title: Iron mitigates DMT1-mediated manganese cytotoxicity via the ASK1-JNK signaling axis: Implications of iron supplementation for manganese toxicity.
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-lysosome activity is important to maintain Fe(2+) homeostasis. Thus, Fe(2+) supplementation could have potential applications in the prevention and treatment of Mn(2+)-mediated toxicity.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Yee Kit
authors.initials: YK
authors.lastname: Tai
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Katherine C M
authors.initials: KCM
authors.lastname: Chew
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Bryce W Q
authors.initials: BWQ
authors.lastname: Tan
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.|National Neuroscience Institute, Singapore 308433.|Duke-NUS Graduate Medical School, Singapore 169857.
authors.forename: Kah-Leong
authors.initials: KL
authors.lastname: Lim
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.|NUS Graduate School for Integrative Science and Engineering, and Neurobiology/Ageing Programme, Singapore 117456.|National Neuroscience Institute, Singapore 308433.
authors.forename: Tuck Wah
authors.initials: TW
authors.lastname: Soong
mesh_terms: D001343:Autophagy; D001692:Biological Transport; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D019587:Dietary Supplements; D005293:Ferritins / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007501:Iron / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D008345:Manganese / Q000378:metabolism* / Q000633:toxicity; D020149:Manganese Poisoning; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D005293:Ferritins; D007501:Iron; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D008345:Manganese; D013879:Thioredoxins; D000099236:Solute Carrier Family 11, Member 2