MITF-associated metabolic signature in mast cells: A potential link to food anaphylaxis.

Abstract

Background: Microphthalmia-associated transcription factor (MITF) is a master regulator of mast cell (MC) differentiation and effector function; it 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: Our aim was to determine how MITF regulates MC mitochondrial function and metabolic fitness beyond pyruvate dehydrogenase control, as well as 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, compared with MCs from sensitized and healthy individuals, MCs from patients with food anaphylaxis exhibited increased MITF expression, elevated levels of mitochondrial markers, enhanced mitochondrial respiration, and a glycolytic shift after allergen activation,. Notably, pharmacologic inhibition of MITF reduced mitochondrial membrane potential in patient-derived MCs.

Conclusions: MITF is a central regulator of MC mitochondrial function; it is associated with enhanced metabolic activity in anaphylaxis, highlighting MITF-driven pathways as potential therapeutic targets in MC-mediated allergic disease.