bims-lypmec 2024-01-28 papers

Issue of 2024‒01‒28
four papers selected by
Satoru Kobayashi, New York Institute of Technology

Biology (Basel). 2024 Jan 07. pii: 34. [Epub ahead of print]13(1):

Lysosomal Dysfunction: Connecting the Dots in the Landscape of Human Diseases.

Elisabet Uribe-Carretero, Verónica Rey, Jose Manuel Fuentes, Isaac Tamargo-Gómez.

Lysosomes are the main organelles responsible for the degradation of macromolecules in eukaryotic cells. Beyond their fundamental role in degradation, lysosomes are involved in different physiological processes such as autophagy, nutrient sensing, and intracellular signaling. In some circumstances, lysosomal abnormalities underlie several human pathologies with different etiologies known as known as lysosomal storage disorders (LSDs). These disorders can result from deficiencies in primary lysosomal enzymes, dysfunction of lysosomal enzyme activators, alterations in modifiers that impact lysosomal function, or changes in membrane-associated proteins, among other factors. The clinical phenotype observed in affected patients hinges on the type and location of the accumulating substrate, influenced by genetic mutations and residual enzyme activity. In this context, the scientific community is dedicated to exploring potential therapeutic approaches, striving not only to extend lifespan but also to enhance the overall quality of life for individuals afflicted with LSDs. This review provides insights into lysosomal dysfunction from a molecular perspective, particularly in the context of human diseases, and highlights recent advancements and breakthroughs in this field.

Keywords: autophagosome; autophagy; genetic mutations; lysosomal storage disease; lysosome; therapeutic approaches

DOI: https://doi.org/10.3390/biology13010034

Inhal Toxicol. 2024 Jan 23. 1-13

Lysosomal BK channels facilitate silica-induced inflammation in macrophages.

Rebekah L Kendall, Andrij Holian.

BACKGROUND: Lysosomal ion channels are proposed therapeutic targets for a number of diseases, including those driven by NLRP3 inflammasome-mediated inflammation. Here, the specific role of the lysosomal big conductance Ca2+-activated K+ (BK) channel was evaluated in a silica model of inflammation in murine macrophages. A specific-inhibitor of BK channel function, paxilline (PAX), and activators NS11021 and NS1619 were utilized to evaluate the role of lysosomal BK channel activity in silica-induced lysosomal membrane permeabilization (LMP) and NLRP3 inflammasome activation resulting in IL-1β release.METHODS: Murine macrophages were exposed in vitro to crystalline silica following pretreatment with BK channel inhibitors or activators and LMP, cell death, and IL-1β release were assessed. In addition, the effect of PAX treatment on silica-induced cytosolic K+ decrease was measured. Finally, the effects of BK channel modifiers on lysosomal pH, proteolytic activity, and cholesterol transport were also evaluated.
RESULTS: PAX pretreatment significantly attenuated silica-induced cell death and IL-1β release. PAX caused an increase in lysosomal pH and decrease in lysosomal proteolytic activity. PAX also caused a significant accumulation of lysosomal cholesterol. BK channel activators NS11021 and NS1619 increased silica-induced cell death and IL-1β release. BK channel activation also caused a decrease in lysosomal pH and increase in lysosomal proteolytic function as well as a decrease in cholesterol accumulation.
CONCLUSION: Taken together, these results demonstrate that inhibiting lysosomal BK channel activity with PAX effectively reduced silica-induced cell death and IL-1β release. Blocking cytosolic K+ entry into the lysosome prevented LMP through the decrease of lysosomal acidification and proteolytic function and increase in lysosomal cholesterol.

Keywords: LMP; Macrophage; cholesterol; inflammation; ion channels; lysosome; silica

DOI: https://doi.org/10.1080/08958378.2024.2305112

Dev Cell. 2024 Jan 19. pii: S1534-5807(24)00003-0. [Epub ahead of print]

A single fluorescent probe to examine the dynamics of mitochondria-lysosome interplay and extracellular vesicle role in ferroptosis.

Ling-Li Wang, Yu-Zhuo Mai, Ming-Hua Zheng, Guang-Hai Yan, Jing-Yi Jin.

Ferroptosis is a non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation and glutathione (GSH) depletion. Despite recent advances, challenges remain in understanding the bidirectional interactions or interplay between organelles during ferroptosis. In this study, we aimed to understand the interplay between mitochondria (Mito) and lysosomes (Lyso) in cell homeostasis and ferroptosis. For this purpose, we designed a single fluorescent probe that marks GSH in Mito and hypochlorous acid (HOCl) in Lyso with two distinct emissions. Using this dual-targeted single fluorescent probe (9-morphorino pyronine), we detected Mito-Lyso interplay in ferroptosis. We disclosed differences in Mito-Lyso interplay depending on the induction of ferroptosis. Although erastin treatment decreased GSH, RSL3 triggered a HOCl burst, and FIN56- and FINO2-induced ferroptosis increased GSH and HOCl. Additionally, we showed that only extracellular vesicles generated during erastin-induced ferroptosis could spontaneously move and dock to neighboring cells, resulting in accelerated cell death.

Keywords: cell imaging; extracellular vesicles; ferroptosis; fluorescent probe; mitochondria-lysosome interplay

DOI: https://doi.org/10.1016/j.devcel.2024.01.003

Transl Oncol. 2024 Jan 22. pii: S1936-5233(23)00246-2. [Epub ahead of print]41 101860

Lysosomal alkalinization in nutrient restricted cancer cells activates cytoskeletal rearrangement to enhance partial epithelial to mesenchymal transition.

H Hazal Hüsnügil, Aliye Ezgi Güleç Taşkıran, Ismail Güderer, Leman Nur Nehri, Göksu Oral, Nazlı Şevval Menemenli, Özün Özcan, Ariana Noghreh, Aytekin Akyol, Sreeparna Banerjee.

INTRODUCTION: Nutrient restriction in cancer cells can activate a number of stress response pathways for cell survival. We aimed to determine mechanistically how nutrient depletion in colorectal cancer (CRC) cells leads to cellular adaptation.MATERIALS AND METHODS: Cell survival under nutrient depletion (ND) was evaluated by colony formation and in vivo tumor formation assays. Lysosomes are activated with ND; therefore, we incubated the ND cells with the V-ATPase inhibitor Bafilomycin A1 (ND+Baf). The expression of epithelial and mesenchymal markers with ND+Baf was determined by RNA sequencing and RT-qPCR while motility was determined with an in vivo Chorioallantoic membrane (CAM) assay. Reorganization of cytoskeletal network and lysosomal positioning was determined by immunocytochemistry.
RESULTS: 4 different colorectal cancer (CRC) cell lines under ND showed high viability, tumor forming ability and increased expression of one or more epithelial and mesenchymal markers, suggesting the activation of partial (p)-EMT. We observed a further increase in p-EMT markers, numerous membrane protrusions, decreased cell-cell adhesion in 3D, and increased motility in ND+Baf cells. The protrusions in the ND+Baf cells were primarily mediated by microtubules and enabled the relocalization of lysosomes from the perinuclear region to the periphery.
CONCLUSIONS: ND activated p-EMT in CRC cells, which was exacerbated by lysosomal alkalinization. The ND+Baf cells also showed numerous protrusions containing lysosomes, which may lead to lysosomal exocytosis and enhanced motility.

Keywords: Lysosome, cytoskeleton; Nutrient restriction; Partial EMT

DOI: https://doi.org/10.1016/j.tranon.2023.101860