title: The lampricide 3-trifluoromethyl-4-nitrophenol (TFM) uncouples mitochondrial oxidative phosphorylation in both sea lamprey (Petromyzon marinus) and TFM-tolerant rainbow trout (Oncorhynchus mykiss).
abstract: The toxicity of 3-trifluoromethyl-4-nitrophenol (TFM) appears to be due to a mismatch between ATP supply and demand in lamprey, depleting glycogen stores and starving the nervous system of ATP. The cause of this TFM-induced ATP deficit is unclear. One possibility is that TFM uncouples mitochondrial oxidative phosphorylation, thus impairing ATP production. To test this hypothesis, mitochondria were isolated from the livers of sea lamprey and rainbow trout, and O(2) consumption rates were measured in the presence of TFM or 2,4-dinitrophenol (2,4-DNP), a known uncoupler of oxidative phosphorylation. TFM and 2,4-DNP markedly increased State IV respiration in a dose-dependent fashion, but had no effect on State III respiration, which is consistent with uncoupling of oxidative phosphorylation. To determine how TFM uncoupled oxidative phosphorylation, the mitochondrial transmembrane potential (TMP) was recorded using the mitochondria-specific dye rhodamine 123. Mitochondrial TMP decreased by 22% in sea lamprey, and by 28% in trout following treatment with 50μmolL(-1) TFM. These findings suggest that TFM acted as a protonophore, dissipating the proton motive force needed to drive ATP synthesis. We conclude that the mode of TFM toxicity in sea lamprey and rainbow trout is via uncoupling of oxidative phosphorylation, leading to impaired ATP production.
authors.affiliation: Department of Biology, Wilfrid Laurier University, 75 University Avenue W, Waterloo, Ontario, Canada N2L 3C5. obircean@uwaterloo.ca
authors.forename: Oana
authors.initials: O
authors.lastname: Birceanu
authors.forename: Grant B
authors.initials: GB
authors.lastname: McClelland
authors.forename: Yuxiang S
authors.initials: YS
authors.lastname: Wang
authors.forename: Jason C L
authors.initials: JC
authors.lastname: Brown
authors.forename: Michael P
authors.initials: MP
authors.lastname: Wilkie
mesh_terms: D019297:2,4-Dinitrophenol / Q000633:toxicity; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology; D009596:Nitrophenols / Q000633:toxicity*; D017686:Oncorhynchus mykiss / Q000502:physiology*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption; D010575:Pesticides / Q000633:toxicity*; D048428:Petromyzon / Q000502:physiology*; D014475:Uncoupling Agents / Q000633:toxicity*
chemical_list: D009596:Nitrophenols; D010575:Pesticides; D014475:Uncoupling Agents; D000255:Adenosine Triphosphate; C003687:3-trifluoromethyl-4-nitrophenol; D019297:2,4-Dinitrophenol