title: Lysosome acidification by photoactivated nanoparticles restores autophagy under lipotoxicity.
abstract: In pancreatic β-cells, liver hepatocytes, and cardiomyocytes, chronic exposure to high levels of fatty acids (lipotoxicity) inhibits autophagic flux and concomitantly decreases lysosomal acidity. Whether impaired lysosomal acidification is causally inhibiting autophagic flux and cellular functions could not, up to the present, be determined because of the lack of an approach to modify lysosomal acidity. To address this question, lysosome-localizing nanoparticles are described that, upon UV photoactivation, enable controlled acidification of impaired lysosomes. The photoactivatable, acidifying nanoparticles (paNPs) demonstrate lysosomal uptake in INS1 and mouse β-cells. Photoactivation of paNPs in fatty acid-treated INS1 cells enhances lysosomal acidity and function while decreasing p62 and LC3-II levels, indicating rescue of autophagic flux upon acute lysosomal acidification. Furthermore, paNPs improve glucose-stimulated insulin secretion that is reduced under lipotoxicity in INS1 cells and mouse islets. These results establish a causative role for impaired lysosomal acidification in the deregulation of autophagy and β-cell function under lipotoxicity.
authors.affiliation: Obesity and Nutrition Section, Department of Medicine, Evans Biomedical Research Center, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Trudeau
authors.affiliation: Departments of Biomedical Engineering, Chemistry, and Medicine, Boston University, Boston, MA 02215 Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215.
authors.forename: Aaron H
authors.initials: AH
authors.lastname: Colby
authors.affiliation: Departments of Biomedical Engineering, Chemistry, and Medicine, Boston University, Boston, MA 02215.
authors.forename: Jialiu
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84103, Israel.
authors.forename: Guy
authors.initials: G
authors.lastname: Las
authors.affiliation: Departments of Biomedical Engineering, Chemistry, and Medicine, Boston University, Boston, MA 02215.
authors.forename: Jiazuo H
authors.initials: JH
authors.lastname: Feng
authors.affiliation: Departments of Biomedical Engineering, Chemistry, and Medicine, Boston University, Boston, MA 02215 oshirihai@mednet.ucla.edu mgrin@bu.edu.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Grinstaff
authors.affiliation: Obesity and Nutrition Section, Department of Medicine, Evans Biomedical Research Center, Boston University School of Medicine, Boston, MA 02118 Department of Clinical Biochemistry and Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84103, Israel Division of Endocrinology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90045.
authors.forename: Orian S
authors.initials: OS
authors.lastname: Shirihai
mesh_terms: D000143:Acids / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004705:Endocytosis / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008027:Light; D008055:Lipids / Q000633:toxicity*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry / Q000528:radiation effects* / Q000648:ultrastructure; D019308:Palmitic Acid / Q000633:toxicity; D014466:Ultraviolet Rays
chemical_list: D000143:Acids; D007328:Insulin; D008055:Lipids; D019308:Palmitic Acid; D005947:Glucose