title: Nickel inhibits mitochondrial fatty acid oxidation.
abstract: Nickel exposure is associated with changes in cellular energy metabolism which may contribute to its carcinogenic properties. Here, we demonstrate that nickel strongly represses mitochondrial fatty acid oxidation-the pathway by which fatty acids are catabolized for energy-in both primary human lung fibroblasts and mouse embryonic fibroblasts. At the concentrations used, nickel suppresses fatty acid oxidation without globally suppressing mitochondrial function as evidenced by increased glucose oxidation to CO2. Pre-treatment with l-carnitine, previously shown to prevent nickel-induced mitochondrial dysfunction in neuroblastoma cells, did not prevent the inhibition of fatty acid oxidation. The effect of nickel on fatty acid oxidation occurred only with prolonged exposure (>5 h), suggesting that direct inhibition of the active sites of metabolic enzymes is not the mechanism of action. Nickel is a known hypoxia-mimetic that activates hypoxia inducible factor-1α (HIF1α). Nickel-induced inhibition of fatty acid oxidation was blunted in HIF1α knockout fibroblasts, implicating HIF1α as one contributor to the mechanism. Additionally, nickel down-regulated the protein levels of the key fatty acid oxidation enzyme very long-chain acyl-CoA dehydrogenase (VLCAD) in a dose-dependent fashion. In conclusion, inhibition of fatty acid oxidation by nickel, concurrent with increased glucose metabolism, represents a form of metabolic reprogramming that may contribute to nickel-induced carcinogenesis.
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors.forename: Radha
authors.initials: R
authors.lastname: Uppala
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors.forename: Richard W
authors.initials: RW
authors.lastname: McKinney
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15219, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Brant
authors.affiliation: Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15219, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Fabisiak
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA. Electronic address: eric.goetzman@chp.edu.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Goetzman
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009532:Nickel / Q000494:pharmacology*; D010084:Oxidation-Reduction; D013379:Substrate Specificity
chemical_list: D005227:Fatty Acids; D009532:Nickel; D063989:Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase
keywords: Fatty acid oxidation; Hypoxia inducible factor-1α; Lung fibroblast; Mitochondria; Nickel; Very long-chain acyl-CoA dehydrogenase