Mitochondrial L-2-hydroxyglutarate is a physiological signalling metabolite.

Area of Science:

• Biochemistry and Metabolism
• Epigenetics and Gene Regulation
• Cellular Signaling

Background:

• L-2-Hydroxyglutarate (L-2-HG) is typically a low-abundance metabolite due to oxidation by L-2-HG dehydrogenase (L2HGDH).
• Human L2HGDH deficiency causes L-2-hydroxyglutaric aciduria, leading to L-2-HG's classification as a toxic metabolite.
• The physiological role of L-2-HG remains largely unexplored.

Purpose of the Study:

• To investigate if L-2-HG functions as a physiological signaling metabolite.
• To identify molecular targets and physiological functions of L-2-HG.
• To elucidate the regulatory mechanisms of L-2-HG levels in mitochondria.

Main Methods:

• Assessed L-2-HG production via malate dehydrogenase 2 (MDH2) activity under varying mitochondrial NADH/NAD+ ratios.
• Utilized proteome integral solubility alteration assays to identify L-2-HG targets.
• Examined gene transcription, histone modifications (H3K9me3), and retrotransposon activity in mouse models with altered L2HGDH levels.

Main Results:

• Increased mitochondrial NADH/NAD+ ratio promotes MDH2-dependent reduction of 2-oxoglutarate (2-OG) to L-2-HG.
• L2HGDH oxidizes L-2-HG to 2-OG in the mitochondrial matrix.
• KDM4 family demethylases are identified as L-2-HG targets; L-2-HG represses gene transcription and increases H3K9me3.
• In vivo L2HGDH overexpression in mice leads to reduced L-2-HG, impaired growth, mortality, and renal vulnerabilities.
• Reduced L-2-HG in postnatal kidneys causes H3K9me3 loss at L1MdTf retrotransposons, leading to their derepression and activation of stress/inflammation pathways.

Conclusions:

• Mitochondrial L-2-HG acts as a physiological signaling metabolite, challenging its 'toxic' classification.
• L-2-HG signaling regulates gene transcription and epigenetic modifications, particularly affecting retrotransposon stability.
• Metabolites previously deemed toxic may possess critical physiological functions.