Peroxynitrite and Brain Mitochondria: Evidence for Increased Proton Leak
Article first published online: 13 NOV 2002
Journal of Neurochemistry
Volume 70, Issue 5, pages 2195–2202, May 1998
How to Cite
Brookes, P. S., Land, J. M., Clark, J. B. and Heales, S. J. R. (1998), Peroxynitrite and Brain Mitochondria: Evidence for Increased Proton Leak. Journal of Neurochemistry, 70: 2195–2202. doi: 10.1046/j.1471-4159.1998.70052195.x
- Issue published online: 13 NOV 2002
- Article first published online: 13 NOV 2002
- Received October 28, 1997; revised manuscript received December 15, 1997; accepted December 15, 1997.
- Mitochondrial respiratory chain;
- Nitric oxide;
- Oxidative stress;
- Lipid peroxidation
Abstract: Peroxynitrite has been reported to inhibit irreversibly mitochondrial respiration. Here we show that three sequential additions of 200 µM peroxynitrite (initial concentration) to rat brain mitochondria (0.2 mg of protein/ml) significantly stimulated state 4 respiration and that further additions progressively inhibited it. No stimulation of state 3 respiration or of the maximal enzymatic activities of the respiratory chain complexes was observed on identical peroxynitrite exposure. State 4 respiration is a consequence of the proton permeability of the mitochondrial inner membrane, and we demonstrate that the peroxynitrite-induced stimulation of state 4 respiration is accompanied by a decreased mitochondrial membrane potential, suggesting an increase in this proton leak. Cyclosporin A did not affect the stimulation, suggesting no involvement of the mitochondrial permeability transition pore. The stimulation was prevented by the lipid-soluble vitamin E analogue Trolox, suggesting the involvement of lipid peroxidation, a proposed mechanism of peroxynitrite cytotoxicity. Lipid peroxidation has previously been reported to increase membrane bilayer proton permeability. The high polyunsaturate content of brain mitochondrial phospholipids may predispose them to peroxidation, and thus a peroxynitrite-induced, lipid peroxidation-mediated increase in proton leak may apply particularly to brain mitochondria and to certain neurodegenerative disorders thought to proceed via mechanisms of mitochondrial oxidative damage.