Metabolic stress in PC12 cells induces the formation of the endogenous dopaminergic neurotoxin, 3,4-dihydroxyphenylacetaldehyde

3,4-Dihydroxyphenylacetaldehyde (DOPAL) has been reported to be a toxic met abolite formed by the oxidative-deamination of dopamine (DA) catalyzed by m onoamine oxidase. This aldehyde is either oxidized to 3,4-dihydroxyphenylac etic acid (DOPAC) by aldehyde dehydrogenase, an NAD-dependent enzyme or red uced to 3,4-dihydroxyphenylethanol (DOPET) by aldehyde or aldose reductase. In the present study we examined whether levels of DOPAL are elevated by i nhibition of the mitochondrial respiratory chain. Using inhibitors of mitoc hondrial complexes I, II, III and IV we found that inhibition of complex I and III increased levels of DOPAL and DOPET. Nerve growth factor-induced di fferentiation of PC12 cells markedly potentiated DOPAL and DOPET accumulati on in response to metabolic stress. DOPAL was toxic to differentiated PC12 as well as to SK-N-SH cell lines. Because complex I dysfunction has been im plicated in the pathogenesis of Parkinson's disease, the accumulation of DO PAL may explain the vulnerability of the dopaminergic system to complex I i nhibition. The rapid appearance of DOPAL and DOPET after inhibition of comp lex I may be a useful early index of oxidative stress in DA-forming neurons . Published 2000 Wiley-Liss, Inc.(dagger)