Truncating ASXL1 variants rewire cellular metabolism via mitochondrial pyruvate carrier repression

Area of Science:

• Genetics and Epigenetics
• Cellular Metabolism
• Developmental Biology

Background:

• Bohring-Opitz syndrome (BOS) is a rare neurodevelopmental disorder linked to ASXL1 variants.
• ASXL1 variants are also implicated in myeloid leukemia.
• The metabolic impact of ASXL1 mutations is largely unknown.

Purpose of the Study:

• To investigate the metabolic consequences of truncating ASXL1 variants.
• To elucidate the chromatin-to-metabolism axis in BOS and myeloid malignancies.
• To identify the role of mitochondrial pyruvate transport in ASXL1-associated phenotypes.

Main Methods:

• Analysis of patient-derived dermal fibroblasts with truncating ASXL1 variants.
• Chromatin immunoprecipitation sequencing (ChIP-seq) to assess protein occupancy.
• Quantitative PCR and Western blotting to measure gene and protein expression.
• Pharmacologic inhibition of mitochondrial pyruvate carrier (MPC) and Wnt signaling pathway activation.

Main Results:

• Truncating ASXL1 variants induce a Warburg-like metabolic state with increased glycolysis and lactate production.
• Aberrant ASXL1 and BAP1 co-occupancy at an intronic regulatory element of MPC2 leads to reduced MPC2 transcript and significantly lower MPC1/MPC2 protein levels.
• Mitochondrial pyruvate restriction, mediated by MPC dysfunction, is upstream of Wnt signaling dysregulation in BOS cells.

Conclusions:

• ASXL1 truncation establishes a novel chromatin-to-metabolism axis impacting mitochondrial pyruvate transport.
• Mitochondrial pyruvate carrier (MPC) is a key mediator of epigenetic-metabolic crosstalk in BOS and ASXL1-mutant myeloid leukemia.
• Targeting MPC may offer therapeutic potential for ASXL1-related disorders.