Binding of copper is a mechanism of homocysteine toxicity leading to COX deficiency and apoptosis in primary neurons, PC12 and SHSY-5Y cells.
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+).
Linnebank
Michael
M
Department of Neurology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53125 Bonn, Germany. Michael.Linnebank@ukb.uni-bonn.de
Lutz
Holger
H
Jarre
Eva
E
Vielhaber
Stefan
S
Noelker
Carmen
C
Struys
Eduard
E
Jakobs
Cornelis
C
Klockgether
Thomas
T
Evert
Bernd O
BO
Kunz
Wolfram S
WS
Wüllner
Ullrich
U
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
D002614:Chelating Agents; D018696:Neuroprotective Agents; D006710:Homocysteine; D003300:Copper; D003576:Electron Transport Complex IV