Publication: Ethanol-induced mitophagy in liver is associated with activation of the PINK1-Parkin pathway triggered by oxidative DNA damage
Authors
Eid, Nabil ; Ito, Yuko ; Horibe, Akio ; Otsuki, Yoshinori
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Publisher
Universidad de Murcia. Departamento de BiologĂa Celular e HistologĂa
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DOI
DOI: 10.14670/HH-11-747
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info:eu-repo/semantics/article
Description
Abstract
Mitophagy is a cytoprotective mechanism
against mitochondrial damaging agents. Studies
demonstrating morphological evidence for the
involvement of the PINK1-Parkin pathway in the
hepatocyte mitophagic response to ethanol toxicity, and
potential links to apoptosis and mitochondrial alterations
such as spheroid formation are still lacking. We
addressed these unresolved issues using a rat model of
binge alcohol exposure. Adult rats were injected with
ethanol (5g/kg) and liver samples were taken at 0, 3, 6,
and 24 hours after ethanol administration and processed
for light and electron microscopic studies. Ethanol
induced a low level of hepatocyte apoptosis, peaking at 3
h and decreasing significantly by 24 h. In contrast, there
was enhanced formation of mitophagic vacuoles in the
majority of normal hepatocytes of ethanol-treated rats
(ETRs), which peaked at 6 h and was maintained up to
24 h based on electron microscopy and TUNEL/LC3
double labelling. Moreover, enhanced mitophagy in ETR
hepatocytes was confirmed by increased LC3 puncta
formation, and co-localization of Parkin and LC3 with
mitochondrial and lysosomal markers. Immunoelectron
microscopy demonstrated the localization of PINK1 and
Parkin to damaged mitochondria of ETR hepatocytes,
which was consistent with co-localization of Parkin with
8-OHdG, a marker of oxidative mitochondrial DNA
damage. Furthermore, electron microscopy showed
enhanced formation of mitochondrial spheroids in ETR
hepatocytes. These data are the first direct
morphological evidence linking PINK1-Parkin pathway
activation to the enhanced mitophagic response of
hepatocytes to ethanol toxicity. Ethanol-induced hepatic
mitophagy may be a prosurvival mechanism, which may
have therapeutic implications.
Citation
Histology and Histopathology, Vol.31, nÂş10, (2016)
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