2-Phenyl-β-lapachone can affect mitochondrial function by redox cycling mediated oxidation
Section snippets
Chemicals
2PBL and 2-ethyl-β-lapachone were obtained from Novartis (Ciba-Geigy), Basle, Switzerland. Atovaquone was provided by Welcome Laboratories, Langley Court, Beckenham, Kent, UK. Naphthoquinones were used dissolved in dimethylformamide (DMFA). KCl, KCN, and MgCl2 were purchased from Mallinckrodt Chemical Works, New York, USA. DMFA, bovine serum albumin (A-4503), ADP, l-glutamate, l-malate, l-malonate, l-succinate, NADH, sucrose, Tris(hydroxymethyl)aminomethane, menadione, rotenone, antimycin A,
Effect of 2PBL, menadione and atovaquone, on electron transfer and oxidative phosphorylation in coupled mitochondria
Table 1 shows the effect of 2PBL, menadione and atovaquone on the respiration rate of coupled mitochondria. Using malate–glutamate as substrate, 2PBL inhibited state 3 mitochondrial respiration at 10 μM, increased state 4 respiration at 5 μM and decreased RCI at 2.5 μM. Using succinate as substrate, 2PBL inhibited state 3 mitochondrial respiration at 25 μM, activated state 4 at 5 μM and decreased RCI at 2.5 μM. Similar results were obtained with 2-ethyl-β-lapachone (data not shown).
Equivalent
Discussion
Our results show that, within the 2.5–50 μM range, 2PBL induces changes in mitochondrial respiration states, where there is an increased rate of production, an inhibition of mitochondrial electron transport, the uncoupling of oxidative phosphorylation and the collapse of mitochondrial membrane potential.
The NADH oxidation, insensitive to rotenone, antimycin, myxothiazol or cyanide (Fig. 2) and the significant correlation between 2PBL effect on NADH oxidation and production in
Acknowledgments
This work was aided in part by grants from CONICET and Fundación Navarro Viola (Dr. C. Valiente Noailles), Buenos Aires, Argentina. Dr. Natacha de Witte was a fellow from Academy of Sciences, Buenos Aires (Dr. Rodolfo Brenner). We thank Dr. Alicia Fuchs for helpful discussion and Mrs. A. Verón, S. del Valle and C. Lincon for technical assistance.
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Professor Stoppani passed away on March 18, 2003.