The impairment of MTCH2 accelerates autoreactive B cell expansion by enhancing Oxidative Phosphorylation in SLE 2307315

Abstract

Abstract Introduction In systemic lupus erythematosus (SLE), aberrant B cell activation is fueled by elevated oxidative phosphorylation (OXPHOS), yet checkpoints restraining this metabolic hyperactivity remain undefined. We identify mitochondrial carrier homolog 2 (MTCH2),as a critical metabolic gatekeeper that limits OXPHOS-driven autoreactive B cell expansion and maintains germinal center (GC) tolerance in autoimmunity. Methods We analyzed metabolic profiles of B cells from SLE patients and healthy controls using scRNA-seq. B cell-specific MTCH2-deficient mice (Mb1-Cre; Mtch2fl/fl) were subjected to pristane-induced lupus. GC responses, BCR repertoire, and somatic hypermutation (SHM) were assessed by flow cytometry, and BCR sequencing. Mechanistic studies employed immunoprecipitation and GTPase activity to define the MTCH2—FUNDC2 axis, and a high-throughput screen identified a pharmacological agonist. Results B cells from SLE patients exhibited an OXPHOS signature and concomitantly downregulated MTCH2. B cell-specific MTCH2 deletion in mice exacerbated lupus, with expanded GCs, elevated autoantibodies. Sc-metabolic profiling revealed profound metabolic reprogramming across B cell subsets, with dark-zone GC B cells exhibiting the highest OXPHOS activity. This metabolic rewiring skewed the BCR, promoting the clonal expansion of autoreactive cells with excessive SHM. Mechanistically, MTCH2 governed mitochondrial dynamics via the FUNDC2—MFN1/2 axis which led to dysregulated mitochondrial fusion and B cell activation threshold. Pharmacological upregulation of MTCH2 by agonist restored mitochondrial homeostasis and ameliorated lupus in vivo. Conclusion We establish MTCH2 as a pivotal metabolic checkpoint that restrains autoreactive B cell expansion. Loss of MTCH2 disrupts GC tolerance, driving clonal dominance of autoreactive B cells and accelerating systemic autoimmunity. Targeting the MTCH2 axis represents a clinically translatable strategy to reinstate metabolic control and restore immune tolerance in SLE. Funding Source National Natural Science Foundation of China ( 82230060, 32141004, 32430036, 32441093) Topic Categories Basic Autoimmunity (BA)