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

• DOI: 10.1371/journal.pone.0165780
• Publication Date: 2016-10-31T17:39:48Z
• Authors: Barbara Canonico; Erica Cesarini; Sara Salucci; Francesca Luchetti; Elisabetta Falcieri; Gianna Di Sario; Fulvio Palma; Stefano Papa
• Keywords: Niemann-Pick Diseases; 0301 basic medicine; B-Lymphocytes; Science; Q; R; Intracellular Space; Mitophagy; B-Lymphocytes; Biomarkers; Cell-Derived Microparticles; Endocytosis; Exocytosis; Extracellular Space; Flow Cytometry; Humans; Intracellular Space; Lysosomes; Mitochondria; Mitophagy; Niemann-Pick Diseases; Phagosomes; Autophagy; Lipid Metabolism; Flow Cytometry; Lipid Metabolism; Endocytosis; Exocytosis; Mitochondria; 03 medical and health sciences; Cell-Derived Microparticles; Phagosomes; Autophagy; Medicine; Humans; Extracellular Space; Lysosomes; Biomarkers; Research Article

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.