Investigating the Receptor-independent Neuroprotective Mechanisms of Nicotine in Mitochondria

• Published in: The Journal of biological chemistry Vol. 280; no. 37; pp. 32405 - 32412
• Main Authors: Xie, Yu-Xiang, Bezard, Erwan, Zhao, Bao-Lu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.09.2005; American Society for Biochemistry and Molecular Biology
• Subjects: 1-Methyl-4-phenylpyridinium - pharmacology; Animals; Binding Sites; Blotting, Western; Brain - metabolism; Calcium - metabolism; Cell Line; Cell Line, Tumor; Cytochromes c - metabolism; Dose-Response Relationship, Drug; Electrons; Free Radicals; Green Fluorescent Proteins - metabolism; Humans; Hydrogen Peroxide - pharmacology; Intracellular Membranes - metabolism; Male; Membrane Potentials; Microscopy, Confocal; Mitochondria - metabolism; Mitochondrial Swelling; Nicotine - metabolism; Nicotine - pharmacology; Oxidopamine - pharmacology; Oxygen - metabolism; Permeability; Plasmids - metabolism; Rats; Rats, Sprague-Dawley; Spectrophotometry; Time Factors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M504664200

Although nicotine has been associated with a decreased risk of developing Parkinson disease, the underlying mechanisms are still unclear. By using isolated brain mitochondria, we found that nicotine inhibited N-methyl-4-phenylpyridine (MPP+) and calcium-induced mitochondria high amplitude swelling and cytochrome c release from intact mitochondria. Intra-mitochondria redox state was also maintained by nicotine, which could be attributed to an attenuation of mitochondria permeability transition. Further investigation revealed that nicotine did not prevent MPP+- or calcium-induced mitochondria membrane potential loss, but instead decreased the electron leak at the site of respiratory chain complex I. In the presence of mecamylamine hydrochloride, a nonselective nicotinic acetylcholine receptor inhibitor, nicotine significantly postponed mitochondria swelling and cytochrome c release induced by a mixture of neurotoxins (MPP+ and 6-hydroxydopamine) in SH-SY5Y cells, suggesting that there is a receptor-independent nicotine-mediated neuroprotective effect of nicotine. These results show that interaction of nicotine with mitochondria respiratory chain together with its antioxidant effects should be considered in the neuroprotective effects of nicotine.