Download Melatonin modulates autophagy through a redox

J. Pineal Res. 2012; 52:80–92
2011 John Wiley & Sons A/S
Journal of Pineal Research
Molecular, Biological, Physiological and Clinical Aspects of Melatonin
Doi:10.1111/j.1600-079X.2011.00922.x
Melatonin modulates autophagy through a redox-mediated action
in female Syrian hamster Harderian gland controlling cell types and
gland activity
Abstract: The Syrian hamster Harderian gland exhibits sexually dimorphic
porphyrin biosynthesis, wherein the female glands display an extraordinarily
high concentration of porphyrins. Damage derived from this production of
porphyrins, mediated by reactive oxygen species, causes the glands to
develop autophagic processes, which culminate in detachment-derived cell
death; these cells normally play a central role in the secretory activity of the
gland. The main aim of this study was to analyze how a change in the redox
state impacts autophagy. Female Syrian hamsters were treated daily with
melatonin (25 lg, subcutaneously) at ZT 10 for 1–2 months (N-acetyl-5methoxytryptamine), an endogenous antioxidant that ameliorates the
deleterious effects of free radicals via a variety of mechanisms. The length of
treatment affected the redox balance, the autophagy machinery, and the
activation of p53 and NF-jB. One-month treatment displaces redox balance
to the antioxidant side, promotes autophagy through a p53-mediated
mechanism, and increases cell detachment. Meanwhile, 2-month treatment
restores redox balance to the oxidant side, activates NF-jB reducing
autophagy to basal levels, increases number of type II cells, and reduces
number of detached cells. Our results conclude that the redox state can
modulate autophagy through redox-sensitive transcriptions factors.
Additionally, these findings support a hypothesis that ascribes differences in
the autophagic-lysosomal pathway to epithelial cell types, thereby restricting
detachment-induced autophagic cell death to epithelial cell type I.
Ignacio Vega-Naredo1, Beatriz
Caballero2, Verónica Sierra3,
Marina Garcı́a-Macia3, David de
Gonzalo-Calvo3, Paulo J.
Oliveira1, Marı́a Josefa
Rodrı́guez-Colunga3 and Ana
Coto-Montes3
1
Center for Neuroscience and Cell Biology,
University of Coimbra, Coimbra, Portugal;
2
The Bruce Rappaport Faculty of Medicine,
Israel Institute of Technology, Haifa, Israel;
3
Departamento de Morfologı́a y Biologı́a
Celular, Facultad de Medicina, Universidad de
Oviedo, Oviedo, Spain
Key words: autophagy, Harderian gland,
melatonin, oxidative stress, p53
Address reprint requests to Ignacio Vega
Naredo, Center for Neuroscience and Cell
Biology, University of Coimbra, 3004-517
Coimbra, Portugal.
E-mail: [email protected]
Received April 10, 2011;
Accepted June 24, 2011.
Introduction
The Syrian hamster Harderian gland (HG) exhibits marked
sexual differences in cell type and porphyrin production.
The glands of male hamsters have two secretory cell types
(types I and II), while the glands of females consist of a
single secretory cell type (female type I) and large intraluminal deposits of porphyrins [1]. Furthermore, the gland is
physiologically exposed to oxidative stress [2], which is
moderate in male glands and extensive in female glands;
consequently, the glandular structure is altered showing
autophagic and invasive processes [3].
Previous studies have shown that the physiological
autophagy found in the Syrian hamster is a constant
renovating system that allows cells to maintain vital
functions and adapt to environmental stress [3–5], which
is a prominent feature associated with reproductive organ
changes. Our latest results [6] confirm the presence of
macroautophagy and chaperone-mediated autophagy in
both male and female HGs. Each gender presents its own
peculiarities in the autophagic-lysosomal pathway, with
female HGs exhibiting a deficiency in the lysosomal
80
pathway and a prolonged half-life of early and late
autophagic vacuoles. Thus, the endosomal/lysosomal constituents are delivered to the autophagic vacuoles that
accumulate in the cytoplasm, and cells succumb to cell
death. However, because apoptosis is inhibited in female
HG, cell death must proceed through another pathway.
Thus, the female HG develops a detachment-related cell
death process with intermediate characteristics between
apoptotic and autophagic cell death, such as autophagic
morphology, microtubule-associated protein 1 light chain 3
(LC3) lipidation, collapse of the actin cytoskeleton, caspase-3 independence, and absence of DNA fragmentation
in the presence of DNA repair events. This process plays a
central role in the secretory activity of the gland, leading to
massive holocrine secretion [6].
In addition, the Syrian hamster HG also shows genderrelated differences in nuclear factor-kappa B (NF-jB) and
p53 pathways, promoting different responses, survival, or
cell death signaling related, which are gender-dependent [6].
Female HGs show NF-jB inactivation and a higher nuclear
translocation of p53, advocating death-mediated actions.
Male glands exhibit p53-mediated activation of target genes