Role of Lysosomal Acidification Dysfunction in Mesenchymal Stem Cell Senescence

Zhang, Weijun; Bai, Jinwu; Hang, Kai; Xu, Jianxiang; Zhou, Chengwei; Li, Lijun; Wang, Zhongxiang; Wang, Yibo; Wang, Kanbin; Xue, Deting

doi:10.3389/fcell.2022.817877

Cited by 11 publications

(9 citation statements)

References 112 publications

(100 reference statements)

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“…Besides the induction of cell death pathways, disruption of the lysosomal pH and loss of lysosomal integrity have consequences on various cellular processes. The neutralization of lysosomal pH impairs the degrading activity of lysosomes essential for recycling and scavenging, and can cause the formation of toxic digestion products or reactive oxygen species (ROS) [ 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

Ursolic Acid Impairs Cellular Lipid Homeostasis and Lysosomal Membrane Integrity in Breast Carcinoma Cells

Fogde

Xavier

Balnytė

et al. 2022

Cells

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Cancer is one of the leading causes of death worldwide, thus the search for new cancer therapies is of utmost importance. Ursolic acid is a naturally occurring pentacyclic triterpene with a wide range of pharmacological activities including anti-inflammatory and anti-neoplastic effects. The latter has been assigned to its ability to promote apoptosis and inhibit cancer cell proliferation by poorly defined mechanisms. In this report, we identify lysosomes as the essential targets of the anti-cancer activity of ursolic acid. The treatment of MCF7 breast cancer cells with ursolic acid elevates lysosomal pH, alters the cellular lipid profile, and causes lysosomal membrane permeabilization and leakage of lysosomal enzymes into the cytosol. Lysosomal membrane permeabilization precedes the essential hallmarks of apoptosis placing it as an initial event in the cascade of effects induced by ursolic acid. The disruption of the lysosomal function impairs the autophagic pathway and likely partakes in the mechanism by which ursolic acid kills cancer cells. Furthermore, we find that combining treatment with ursolic acid and cationic amphiphilic drugs can significantly enhance the degree of lysosomal membrane permeabilization and cell death in breast cancer cells.

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Section: Discussionmentioning

confidence: 99%

Ursolic Acid Impairs Cellular Lipid Homeostasis and Lysosomal Membrane Integrity in Breast Carcinoma Cells

Fogde

Xavier

Balnytė

et al. 2022

Cells

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“…It is known that lysosomes contain a variety of degrading enzymes. 2–5,50 These enzymes, such as Cathepsin B enzyme exert the highest biological activity in an acidic environment (pH 4.5–5.0), and lysosomal alkalization leads to a decrease or deactivation in the activity of lysosomal hydrolytic enzymes. 14,38 Thus, we tested the effect of compounds 1–12 on the activity of Cathepsin B enzyme using a Magic Red Cathepsin assay.…”

Section: Resultsmentioning

confidence: 99%

“…It is known that lysosomes are membrane-bound subcellular organelles and maintain cellular homeostasis by generating a highly acidic environment. 1 Lysosomal enzymes are responsible for breaking down carbohydrates, nucleic acids, lipids and proteins, 2–6 and usually exert the maximal activity in an acidic environment (pH 4.5–5.0). 7–14 Leakage of protons due to a defective proton pump or lysosomal permeabilization would lead to lysosomal alkalization and consequently a decrease or deactivation in the activity of lysosomal hydrolytic enzymes.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and mechanism of biological action of morpholinyl-bearing arylsquaramides as small-molecule lysosomal pH modulators

et al. 2022

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“…ALP impairment is widely observed in AD and other neurodegenerative diseases [ 3 , 70 ]. Some studies have suggested that lysosome alkalinization may cause rupture of lysosomes and lead to premature release of undigested content [ 71 ]. Therefore, it is believed that alkaline lysosomes are more harmful than acidic lysosomes.…”

Section: Discussionmentioning

confidence: 99%

“…In summary, our data suggest that hyperphosphorylated tau leads to TPC2 overactivity and impairs ALP function in neurons via lysosome alkalinization. Impairment of ALP-mediated clearance of tau may lead to premature release of undigested content and promote tau seeding and transmission [ 66 , 71 ]. Microglia can cease such transmission by scavenging these aggregates [ 35 , 78 ].…”

Section: Discussionmentioning

confidence: 99%

Tetrandrine ameliorates cognitive deficits and mitigates tau aggregation in cell and animal models of tauopathies

Tong

Huang

et al. 2022

J Biomed Sci

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Background Tauopathies are neurodegenerative diseases that are associated with the pathological accumulation of tau-containing tangles in the brain. Tauopathy can impair cognitive and motor functions and has been observed in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The aetiology of tauopathy remains mysterious; however, recent studies suggest that the autophagic-endolysosomal function plays an essential role in the degradation and transmission of pathological tau. We previously demonstrated that tetrandrine could ameliorate memory functions and clear amyloid plaques in transgenic AD mice by restoring autophagic-endolysosomal function. However, the efficacy of tetrandrine and the associated therapeutic mechanism in tauopathies have not been evaluated and elucidated. Methods Novel object recognition, fear conditioning and electrophysiology were used to evaluate the effects of tetrandrine on memory functions in transgenic tau mice. Western blotting and immunofluorescence staining were employed to determine the effect of tetrandrine on autophagy and tau clearance in vivo. Calcium (Ca2+) imaging and flow cytometry were used to delineate the role of pathological tau and tetrandrine in lysosomal Ca2+ and pH homeostasis. Biochemical BiFC fluorescence, Western blotting and immunofluorescence staining were used to evaluate degradation of hyperphosphorylated tau in vitro, whereas coculture of brain slices with isolated microglia was used to evaluate tau clearance ex vivo. Results We observed that tetrandrine treatment mitigated tau tangle development and corrected memory impairment in Thy1-hTau.P301S transgenic mice. Mechanistically, we showed that mutant tau expression disrupts lysosome pH by increasing two-pore channel 2 (TPC2)-mediated Ca2+ release, thereby contributing to lysosome alkalinization. Tetrandrine inhibits TPC2, thereby restoring the lysosomal pH, promotes tau degradation via autophagy, and ameliorates tau aggregation. Furthermore, in an ex vivo assay, we demonstrated that tetrandrine treatment promotes pathological tau clearance by microglia. Conclusions Together, these findings suggest that pathological tau disturbs endolysosomal homeostasis to impair tau clearance. This impairment results in a vicious cycle that accelerates disease pathogenesis. The success of tetrandrine in reducing tau aggregation suggests first, that tetrandrine could be an effective drug for tauopathies and second, that rescuing lysosomal Ca2+ homeostasis, thereby restoring ALP function, could be an effective general strategy for the development of novel therapies for tauopathies.

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Role of Lysosomal Acidification Dysfunction in Mesenchymal Stem Cell Senescence

Cited by 11 publications

References 112 publications

Ursolic Acid Impairs Cellular Lipid Homeostasis and Lysosomal Membrane Integrity in Breast Carcinoma Cells

Ursolic Acid Impairs Cellular Lipid Homeostasis and Lysosomal Membrane Integrity in Breast Carcinoma Cells

Synthesis and mechanism of biological action of morpholinyl-bearing arylsquaramides as small-molecule lysosomal pH modulators

Tetrandrine ameliorates cognitive deficits and mitigates tau aggregation in cell and animal models of tauopathies

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