Neuroprotective thiourea derivative uncouples mitochondria and exerts weak protonophoric action on lipid membranes

The isothiourea derivative NT-1505 is known as a neuroprotector and cognition enhancer in animal models of neurodegenerative diseases. Bearing in mind possible relation of the NT-1505-mediated neuroprotection to mitochondrial uncoupling activity, here, we examine NT-1505 effects on mitochondria func...

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Published in:Chemico-biological interactions 2024-10, Vol.402, p.111190, Article 111190
Main Authors: Antonenko, Yuri N., Veselov, Ivan M., Rokitskaya, Tatyana I., Vinogradova, Daria V., Khailova, Lyudmila S., Kotova, Elena A., Maltsev, Andrey V., Bachurin, Sergey O., Shevtsova, Elena F.
Format: Article
Language:English
Subjects:
Mitochondria
Neuroprotection
Protonophore
Thiourea derivative
Uncoupling
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Summary:The isothiourea derivative NT-1505 is known as a neuroprotector and cognition enhancer in animal models of neurodegenerative diseases. Bearing in mind possible relation of the NT-1505-mediated neuroprotection to mitochondrial uncoupling activity, here, we examine NT-1505 effects on mitochondria functioning. At concentrations starting from 10 μM, NT-1505 prevented Ca2+-induced mitochondrial swelling, similar to common uncouplers. Alongside the inhibition of the mitochondrial permeability transition, NT-1505 caused a decrease in mitochondrial membrane potential and an increase in respiration rate in both isolated mammalian mitochondria and cell cultures, which resulted in the reduction of energy-dependent Ca2+ uptake by mitochondria. Based on the oppositely directed effects of bovine serum albumin and palmitate, we suggest the involvement of fatty acids in the NT-1505–mediated mitochondrial uncoupling. In addition, we measured the induction of electrical current across planar bilayer lipid membrane upon the addition of NT-1505 to the bathing solution. Importantly, introduction of the palmitic acid into the lipid bilayer composition led to weak proton selectivity of the NT-1505-mediated BLM current. Thus, the present study revealed an ability of NT-1505 to cause moderate protonophoric uncoupling of mitochondria, which could contribute to the neuroprotective effect of this compound. [Display omitted] •The isothiourea neuroprotector NT-1505 prevents Ca2+-induced mitochondrial swelling.•NT-1505 decreases mitochondrial membrane potential and stimulates oxygen consumption.•Palmitate renders NT-1505-induced electric current across BLM weakly proton-selective.•Fatty acids are probably involved in the NT-1505-mediated mitochondrial uncoupling.•Protonophoric uncoupling of mitochondria may contribute to its neuroprotective effect.
ISSN:0009-2797
1872-7786
1872-7786
DOI:10.1016/j.cbi.2024.111190