Dopamine-derived dopaminochrome promotes H(2)O(2) release at mitochondrial complex I: stimulation by rotenone, control by Ca(2+), and relevance to Parkinson disease.
Inhibitors of Complex I of the mitochondrial respiratory chain, such as rotenone, promote Parkinson disease-like symptoms and signs of oxidative stress. Dopamine (DA) oxidation products may be implicated in such a process. We show here that the o-quinone dopaminochrome (DACHR), a relatively stable DA oxidation product, promotes concentration (0.1-0.2 mum)- and respiration-dependent generation of H(2)O(2) at Complex I in brain mitochondria, with further stimulation by low concentrations of rotenone (5-30 nm). The rotenone effect required that contaminating Ca(2+) (8-10 mum) was not removed. DACHR apparently extracts an electron from the constitutively autoxidizable site in Complex I, producing a semiquinone, which then transfers an electron to O(2), generating O(2)(.) and then H(2)O(2). Mitochondrial removal of H(2)O(2) monoamine, formed by either oxidase activity or DACHR, was performed largely by glutathione peroxidase and glutathione reductase, which were negatively regulated by low intramitochondrial Ca(2+) levels. Thus, the H(2)O(2) formed accumulated in the medium if contaminating Ca(2+) was present; in the absence of Ca(2+), H(2)O(2) was completely removed if it originated from monoamine oxidase, but was less completely removed if it originated from DACHR. We propose that the primary action of rotenone is to promote extracellular O(2)(.) release via activation of NADPH oxidase in the microglia. In turn, O(2)(.) oxidizes DA to DACHR extracellularly. (The reaction is favored by the lack of GSH, which would otherwise preferably produce GSH adducts of dopaminoquinone.) Once formed, DACHR (which is resistant to GSH) enters neurons to activate the rotenone-stimulated redox cycle described.
Zoccarato
Franco
F
Dipartimento di Chimica Biologica and the Istituto di Neuroscienze, Sezione di Biomembrane (Consiglio Nazionale delle Ricerche), Università di Padova, Viale G. Colombo 3, 35121 Padova, Italy.
Toscano
Paola
P
Alexandre
Adolfo
A
D000818:Animals; D001921:Brain / Q000378:metabolism; D003548:Cysteinyldopa / Q000031:analogs & derivatives* / Q000378:metabolism; D042967:Electron Transport Complex I / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D045563:Indolequinones / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism; D051381:Rats
C086394:5-S-glutathionyldopamine; D045563:Indolequinones; D003548:Cysteinyldopa; C091584:aminochrome 1; D006861:Hydrogen Peroxide; D042967:Electron Transport Complex I