Drosophila larvae synthesize the putative oncometabolite L-2-hydroxyglutarate during normal developmental growth

Area of Science:

• Metabolic regulation
• Epigenetics
• Developmental biology

Background:

• L-2-hydroxyglutarate (L-2HG) is recognized as a potential oncometabolite affecting cellular processes.
• Despite its roles, L-2HG is often considered a metabolic byproduct.

Purpose of the Study:

• Investigate the endogenous synthesis and function of L-2HG during normal development.
• Determine the regulatory mechanisms controlling L-2HG levels in vivo.
• Establish Drosophila as a model for studying L-2HG's role in cell growth and proliferation.

Main Methods:

• Utilized Drosophila larvae and genetic manipulation.
• Quantified L-2HG levels and analyzed metabolic pathways.
• Assessed the impact of L-2HG on epigenetic modifications like DNA methylation and position effect variegation.

Main Results:

• Drosophila larvae accumulate high L-2HG concentrations during development, derived from glucose via aerobic glycolysis.
• Drosophila estrogen-related receptor (dERR) and lactate dehydrogenase (dLDH) are crucial for L-2HG synthesis.
• Lactate dehydrogenase (dLDH) also stabilizes L-2HG by inhibiting its degradation via L-2-hydroxyglutarate dehydrogenase (dL2HGDH).
• L-2HG and dLDH influence DNA methylation and position effect variegation, linking metabolism to epigenetics.

Conclusions:

• Growing tissues synthesize L-2HG in a regulated manner, not merely as waste.
• A novel mechanism coordinates glycolytic flux with L-2HG synthesis and epigenetic regulation.
• Drosophila serves as a valuable model for exploring L-2HG's endogenous functions in development and disease.