Using Multi-omics To Study 2-Hydroxyglutarate (Patho)Biology

Abstract

The term 2-hydroxyglutarate (2HG) is often used broadly in the biomedical literature, yet it overlooks a key biochemical nuance: chirality. 2HG exists as two enantiomers, L2HG and D2HG, which are structurally identical except for the configuration around the chiral hydroxyl-bearing carbon at the C2 position. This enantioselectivity is biologically consequential as the two forms arise from distinct metabolic pathways engaged under different physiological and pathological stresses. L2HG, but not D2HG, accumulates robustly under conditions of hypoxia, acidosis, and myocardial ischemia. This thesis begins with an introduction (Chapter 1) tracing the evolution of 2HG research from its early chemical characterization to its recognition as a signaling metabolite. Building on this conceptual framework, the first results chapter (Chapter 2) investigates the relationship between L2HG and triglyceride / fatty acid metabolism and demonstrates that conditions promoting L2HG accumulation are accompanied by coordinated remodeling of neutral lipid pools, consistent with altered fatty acid handling and energy storage pathways. The second results chapter (Chapter 3) focuses on phosphatidylethanolamine metabolism, implicating L2HG in regulation of glycerophospholipids. The final results chapter (Chapter 4) moves beyond reductionist analysis by applying a holistic, network medicine–based framework to integrate proteomics data, leading to the identification of major vault protein (MVP), the principal structural component of vault nanoparticles, as a previously unrecognized molecular target of L2HG-associated metabolic stress. Finally, Chapter 5 integrates the findings of this thesis and highlights future directions for the field. Collectively, this thesis defines a connection between L2HG metabolism and lipid and protein remodeling, establishing an integrated framework for understanding how L2HG functions as a metabolic signal in (patho)biology.