Binding of copper is a mechanism of homocysteine toxicity leading to COX deficiency and apoptosis in primary neurons, PC12 and SHSY-5Y cells

Neurobiology of Disease

Holger Lutz¹  Cornelis Jakobs²  Thomas Klockgether²  Ullrich Wüllner³  Stefan Vielhaber⁴  Bernd O. Evert⁴  Eva Jarre⁴  Michael Linnebank⁴  Eduard Struys⁴  Wolfram S. Kunz⁴  Carmen Noelker⁵ 

[1] Corresponding author. Fax: [phone].;Department of Clinical Chemistry, Free University Hospital Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands;Department of Epileptology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53125 Bonn, Germany;Department of Neurology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53125 Bonn, Germany;Department of Neurology, University Hospital Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany;

关键词: Copper;    COX;    Homocysteine;    Homocystinuria;    Hyperhomocysteinemia;    Menkes disease;   

DOI  :  

来源: DOAJ

【 摘 要 】

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 Cu2+, and Cu2+ supplementation prior to HCys treatment preserved COX activity and prevented cell death. The Cu2+ chelating action of HCys and impairement of COX activity represent novel mechanisms of HCys neurotoxicity, which might be preventable by supplementation of Cu2+.

【 授权许可】

Unknown