Objective:

To investigate the role of lactate dehydrogenase A (LDHA) in hypoxia-associated sorbitol and fructose metabolism in U87MG tumor cells with low sorbitol dehydrogenase (SDH) expression, highlighting its potential implications in tumor metabolism.

Approach:

• Metabolomic Analysis: Intracellular metabolites in normoxic and hypoxic U87MG cells were analyzed using mass spectrometry to quantify levels of sorbitol and fructose.

Key Findings:

• Fructose accumulation was marked in hypoxic U87MG cells.
• Both SDH and LDHA catalyzed sorbitol oxidation and fructose reduction in vitro.
• LDHA was detectable and increased under hypoxia, while SDH levels remained low.
• LDHA knockdown reduced intracellular fructose levels and increased sorbitol accumulation, elevating ROS levels and decreasing cell viability under hypoxia.
• LDHA overexpression showed the opposite effects.

Interpretation:

LDHA contributes to hypoxia-associated sorbitol/fructose metabolism, linking this metabolic activity to redox balance and cell viability in U87MG cells.

Limitations:

• The study primarily focuses on U87MG cells and may not be generalizable to other tumor types.
• The effects of LDHA on other metabolic pathways were not explored.

Conclusion:

LDHA plays a significant role in facilitating sorbitol and fructose metabolism in hypoxic tumor cells.