Mitochondria-targeted triphenylphosphonium-based compounds inhibit FceRI-dependent degranulation of mast cells by preventing mitochondrial dysfunction through Erk1/2

Pavlyuchenkova, A.N.; Zinovkin, R.A.; Makievskaya, C.I.; Galkin, I.I.; Chelombitko, M.A.

Авторы: Pavlyuchenkova Anastasia N., Zinovkin Roman A., Makievskaya Ciara I., Galkin Ivan I., Chelombitko Maria A.
Журнал: Life Sciences
Год издания: 2022
Издательство: Elsevier BV
Местоположение издательства: Netherlands
Номер статьи: 120174
DOI: 10.1016/j.lfs.2021.120174
Аннотация: AbstractAimsFcεRI-dependent activation and degranulation of mast cells (MC) play an important role in allergic diseases. We have previously demonstrated that triphenylphosphonium (TPP)-based antioxidant SkQ1 inhibits mast cell degranulation, but the exact mechanism of this inhibition is still unknown. This study focused on investigating the influence of TPP-based compounds SkQ1 and C12TPP on FcεRI-dependent mitochondrial dysfunction and signaling during MC degranulation.Main methodsMC were sensitized by anti-dinitrophenyl IgE and stimulated by BSA-conjugated dinitrophenyl. The degranulation of MC was estimated by β-hexosaminidase release. The effect of TPP-based compounds on FcεRI-dependent signaling was determined by Western blot analysis for adapter molecule LAT, kinases Syk, PI3K, Erk1/2, and p38. Fluorescent microscopy was used to evaluate mitochondrial parameters such as morphology, membrane potential, reactive oxygen species and ATP level.Key findingsPretreatment with TPP-based compounds significantly decreased FcεRI-dependent degranulation of MC. TPP-based compounds also prevented mitochondrial dysfunction (drop in mitochondrial ATP level and mitochondrial fission), and decreased Erk1/2 kinase phosphorylation. Selective Erk1/2 inhibition by U0126 also reduced β-hexosaminidase release and prevented mitochondrial fragmentation during FcεRI-dependent degranulation of MC.SignificanceThese findings expand the fundamental understanding of the role of mitochondria in the activation of MC. It also contributes to the rationale for the development of mitochondrial-targeted drugs for the treatment of allergic diseases.
Добавил в систему: Челомбитько Мария Александровна

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Mitochondria-targeted triphenylphosphonium-based compounds inhibit FceRI-dependent degranulation of mast cells by preventing mitochondrial dysfunction through Erk1/2статья