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 metabolite formed by the oxidative-deamination of dopamine (DA) catalyzed by monoamine oxidase. This aldehyde is either oxidized to 3,4-dihydroxyphenylacetic acid (DOPAC) by aldehyde dehydrogenase, an NAD-dependent enzyme or reduced to 3, 4-dihydroxyphenylethanol (DOPET) by aldehyde or aldose reductase. In the present study we examined whether levels of DOPAL are elevated by inhibition of the mitochondrial respiratory chain. Using inhibitors of mitochondrial 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 differentiation of PC12 cells markedly potentiated DOPAL and DOPET accumulation 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 implicated in the pathogenesis of Parkinson's disease, the accumulation of DOPAL may explain the vulnerability of the dopaminergic system to complex I inhibition. The rapid appearance of DOPAL and DOPET after inhibition of complex I may be a useful early index of oxidative stress in DA-forming neurons.
Lamensdorf
I
I
CNS, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. lamensdo@helix.nih.gov
Eisenhofer
G
G
Harvey-White
J
J
Hayakawa
Y
Y
Kirk
K
K
Kopin
I J
IJ
D015102:3,4-Dihydroxyphenylacetic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009498:Neurotoxins / Q000096:biosynthesis*; D010084:Oxidation-Reduction / Q000187:drug effects; D016716:PC12 Cells; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000378:metabolism; D051381:Rats; D012402:Rotenone / Q000633:toxicity; D013312:Stress, Physiological / Q000378:metabolism*; D014475:Uncoupling Agents / Q000633:toxicity
D009498:Neurotoxins; D014475:Uncoupling Agents; D012402:Rotenone; D015102:3,4-Dihydroxyphenylacetic Acid; C005975:3,4-dihydroxyphenylethanol; C007430:3,4-dihydroxyphenylacetaldehyde; D020932:Nerve Growth Factor; D007770:L-Lactate Dehydrogenase; D005947:Glucose; D010626:Phenylethyl Alcohol; D004298:Dopamine; D006719:Homovanillic Acid