Clorgyline and other propargylamine derivatives as inhibitors of succinate-dependent H₂O₂ release at NADH:UBIQUINONE oxidoreductase (Complex I) in brain mitochondria

• Published in: Journal of bioenergetics and biomembranes Vol. 40; no. 4; pp. 289 - 296
• Main Authors: Zoccarato, Franco, Cappellotto, Mara, Alexandre, Adolfo
• Format: Journal Article
• Language: English
• Published: Boston Boston : Springer US 01.08.2008; Springer US; Springer Nature B.V
• Subjects: Animal Anatomy; Animal Biochemistry; Biochemistry; Bioorganic Chemistry; Brain; Brain mitochondria; Chemistry; Chemistry and Materials Science; Complex I; Dopamine-derived dopaminochrome; Electron transport chain; Histology; Hydrogen peroxide; Inhibitors; Membrane potential; Membranes; Mitochondria; Morphology; Movement disorders; NAD; NADH; NADH-ubiquinone oxidoreductase; Neurodegenerative diseases; Nicotinamide adenine dinucleotide; Organic Chemistry; Oxidation; Parkinson's disease; Propargylamine containing compounds; Rasagiline; reactive oxygen species; Reverse electron flow; Rotenone; Studies; Substrates; Succinate; Toxins; Ubiquinone oxidoreductase; Propargylamine containing compounds; Brain mitochondria; Reactive oxygen species; Reverse electron flow; Succinate; Complex I; Dopamine-derived dopaminochrome
• ISSN: 0145-479X; 1573-6881
• DOI: 10.1007/s10863-008-9160-z

Complex I is the main O₂ ⁻ producer of the mitochondrial respiratory chain. O₂ ⁻ release is low with NAD-linked substrates and increases strongly during succinate oxidation, which increases the QH₂/Q ratio and is rotenone sensitive. We show that the succinate dependent O₂ ⁻ production (measured as H₂O₂ release) is inhibited by propargylamine containing compounds (clorgyline, CGP 3466B, rasagiline and TVP-1012). The inhibition does not affect membrane potential and is unaffected by ΔpH modifications. Mitochondrial respiration is similarly unaffected. The propargylamines inhibition of O₂ ⁻/H₂O₂ production is monitored also in the presence of the Parkinson's disease toxin dopaminochrome which stimulates O₂ ⁻ release. Propargylamine-containing compounds are the first pharmacological inhibitors described for O₂ ⁻ release at Complex I.