Truncating ASXL1 variants rewire cellular metabolism via mitochondrial pyruvate carrier repression

Bohring-Opitz syndrome (BOS, OMIM#605309) is a rare neurodevelopmental disorder caused by heterozygous and truncating variants in ASXL1 (Additional Sex Combs Like 1), a chromatin-associated epigenetic regulator that forms the catalytic PR-DUB complex with BAP1. Truncating ASXL1 variants are also recurrent somatic drivers in myeloid leukemia, yet the metabolic consequences of these mutations remain undefined. Using patient derived dermal fibroblasts, we show that truncating ASXL1 variants drive a Warburg-like metabolic state characterized by increased glycolytic flux, and accumulation of pyruvate and lactate. Stable isotope tracing revealed preservation of glucose-derived carbon incorporation into tricarboxylic acid (TCA) cycle intermediates, suggesting compensatory metabolic adaptation to maintain pyruvate-dependent TCA cycle metabolism. Overexpression of truncating ASXL1 constructs in cell models replicated this phenotype. Mechanistically, truncated ASXL1 shows decreased occupancy at an H3K4me3-marked enhancer upstream of mitochondrial pyruvate carrier 2 (MPC2), together with BAP1 co-recruitment, and selectively reduces MPC1 and MPC2 protein levels through a mechanism that is independent of transcript levels. Pharmacologic inhibition of the MPC reproduces both the metabolic and Wnt signaling phenotypes of BOS cells, while canonical Wnt activation also increases glycolytic flux but without reducing the MPC abundance, implicating that reduced MPC abundance acts upstream of signaling dysregulation. These findings define a previously unrecognized pathway connecting gain-of-function ASXL1 truncation to chromatin-level regulation of mitochondrial pyruvate transport, and identify the MPC as a central mediator of epigenetic-metabolic crosstalk in both a rare developmental syndrome and ASXL1-mutated myeloid malignancies.