Научно-исследовательский институт физико-химической биологии им. А.Н. Белозерского
<h4>Aims</h4>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<sub>12</sub>TPP on FcεRI-dependent mitochondrial dysfunction and signaling during MC degranulation.<h4>Main methods</h4>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.<h4>Key findings</h4>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.<h4>Significance</h4>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.