Transcription factor E3 protects against cadmium-induced apoptosis by maintaining the lysosomal-mitochondrial axis but not autophagic flux in Neuro-2a cells.

Abstract:

:Cadmium (Cd), is a well-known environmental and occupational hazard with a potent neurotoxic action. However, the mechanism underlying cadmium-induced neurotoxicity remains unclear. Herein, we exposed Neuro-2a cells to different concentrations of cadmium chloride (CdCl2) (12.5, 25 and 50 μM) for 24 h and found that Cd significantly induced lysosomal membrane permeabilization (LMP) with the release of cathepsin B (CTSB) to the cytosol, which in turn caused the release of mitochondrial cytochrome c (Cyt c) and eventually triggered caspase-dependent apoptosis. Interestingly, Cd decreased TFE3 expression but induced the nuclear translocation of TFE3 and TFE3 target-gene expression, which might be associated with lysosomal stress mediated by Cd. Notably, Tfe3 overexpression protected against Cd-induced neurotoxicity by maintaining the lysosomal-mitochondrial axis, and the protective effect of TFE3 is not dependent on the restoration of autophagic flux. In conclusion, our study demonstrated for the first time that lysosomal-mitochondrial axis dependent apoptosis, a neglected mechanism, may be the most important reason for Cd-induced neurotoxicity and that manipulation of TFE3 signaling may be a potential therapeutic approach for treatment of Cd-induced neurotoxicity.

journal_name

Toxicol Lett

journal_title

Toxicology letters

authors

Pi H,Li M,Xie J,Yang Z,Xi Y,Yu Z,Zhou Z

doi

10.1016/j.toxlet.2018.07.015

subject

Has Abstract

pub_date

2018-10-01 00:00:00

pages

335-350

eissn

0378-4274

issn

1879-3169

pii

S0378-4274(18)31502-9

journal_volume

295

pub_type

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