The Journal of allergy and clinical immunology · 2026
MITF-associated metabolic signature in mast cells: A potential link to food anaphylaxis.
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Ollé Laia, Barrios Mónica, Song Lihong, Carreras-Kàtcheff Sofia, Mir-Ihara Patricia, Valls-Roca Laura, Guitart-Mampel Mariona, Garrabou Glòria, García Carmen, Fernandez-Checa Jose C, Babina Magda, Muñoz-Cano Rosa, Martín Margarita
Аннотация
BACKGROUND: Microphthalmia-associated transcription factor (MITF) is a master regulator of mast cell (MC) differentiation and effector function and is essential for anaphylaxis (severe allergic reactions). Although MITF has been linked to mitochondrial regulation through pyruvate dehydrogenase, whether it broadly controls mitochondrial fitness and metabolic programs that exacerbate MC activation remains unclear.
OBJECTIVE: To determine how MITF regulates MC mitochondrial function and metabolic fitness beyond pyruvate dehydrogenase control, and to define its contribution to heightened MC activation and food anaphylaxis.
METHODS: MITF was silenced, pharmacologically inhibited, or overexpressed in human MCs, followed by IgE- and MRGPRX2-dependent activation. Transcriptomic profiling, and mitochondrial functional analyses were then performed. In parallel, MCs from patients with food anaphylaxis and from healthy controls were analyzed to assess clinical relevance.
RESULTS: Transcriptomic analysis of MITF-silenced MCs revealed a distinct metabolic signature characterized by downregulation of mitochondrial pathways and metabolic cellular compartments. MITF knockdown reduced mitochondrial fission, membrane potential, mitochondrial respiration, and mitochondrial marker expression of TOM20 and COX-IV, supporting a role for MITF in mitochondrial activity and metabolic regulation. Furthermore, MCs from patients with food anaphylaxis exhibited increased MITF expression, elevated mitochondrial markers, enhanced mitochondrial respiration, and a glycolytic shift after allergen activation, compared with those from sensitized and healthy individuals. Notably, pharmacological inhibition of MITF reduced mitochondrial membrane potential in patient-derived MCs.
CONCLUSIONS: MITF is a central regulator of MC mitochondrial function and is associated with enhanced metabolic activity in anaphylaxis, highlighting MITF-driven pathways as potential therapeutic targets in MC-mediated allergic disease.
OBJECTIVE: To determine how MITF regulates MC mitochondrial function and metabolic fitness beyond pyruvate dehydrogenase control, and to define its contribution to heightened MC activation and food anaphylaxis.
METHODS: MITF was silenced, pharmacologically inhibited, or overexpressed in human MCs, followed by IgE- and MRGPRX2-dependent activation. Transcriptomic profiling, and mitochondrial functional analyses were then performed. In parallel, MCs from patients with food anaphylaxis and from healthy controls were analyzed to assess clinical relevance.
RESULTS: Transcriptomic analysis of MITF-silenced MCs revealed a distinct metabolic signature characterized by downregulation of mitochondrial pathways and metabolic cellular compartments. MITF knockdown reduced mitochondrial fission, membrane potential, mitochondrial respiration, and mitochondrial marker expression of TOM20 and COX-IV, supporting a role for MITF in mitochondrial activity and metabolic regulation. Furthermore, MCs from patients with food anaphylaxis exhibited increased MITF expression, elevated mitochondrial markers, enhanced mitochondrial respiration, and a glycolytic shift after allergen activation, compared with those from sensitized and healthy individuals. Notably, pharmacological inhibition of MITF reduced mitochondrial membrane potential in patient-derived MCs.
CONCLUSIONS: MITF is a central regulator of MC mitochondrial function and is associated with enhanced metabolic activity in anaphylaxis, highlighting MITF-driven pathways as potential therapeutic targets in MC-mediated allergic disease.