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J. Biol. Chem., Vol. 280, Issue 16, 15587-15594, April 22, 2005

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Dopamine-derived Dopaminochrome Promotes H₂O₂ Release at Mitochondrial Complex I

STIMULATION BY ROTENONE, CONTROL BY Ca²⁺, AND RELEVANCE TO PARKINSON DISEASE^*

Franco Zoccarato, Paola Toscano, and Adolfo Alexandre

From the 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

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 µM)- and respiration-dependent generation of H₂O₂ at Complex I in brain mitochondria, with further stimulation by low concentrations of rotenone (5–30 nM). The rotenone effect required that contaminating Ca²⁺ (8–10 µM) 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 O₂, generating and then H₂O₂. Mitochondrial removal of H₂O₂ monoamine, formed by either oxidase activity or DACHR, was performed largely by glutathione peroxidase and glutathione reductase, which were negatively regulated by low intramitochondrial Ca²⁺ levels. Thus, the H₂O₂ formed accumulated in the medium if contaminating Ca²⁺ was present; in the absence of Ca²⁺, H₂O₂ 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 release via activation of NADPH oxidase in the microglia. In turn, 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.

Received for publication, January 19, 2005 , and in revised form, February 11, 2005.

^* This work was supported by Ministero dell'Istruzione, dell'Università e della Ricerca Progetti di Ricerca di rilevante Interesse Nazionale 2004 "Apoptosis and Mitochondria: New Targets in Neoplastic, Degenerative, and Immunologic Diseases." The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 39-49-827-6146; Fax: 39-49-807-3310; E-mail: adolfo.alexandre{at}unipd.it.

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