title: Binding of copper is a mechanism of homocysteine toxicity leading to COX deficiency and apoptosis in primary neurons, PC12 and SHSY-5Y cells.
abstract: Children with hereditary severe hyperhomocysteinemia present with a variety of neurological impairment, and mild hyperhomocysteinemia has been associated with neurodegeneration in the elderly. The link of hyperhomocysteinemia to neurological dysfunction is unknown. We investigated mitochondrial mechanisms of homocysteine (HCys) neurotoxicity in rat dopaminergic pheochromocytoma cells, human neuroblastoma cells and primary rat cerebellar granule neurons. HCys dose dependently impaired cytochrome c oxidase (COX) activity as well as stability and induced reactive oxygen species and apoptotic cell death. We found that HCys binds the COX cofactor Cu(2+), and Cu(2+) supplementation prior to HCys treatment preserved COX activity and prevented cell death. The Cu(2+) chelating action of HCys and impairement of COX activity represent novel mechanisms of HCys neurotoxicity, which might be preventable by supplementation of Cu(2+).
authors.affiliation: Department of Neurology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53125 Bonn, Germany. Michael.Linnebank@ukb.uni-bonn.de
authors.forename: Michael
authors.initials: M
authors.lastname: Linnebank
authors.forename: Holger
authors.initials: H
authors.lastname: Lutz
authors.forename: Eva
authors.initials: E
authors.lastname: Jarre
authors.forename: Stefan
authors.initials: S
authors.lastname: Vielhaber
authors.forename: Carmen
authors.initials: C
authors.lastname: Noelker
authors.forename: Eduard
authors.initials: E
authors.lastname: Struys
authors.forename: Cornelis
authors.initials: C
authors.lastname: Jakobs
authors.forename: Thomas
authors.initials: T
authors.lastname: Klockgether
authors.forename: Bernd O
authors.initials: BO
authors.lastname: Evert
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
authors.forename: Ullrich
authors.initials: U
authors.lastname: Wüllner
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000378:metabolism / Q000494:pharmacology; D003300:Copper / Q000378:metabolism* / Q000494:pharmacology; D030401:Cytochrome-c Oxidase Deficiency / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors / Q000378:metabolism; D006710:Homocysteine / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D007706:Menkes Kinky Hair Syndrome / Q000378:metabolism / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats
chemical_list: D002614:Chelating Agents; D018696:Neuroprotective Agents; D006710:Homocysteine; D003300:Copper; D003576:Electron Transport Complex IV