Systemic Effects of Metabolic Enzyme Dysfunctions

Biochemical pathways are fundamental to all biological processes, and dysfunctions of the individual enzymes that comprise them are implicated in a wide array of diseases. Due to the interconnected nature of the metabolic network, dysfunction of a single enzyme can cascade through it, affecting the activity of multiple metabolic pathways and subsequently influencing animal development and physiology. The gap in knowledge regarding the molecular mechanisms that link individual enzyme dysfunctions to a multitude of molecular and physiological consequences presents a major obstacle in effective treatments for metabolic disorders. This project aims to uncover how interactions between metabolic pathways cause systemic disease. The research focuses on the systemic effects of dysfunctions in D-2-hydroxyglutarate (2HG) metabolism using the model organism Caenorhabditis elegans. 2HG, an intermediary in several major biochemical pathways, has been implicated in various disorders, including rare inborn error of metabolism D-2-hydroxyglutaric aciduria. As an oncometabolite, 2HG contributes to metabolic rewiring that promoted several types of cancer. Importantly, dysfunctions of 2HG metabolic enzymes lead to disease not only through changes in 2HG levels, but also through network-wide reshaping of metabolic flux. By examining the interactions of 2HG-processing enzymes metabolism with other biochemical pathways in the metabolic network, the project aims to uncover the molecular mechanisms behind associated pathologies. The project will systematically study 2HG metabolism using C. elegans strains with mutated 2HG enzymes and employing techniques such as metabolomics, isotope tracing, and genetic screening. The outcomes are expected to provide new insights into the connectivity of central metabolism, elucidate the role of these interactions in meeting the physiological needs of an organism, and enhance our ability to interpret changes in the metabolome. This research stands to make significant contributions to our understanding of biochemical pathway interactions and inform the development of more effective therapies. Project Number: 1R35GM162174-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Olga Ponomarova | Institution: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR, ALBUQUERQUE, NM | Award Amount: $419,375 | Activity Code: R35 | Study Section: Special Emphasis Panel[ZRG1 CDB-E (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11269027