when absent or dysfunctional [ 1 ]. In this context, we will also discuss current knowledge on functional roles of other endolysosomal/vesicular/LRO ion channels in the lung.…”

Section: Introductionmentioning

confidence: 99%

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Endolysosomal Cation Channels and Lung Disease

Spix

Jeridi

Ansari

et al. 2022

Cells

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Endolysosomal cation channels are emerging as key players of endolysosomal function such as endolysosomal trafficking, fusion/fission, lysosomal pH regulation, autophagy, lysosomal exocytosis, and endocytosis. Diseases comprise lysosomal storage disorders (LSDs) and neurodegenerative diseases, metabolic diseases, pigmentation defects, cancer, immune disorders, autophagy related diseases, infectious diseases and many more. Involvement in lung diseases has not been a focus of attention so far but recent developments in the field suggest critical functions in lung physiology and pathophysiology. Thus, loss of TRPML3 was discovered to exacerbate emphysema formation and cigarette smoke induced COPD due to dysregulated matrix metalloproteinase 12 (MMP-12) levels in the extracellular matrix of the lung, a known risk factor for emphysema/COPD. While direct lung function measurements with the exception of TRPML3 are missing for other endolysosomal cation channels or channels expressed in lysosome related organelles (LRO) in the lung, links between those channels and important roles in lung physiology have been established such as the role of P2X4 in surfactant release from alveolar epithelial Type II cells. Other channels with demonstrated functions and disease relevance in the lung such as TRPM2, TRPV2, or TRPA1 may mediate their effects due to plasma membrane expression but evidence accumulates that these channels might also be expressed in endolysosomes, suggesting additional and/or dual roles of these channels in cell and intracellular membranes. We will discuss here the current knowledge on cation channels residing in endolysosomes or LROs with respect to their emerging roles in lung disease.

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Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice

Cited by 47 publications

References 75 publications

Transient Receptor Potential (TRP) Channels in Airway Toxicity and Disease: An Update

Transient Receptor Potential (TRP) Channels in Airway Toxicity and Disease: An Update

Lysosomal TRPML1 regulates mitochondrial function in hepatocellular carcinoma cells

Endolysosomal Cation Channels and Lung Disease

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