Study Identifies Mitochondrial l-2-Hydroxyglutarate as Physiological Signalling Metabolite

A Nature research paper examined whether mitochondrial l-2-hydroxyglutarate meets criteria for a physiological signalling metabolite. Researchers tested regulated levels, defined molecular targets, and measurable physiological function. The paper states that an increase in the mitochondrial NADH/NAD+ ratio drives malate dehydrogenase 2 to reduce 2-oxoglutarate into l-2-hydroxyglutarate.

L2HGDH oxidizes l-2-hydroxyglutarate back to 2-oxoglutarate in the mitochondrial matrix without requiring a functional electron transport chain.

Proteome integral solubility alteration assays showed that the KDM4 family of H3K9 demethylases respond to l-2-hydroxyglutarate. The metabolite represses nascent transcription of specific genes in mouse embryonic stem cells and increases H3K9me3 at these loci.

Early embryonic L2HGDH overexpression in mice reduced l-2-hydroxyglutarate levels systemically. The change impaired postnatal growth, caused mortality, and produced selective functional and histological renal vulnerabilities. In postnatal kidneys, reduced l-2-hydroxyglutarate led to H3K9me3 loss at L1MdTf retrotransposons and their derepression.

This coincided with activation of the integrated stress response and inflammation pathways. The findings indicate that metabolites previously regarded as toxic may have physiological functions.