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

Autor: Pavlyuchenkova AN; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia., Zinovkin RA; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia., Makievskaya CI; Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia., Galkin II; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia., Chelombitko MA; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia. Electronic address: chelombitko@mail.bio.msu.ru.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2022 Jan 01; Vol. 288, pp. 120174. Date of Electronic Publication: 2021 Nov 23.
DOI: 10.1016/j.lfs.2021.120174
Abstrakt: Aims: FcεRI-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 C 12 TPP on FcεRI-dependent mitochondrial dysfunction and signaling during MC degranulation.
Main Methods: MC 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 Findings: Pretreatment 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.
Significance: These 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.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: