增强SIRT3活性可通过α-酮戊二酸增强生发中心的表观遗传调控作用。

Abstract

Germinal center (GC) B cells depend on sustained epigenetic modulation to maintain transcriptional identity and support affinity maturation; however, whether mitochondrial metabolism directly enhances this chromatin state remains unclear. Here, we show that enhanced SIRT3 activity promotes glutamine-derived α-ketoglutarate (αKG) accumulation and is associated with reduced H3K27me3 enrichment at the Bcl6 locus. Using SIRT3 K223R gain-of-function mice, metabolomic profiling, and stable isotope tracing, we show that SIRT3 activation increases glutamine-derived αKG accumulation without a uniform increase in downstream tricarboxylic acid (TCA) cycle labeling. Elevated αKG was associated with reduced H3K27me3 at tested Bcl6 regulatory regions, reinforced BCL6 and AID expression, sustained B cell proliferation, and qualitatively enhanced antibody affinity maturation. Glutamine supplementation partially phenocopied these effects, whereas inhibition of glutamine metabolism attenuated them. Importantly, sustained activation of this metabolic-epigenetic axis was associated with enhanced GC expansion accompanied by increased autoantibody levels and renal IgG deposition in a pristane-induced lupus model. Collectively, our findings indicate that enhanced SIRT3 activity potentiates a glutamine-αKG-chromatin axis that links mitochondrial glutamine metabolism to germinal center epigenetic modulation and humoral immune output.