Defective Autophagy, Mitochondrial Clearance and Lipophagy in Niemann-Pick Type B Lymphocytes

Canonico, Barbara; Cesarini, Erica; Salucci, Sara; Luchetti, Francesca; Falcieri, Elisabetta; Sario, Gianna Di; Palma, Francesco; Papa, Stefano

doi:10.1371/journal.pone.0165780

Cited by 37 publications

(41 citation statements)

References 83 publications

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“…In parallel with these findings in NPC, there is also evidence of autophagy defects in NPA/B diseases (Fucho et al, 2014 ; Baulies et al, 2015 ; Canonico et al, 2016 ). For instance, hepatocytes from ASMase −/− mice exhibit impaired autophagy flux determined by the combination of rapamycin with or without chloroquine, an effect that was accompanied by increased LC3BII and p62 levels.…”

Section: Mitochondria-lysosomes Relationship and Mitochondrial Qualitmentioning

confidence: 67%

Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease

et al. 2017

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Lysosomal storage disorders (LSD) are characterized by the accumulation of diverse lipid species in lysosomes. Niemann-Pick type A/B (NPA/B) and type C diseases Niemann-Pick type C (NPC) are progressive LSD caused by loss of function of distinct lysosomal-residing proteins, acid sphingomyelinase and NPC1, respectively. While the primary cause of these diseases differs, both share common biochemical features, including the accumulation of sphingolipids and cholesterol, predominantly in endolysosomes. Besides these alterations in lysosomal homeostasis and function due to accumulation of specific lipid species, the lysosomal functional defects can have far-reaching consequences, disrupting intracellular trafficking of sterols, lipids and calcium through membrane contact sites (MCS) of apposed compartments. Although MCS between endoplasmic reticulum and mitochondria have been well studied and characterized in different contexts, emerging evidence indicates that lysosomes also exhibit close proximity with mitochondria, which translates in their mutual functional regulation. Indeed, as best illustrated in NPC disease, alterations in the lysosomal-mitochondrial liaisons underlie the secondary accumulation of specific lipids, such as cholesterol in mitochondria, resulting in mitochondrial dysfunction and defective antioxidant defense, which contribute to disease progression. Thus, a better understanding of the lysosomal and mitochondrial interactions and trafficking may identify novel targets for the treatment of Niemann-Pick disease.

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Section: Mitochondria-lysosomes Relationship and Mitochondrial Qualitmentioning

confidence: 67%

Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease

et al. 2017

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“…The inhibition of lysosomal-related functions renders the cell unable to degrade the overloaded defective proteins. Several studies demonstrated that many of these proteins are released via EVs to compensate their reduced degradation inside the cell [65]. In this context, an impairment of exosome biogenesis and secretion in neurodegenerative diseases caused by genetic mutations has been demonstrated [66].…”

Section: Exosomesmentioning

confidence: 99%

Lysosomal Exocytosis, Exosome Release and Secretory Autophagy: The Autophagic- and Endo-Lysosomal Systems Go Extracellular

Buratta

Tancini

Sagini

et al. 2020

IJMS

285

204

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Beyond the consolidated role in degrading and recycling cellular waste, the autophagic-and endo-lysosomal systems play a crucial role in extracellular release pathways. Lysosomal exocytosis is a process leading to the secretion of lysosomal content upon lysosome fusion with plasma membrane and is an important mechanism of cellular clearance, necessary to maintain cell fitness. Exosomes are a class of extracellular vesicles originating from the inward budding of the membrane of late endosomes, which may not fuse with lysosomes but be released extracellularly upon exocytosis. In addition to garbage disposal tools, they are now considered a cell-to-cell communication mechanism. Autophagy is a cellular process leading to sequestration of cytosolic cargoes for their degradation within lysosomes. However, the autophagic machinery is also involved in unconventional protein secretion and autophagy-dependent secretion, which are fundamental mechanisms for toxic protein disposal, immune signalling and pathogen surveillance. These cellular processes underline the crosstalk between the autophagic and the endosomal system and indicate an intersection between degradative and secretory functions. Further, they suggest that the molecular mechanisms underlying fusion, either with lysosomes or plasma membrane, are key determinants to maintain cell homeostasis upon stressing stimuli. When they fail, the accumulation of undigested substrates leads to pathological consequences, as indicated by the involvement of autophagic and lysosomal alteration in human diseases, namely lysosomal storage disorders, age-related neurodegenerative diseases and cancer. In this paper, we reviewed the current knowledge on the functional role of extracellular release pathways involving lysosomes and the autophagic-and endo-lysosomal systems, evaluating their implication in health and disease.

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“…Cells were cultured at 37 • C and resuspended in pre-warmed (37 • C) medium containing 100 nM of LysoTracker (diluted in RPMI). After 45 min of incubation, red lysosomal fluorescence was detected by flow cytometry and confocal microscopy [97].…”

Section: Assessment Of Lysosomal Involvementmentioning

confidence: 99%

Rapamycin Re-Directs Lysosome Network, Stimulates ER-Remodeling, Involving Membrane CD317 and Affecting Exocytosis, in Campylobacter Jejuni-Lysate-Infected U937 Cells

Canonico

Cesarini

Montanari

et al. 2020

IJMS

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The Gram-negative Campylobacter jejuni is a major cause of foodborne gastroenteritis in humans worldwide. The cytotoxic effects of Campylobacter have been mainly ascribed to the actions of the cytolethal distending toxin (CDT): it is mandatory to put in evidence risk factors for sequela development, such as reactive arthritis (ReA) and Guillain–Barré syndrome (GBS). Several researches are directed to managing symptom severity and the possible onset of sequelae. We found for the first time that rapamycin (RM) is able to largely inhibit the action of C. jejuni lysate CDT in U937 cells, and to partially avoid the activation of specific sub-lethal effects. In fact, we observed that the ability of this drug to redirect lysosomal compartment, stimulate ER-remodeling (highlighted by ER–lysosome and ER–mitochondria contacts), protect mitochondria network, and downregulate CD317/tetherin, is an important component of membrane microdomains. In particular, lysosomes are involved in the process of the reduction of intoxication, until the final step of lysosome exocytosis. Our results indicate that rapamycin confers protection against C. jejuni bacterial lysate insults to myeloid cells.

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Defective Autophagy, Mitochondrial Clearance and Lipophagy in Niemann-Pick Type B Lymphocytes

Cited by 37 publications

References 83 publications

Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease

Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease

Lysosomal Exocytosis, Exosome Release and Secretory Autophagy: The Autophagic- and Endo-Lysosomal Systems Go Extracellular

Rapamycin Re-Directs Lysosome Network, Stimulates ER-Remodeling, Involving Membrane CD317 and Affecting Exocytosis, in Campylobacter Jejuni-Lysate-Infected U937 Cells

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