title: Defective Autophagy, Mitochondrial Clearance and Lipophagy in Niemann-Pick Type B Lymphocytes.
abstract: Niemann-Pick disease type A (NP-A) and type B (NP-B) are lysosomal storage diseases (LSDs) caused by sphingomyelin accumulation in lysosomes relying on reduced or absent acid sphingomyelinase. A considerable body of evidence suggests that lysosomal storage in many LSD impairs autophagy, resulting in the accumulation of poly-ubiquitinated proteins and dysfunctional mitochondria, ultimately leading to cell death. Here we test this hypothesis in a cellular model of Niemann-Pick disease type B, in which autophagy has never been studied. The basal autophagic pathway was first examined in order to evaluate its functionality using several autophagy-modulating substances such as rapamycin and nocodazole. We found that human NP-B B lymphocytes display considerable alteration in their autophagic vacuole accumulation and mitochondrial fragmentation, as well as mitophagy induction (for damaged mitochondria clearance). Furthermore, lipid traceability of intra and extra-cellular environments shows lipid accumulation in NP-B B lymphocytes and also reveals their peculiar trafficking/management, culminating in lipid microparticle extrusion (by lysosomal exocytosis mechanisms) or lipophagy. All of these features point to the presence of a deep autophagy/mitophagy alteration revealing autophagic stress and defective mitochondrial clearance. Hence, rapamycin might be used to regulate autophagy/mitophagy (at least in part) and to contribute to the clearance of lysosomal aberrant lipid storage.
authors: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.
authors: Barbara
authors: http://orcid.org/0000-0003-3383-715X
authors: B
authors: Canonico
authors: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.
authors: Erica
authors: E
authors: Cesarini
authors: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.
authors: Sara
authors: S
authors: Salucci
authors: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.
authors: Francesca
authors: F
authors: Luchetti
authors: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.|IGM, CNR, Rizzoli Orthopaedic Institute, Bologna, Italy; Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.
authors: Elisabetta
authors: E
authors: Falcieri
authors: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.
authors: Gianna
authors: G
authors: Di Sario
authors: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.
authors: Fulvio
authors: F
authors: Palma
authors: Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.
authors: Stefano
authors: S
authors: Papa
mesh_terms: D001343:Autophagy; D001402:B-Lymphocytes / Q000378:metabolism* / Q000648:ultrastructure; D015415:Biomarkers; D055252:Cell-Derived Microparticles / Q000378:metabolism; D004705:Endocytosis; D005089:Exocytosis; D005110:Extracellular Space / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D050356:Lipid Metabolism; D008247:Lysosomes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D063306:Mitophagy; D009542:Niemann-Pick Diseases / Q000378:metabolism*; D010588:Phagosomes
chemical_list: D015415:Biomarkers