Iron mitigates DMT1-mediated manganese cytotoxicity via the ASK1-JNK signaling axis: Implications of iron supplementation for manganese toxicity

Scientific Reports
Yee Kit TaiTuck Wah Soong

Abstract

Manganese (Mn(2+)) neurotoxicity from occupational exposure is well documented to result in a Parkinson-like syndrome. Although the understanding of Mn(2+) cytotoxicity is still incomplete, both Mn(2+) and Fe(2+) can be transported via the divalent metal transporter 1 (DMT1), suggesting that competitive uptake might disrupt Fe(2+) homeostasis. Here, we found that DMT1 overexpression significantly enhanced Mn(2+) cytoplasmic accumulation and JNK phosphorylation, leading to a reduction in cell viability. Although a robust activation of autophagy was observed alongside these changes, it did not trigger autophagic cell death, but was instead shown to be essential for the degradation of ferritin, which normally sequesters labile Fe(2+). Inhibition of ferritin degradation through the neutralization of lysosomal pH resulted in increased ferritin and enhanced cytoplasmic Fe(2+) depletion. Similarly, direct Fe(2+) chelation also resulted in aggravated Mn(2+)-mediated JNK phosphorylation, while Fe(2+) repletion protected cells, and this occurs via the ASK1-thioredoxin pathway. Taken together, our study presents the novel findings that Mn(2+) cytotoxicity involves the depletion of the cytoplasmic Fe(2+) pool, and the increase in autophagy...Continue Reading

References

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Citations

Feb 19, 2017·Biochemical and Biophysical Research Communications·Matthew Ryan SmithDean P Jones
Jul 1, 2017·Metallomics : Integrated Biometal Science·Dongmei SongPiye Niu
Dec 15, 2017·Nucleic Acids Research·Jia Jia ChanYvonne Tay
Jan 5, 2019·Advanced Pharmaceutical Bulletin·Leila SadeghiVahid Yousefi Babadi
Feb 25, 2020·Free Radical Biology & Medicine·Andrew J GhioMichael C Madden
Jan 24, 2020·Neurochemistry International·Mahfuzur R MiahMichael Aschner
May 19, 2021·Biometals : an International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine·Olga P AjsuvakovaAnatoly V Skalny
Jun 28, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Soledad Porte AlconMónica Lidia Kotler

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Datasets Mentioned

BETA
AF153279

Methods Mentioned

BETA
fluorescence microscopy
fluorescence imaging
phase contrast microscopy
transfection

Software Mentioned

Quantity One

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