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Published on: September 25, 2017
Mitochondria-targeted triphenylphosphonium-based compounds inhibit FcεRI-dependent degranulation of mast cells by
Anastasia N Pavlyuchenkova1, Roman A Zinovkin1, Ciara I Makievskaya2
1Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
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 C12TPP 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.
Insights
Triphenylphosphonium (TPP)-based compounds inhibit mast cell degranulation by preventing mitochondrial dysfunction and Erk1/2 signaling. This research offers a new therapeutic strategy for allergic diseases by targeting mitochondria.
Area of Science:
- Immunology
- Cell Biology
- Mitochondrial Biology
Background:
- Mast cells (MC) are crucial in allergic diseases via FcεRI-dependent activation.
- Triphenylphosphonium (TPP)-based antioxidant SkQ1 inhibits MC degranulation, but its mechanism is unclear.
- This study investigates TPP compounds' effects on FcεRI-dependent mitochondrial dysfunction and signaling in MC.
Purpose of the Study:
- To elucidate the mechanism by which TPP-based compounds inhibit mast cell degranulation.
- To investigate the impact of TPP compounds on FcεRI-dependent mitochondrial function and signaling pathways.
- To explore the potential of TPP compounds as therapeutic agents for allergic diseases.
Main Methods:
- Mast cells (MC) were sensitized and stimulated to induce degranulation, measured by β-hexosaminidase release.
- Western blot analysis assessed FcεRI-dependent signaling pathways (LAT, Syk, PI3K, Erk1/2, p38).
- Fluorescent microscopy evaluated mitochondrial parameters (morphology, membrane potential, ROS, ATP levels).
Main Results:
- TPP-based compounds significantly reduced FcεRI-dependent MC degranulation.
- These compounds prevented mitochondrial dysfunction, including ATP depletion and fission.
- TPP treatment decreased Erk1/2 phosphorylation, and selective Erk1/2 inhibition mimicked these effects.
Conclusions:
- Mitochondria play a critical role in FcεRI-dependent mast cell activation.
- TPP-based compounds offer a promising therapeutic avenue for allergic diseases by targeting mitochondrial pathways.
- This research supports the development of mitochondrial-targeted drugs for managing allergic conditions.
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