KillBaitMitochondrial l-2-Hydroxyglutarate Acts as a Physiological Signaling Molecule with Functional Roles
📰 Original title: Mitochondrial l-2-hydroxyglutarate is a physiological signalling metabolite
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Mitochondrial l-2-Hydroxyglutarate Acts as a Physiological Signaling Molecule with Functional Roles
A recent study published in Nature investigates the role of l-2-hydroxyglutarate (l-2-HG), a metabolite traditionally considered toxic, in normal physiological processes. The researchers found that l-2-HG is produced in mitochondria through the action of malate dehydrogenase 2 (MDH2) when the mitochondrial NADH/NAD+ ratio rises. This metabolite is then converted back to 2-oxoglutarate (2-OG) by the mitochondrial enzyme l-2-HG dehydrogenase (L2HGDH), independent of a functional electron transport chain. l-2-HG interacts with the KDM4 family of H3K9 demethylases, repressing transcription of specific genes in mouse embryonic stem cells and increasing the repressive histone mark H3K9me3 at these loci. In vivo experiments revealed that overexpression of L2HGDH in mice reduced l-2-HG levels, leading to impaired postnatal growth, increased mortality, and selective kidney vulnerabilities, including activation of stress response and inflammation pathways. These findings demonstrate that l-2-HG is a physiologically regulated signaling metabolite and suggest that other metabolites previously labeled as toxic may have important regulatory functions in normal biology.
L'Air du Bois
Garland Jackson Marcus
Oezer Utku
jobRxiv
NicoRey (Forj)
FitBodyScience
Francis Vayeur
Daniele Micci 🇪🇺