title: MiRNA-210 modulates a nickel-induced cellular energy metabolism shift by repressing the iron-sulfur cluster assembly proteins ISCU1/2 in Neuro-2a cells.
abstract: The cellular energy metabolism shift, characterized by the inhibition of oxidative phosphorylation (OXPHOS) and enhancement of glycolysis, is involved in nickel-induced neurotoxicity. MicroRNA-210 (miR-210) is regulated by hypoxia-inducible transcription factor-1α (HIF-1α) under hypoxic conditions and controls mitochondrial energy metabolism by repressing the iron-sulfur cluster assembly protein (ISCU1/2). ISCU1/2 facilitates the assembly of iron-sulfur clusters (ISCs), the prosthetic groups that are critical for mitochondrial oxidation-reduction reactions. This study aimed to investigate whether miR-210 modulates alterations in energy metabolism after nickel exposure through suppressing ISCU1/2 and inactivating ISCs-containing metabolic enzymes. We determined that NiCl2 exposure leads to a significant accumulation of HIF-1α, rather than HIF-1β, in Neuro-2a cells. The miR-210 overexpression and ISCU1/2 downregulation was observed in a dose- and time-dependent manner. The gain-of-function and loss-of-dysfunction assays revealed that miR-210 mediated the ISCU1/2 suppression, energy metabolism alterations, and ISC-containing metabolic enzyme inactivation after nickel exposure. In addition, the impact of miR-210 on ISC-containing metabolic enzymes was independent from cellular iron regulation. Overall, these data suggest that repression of miR-210 on ISCU1/2 may contribute to HIF-1α-triggered alterations in energy metabolism after nickel exposure. A better understanding of how nickel impacts cellular energy metabolism may facilitate the elucidation of the mechanisms by which nickel affects the human health.
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: M
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: S
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Mao
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: W
authors.initials: W
authors.lastname: Duan
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: H
authors.initials: H
authors.lastname: Pi
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: M
authors.initials: M
authors.lastname: Zhong
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Z
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, People's Republic of China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D004785:Environmental Pollutants / Q000633:toxicity*; D020260:Heavy Metal Poisoning, Nervous System / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009532:Nickel / Q000633:toxicity*; D055550:Protein Stability; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D004785:Environmental Pollutants; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007506:Iron-Sulfur Proteins; C523690:IscU protein, mouse; C549325:MIRN210 microRNA, mouse; D035683:MicroRNAs; C022838:nickel chloride; D009532:Nickel; D007501:Iron