Affordable Access

deepdyve-link
Publisher Website

Dysregulation of TFEB contributes to manganese-induced autophagic failure and mitochondrial dysfunction in astrocytes.

Authors
  • Zhang, Ziyan1
  • Yan, Jingqi2
  • Bowman, Aaron B3
  • Bryan, Miles R4, 5, 6
  • Singh, Rajat1, 7, 8, 9
  • Aschner, Michael1
  • 1 Department of Molecular Pharmacology, Albert Einstein College of Medicine , Bronx, NY, USA.
  • 2 Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine , Bronx, NY, USA.
  • 3 School of Health Sciences, Purdue University , West Lafayette, IN, USA.
  • 4 Department of Pediatrics, Vanderbilt University Medical Center , Nashville, TN, USA.
  • 5 Vanderbilt Brain Institute, Vanderbilt University Medical Center , Nashville, TN, USA.
  • 6 Department of Neurology and Biochemistry, Vanderbilt University Medical Center , Nashville, TN, USA.
  • 7 Department of Medicine.
  • 8 Diabetes Research Center.
  • 9 Institute for Aging Research, Albert Einstein College of Medicine , Bronx, NY, USA.
Type
Published Article
Journal
Autophagy
Publisher
Landes Bioscience
Publication Date
Aug 01, 2020
Volume
16
Issue
8
Pages
1506–1523
Identifiers
DOI: 10.1080/15548627.2019.1688488
PMID: 31690173
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Epidemiological and clinical studies have long shown that exposure to high levels of heavy metals are associated with increased risks of neurodegenerative diseases. It is widely accepted that autophagic dysfunction is involved in pathogenesis of various neurodegenerative disorders; however, the role of heavy metals in regulation of macroautophagy/autophagy is unclear. Here, we show that manganese (Mn) induces a decline in nuclear localization of TFEB (transcription factor EB), a master regulator of the autophagy-lysosome pathway, leading to autophagic dysfunction in astrocytes of mouse striatum. We further show that Mn exposure suppresses autophagic-lysosomal degradation of mitochondria and induces accumulation of unhealthy mitochondria. Activation of autophagy by rapamycin or TFEB overexpression ameliorates Mn-induced mitochondrial respiratory dysfunction and reactive oxygen species (ROS) generation in astrocytes, suggesting a causal relation between autophagic failure and mitochondrial dysfunction in Mn toxicity. Taken together, our data demonstrate that Mn inhibits TFEB activity, leading to impaired autophagy that is causally related to mitochondrial dysfunction in astrocytes. These findings reveal a previously unappreciated role for Mn in dysregulation of autophagy and identify TFEB as a potential therapeutic target to mitigate Mn toxicity. BECN1: beclin 1; CTSD: cathepsin D; DMEM: Dulbecco's Modified Eagle Medium; GFAP: glial fibrillary acid protein; GFP: green fluorescent protein; HBSS: hanks balanced salt solution; LAMP: lysosomal-associated membrane protein; LDH: lactate dehydrogenase; Lys Inh: lysosomal inhibitors; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; Mn: manganese; MTOR: mechanistic target of rapamycin kinase; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PFA: paraformaldehyde; PI: propidium iodide; ROS: reactive oxygen species; s.c.: subcutaneous; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB.

Report this publication

Statistics

Seen <100 times