Mitochondrial l-2-hydroxyglutarate identified as physiological signalling metabolite controlling postnatal growth and renal function (nature.com)

• l-2-HG production requires high mitochondrial NADH/NAD+ ratio and MDH2
• L2HGDH can oxidize l-2-HG independently of the electron transport chain
• KDM4 demethylases are primary targets of l-2-HG
• l-2-HG depletion causes postnatal lethality and kidney defects in mice

"l-2-Hydroxyglutarate (l-2-HG) is produced by MDH2 when mitochondrial NADH/NAD+ ratio increases, and is oxidized back to 2-OG by L2HGDH without a functional electron transport chain. It targets KDM4 H3K9 demethylases, repressing transcription of specific genes via H3K9me3. In mice, L2HGDH overexpression reduces l-2-HG, causing postnatal lethality, growth impairment, and renal dysfunction. This establishes l-2-HG as a physiological signalling metabolite."