Mitochondrial L-2-hydroxyglutarate is a physiologic signaling metabolite [PRO-seq]

By contrast, L2HGDH converts L-2-HG to 2-OG in the mitochondrial matrix without requiring a functional ETC. Nascent gene expression analysis in mouse embryonic stem cells (mESCs) demonstrated that the majority of genes were downregulated by elevated L-2-HG levels. To identify proteins involved in L-2-HG-dependent gene regulation, we used proteome integral solubility alteration assays (PISA), which showed that L-2-HG engages the RNA demethylase FTO and H3K9 demethylases KDM4A/B/C in mESC nuclear extracts.

The L-2-HG-dependent accumulation of m6A in mRNAs and H3K9me3 at the gene loci negatively correlated with gene expression. Importantly, mitochondrial L2HGDH overexpression during early embryogenesis lowered basal L-2-HG levels and resulted in viable mice at birth but triggered reduced growth, impaired kidney function, and post-natal mortality. Thus, L-2-HG primarily downregulates gene expression and is a signaling metabolite necessary for post-natal mammalian growth and survival.

These findings suggest that other previously considered toxic metabolites might also play physiological roles.