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

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 C12TPP on FcεRI-dependent mitochondrial dysfunction and signaling during MC degranulation. 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. 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. 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. Mast cell degranulation is accompanied by mitochondrial fragmentation mediated by Erk1/2 activity. Mitochondria-targeted TPP-based compounds SkQ1 and C12TPP accumulate in mitochondria and decrease mast cell degranulation by preventing Erk1/2-dependent mitochondrial dysfunction. [Display omitted] •FcεRI-dependent degranulation of RBL-2H3 cells is accompanied by mitochondrial fragmentation and dysfunction.•The mitochondrial fission is mediated by Erk1/2 activity.•TPP-based compounds inhibit FcεRI-dependent degranulation of mast cells.•TPP-based compounds decrease Erk1/2 phosphorylation during mast cell FcεRI-dependent degranulation.•TPP-based compounds prevent mitochondrial dysfunction during mast cell FcεRI-dependent degranulation.