Mitochondrial ferritin protects SH-SY5Y cells against H 2 O 2 -induced oxidative stress and modulates α-synuclein expression

Abstract

Mitochondrial ferritin (FtMt) is a type of ferritin that sequesters iron. Previous studies have shown that FtMt is expressed by dopaminergic neurons in the substantia nigra and that it may be involved in the pathology of Parkinson's disease. However, the functional roles of FtMt in dopaminergic neurons remain unclear. In this study, we investigated the function of FtMt in α-synuclein regulation and its antioxidant roles in dopaminergic cells using human dopaminergic neuroblastoma cells, SH-SY5Y. In physiological conditions, FtMt knockdown increased α-synuclein expression at the protein level but not at the mRNA level. By contrast, FtMt overexpression reduced α-synuclein expression at the protein level but not at the mRNA level. FtMt enhanced the iron levels in mitochondria but decreased the iron levels in the intracellular labile iron pool. We found that FeCl could abolish the effects of FtMt overexpression on α-synuclein expression. Under oxidative stress conditions induced by HO, we found that HO treatment induced FtMt and α-synuclein expression at both the mRNA and protein levels in a dose-dependent manner. FtMt overexpression protected cells against oxidative stress and alleviated the enhanced α-synuclein expression induced by HO at the posttranscriptional level. Our results indicate that FtMt modulates α-synuclein expression at the posttranscriptional level via iron regulation in physiological conditions. FtMt expression is enhanced under oxidative stress conditions, where FtMt protects cells against the oxidative stress as well as plays an important role in maintaining α-synuclein levels.

Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells

“…3D and E). Iron storage in the mitochondria is partly regulated by mitochondrial ferritin, which functions in the sequestration of excess iron and responding to oxidative stress (Guan et al, 2017). In accordance to our data for L-and Hferritin, we observed reduced protein levels of mitochondrial ferritin precursor in WDR45 mutant fibroblasts (Fig.…”

“…5F). Previous studies have shown that mitochondrial ferritin is expressed mainly in neurons and that it protects dopaminergic neurons from oxidative stressors (Guan et al, 2017). Recent findings demonstrated that hepcidin, an iron-regulating hormone, reduced brain iron in iron-overloaded rats (Du et al, 2015).…”

The Aging of Iron Man

“…Mitochondrial ferritin displays high sequence homology to cytosolic H-ferritin (Levi et al, 2001 ) and helps to regulate iron distribution between the cytosol and mitochondria to attenuate ROS-generation. Mitochondrial ferritin has been associated with an anti-oxidative (neuroprotective) effect in neurodegenerative diseases including AD and PD cells ( in vitro ) and mouse models (Wu et al, 2013 ; Arber et al, 2016 ; Guan et al, 2017 ). Ten-month old mitochondrial ferritin knock-out (KO) mice infused with Aß 25−35 had exacerbated learning and memory impairment compared to wild-type counterparts, and augmented apoptosis (reflected by decreased Bcl-2/Bax ratio) in the hippocampus (Wu et al, 2013 ; Wang et al, 2017 ).…”

Role of autophagy in a model of obesity: A long‑term high fat diet induces cardiac dysfunction

“…Mitochondria are essential organelles that serve important roles in cellular energy metabolism. The mitochondrial quality control systems that have evolved to repair or eliminate dysfunctional mitochondria are of importance ( 19 ). Furthermore, mitochondrial quality surveillance systems attenuate potentially damaging processes that occur in the cytosol and ER ( 20 ).…”