Tetrahydrobiopterin causes mitochondrial dysfunction in dopaminergic cells: implications for Parkinson's disease.
Parkinson's disease (PD) is a neurodegenerative disorder associated with a selective loss of dopaminergic neurons in the substantia nigra. While the underlying cause of PD is not clearly understood, oxidative stress and mitochondrial dysfunction are thought to play a role. We have previously suggested tetrahydrobiopterin (BH4), an obligatory cofactor for the dopamine synthesis enzyme tyrosine hydroxylase and present selectively in monoaminergic neurons in the brain, as an endogenous molecule that contributes to the dopaminergic neurodegeneration. In the present study, we show that BH4 leads to inhibition of activities of complexes I and IV of the electron transport chain (ETC) and reduction of mitochondrial membrane potential. BH4 appears to be different from rotenone and MPP(+), the synthetic compounds used to generate Parkinson models, in its effect on complex IV. BH4 also induces the release of mitochondrial cytochrome c. Pretreatment with the sulfhydryl antioxidant N-acetylcysteine or the quinone reductase inducer dimethyl fumarate prevents the ETC inhibition and cytochrome c release following BH4 exposure, suggesting the involvement of quinone products. Together with our previous observation that BH4 leads to generation of oxidative stress and selective dopaminergic neurodegeneration both in vitro and in vivo via inducing apoptosis, the mitochondrial involvement in BH4 toxicity further suggests possible relevance of this endogenous molecule to pathogenesis of PD.
Choi
Hyun Jin
HJ
Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, 388-1 Pungnap-dong, Songpa-ku, Seoul 138-736, South Korea.
Lee
So Yeon
SY
Cho
Yuri
Y
No
Haja
H
Kim
Seong Who
SW
Hwang
Onyou
O
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D001708:Biopterins / Q000031:analogs & derivatives* / Q000502:physiology; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D004298:Dopamine / Q000502:physiology*; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000201:enzymology / Q000502:physiology*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000503:physiopathology*; D012402:Rotenone / Q000494:pharmacology
D012402:Rotenone; D001708:Biopterins; D045304:Cytochromes c; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C003402:sapropterin; D004298:Dopamine