R01HL155107

L-2-Hydroxyglutarate and Metabolic Remodeling in Hypoxia - Project Summary

Adaptive metabolic responses to hypoxia reflect essential evolutionary survival strategies in all eukaryotes. We recently identified a unique metabolite that increases in cardiovascular (CV) cells in response to hypoxia, L-2-hydroxyglutarate (L2HG). This metabolite is derived from α-ketoglutarate, or 2-oxoglutarate (2OG), a key intermediate in the tricarboxylic acid cycle.

Once formed from 2OG and NADH, L2HG has no other metabolic fate except to undergo oxidation back to 2OG by the stereospecific dehydrogenase, L2HG dehydrogenase (L2HGDH), suggesting that it accommodates ('buffers') the increase in reducing equivalents accompanying hypoxia. L2HG has two other unique actions: it suppresses glycolysis and, as we show here, it increases pentose phosphate pathway (PPP) activity.

The central hypothesis of this proposal is that L2HG suppresses glycolysis and enhances PPP activity in CV cells to eliminate reactive oxygen species (ROS), maintain cell redox potential, and preserve cell function in hypoxia. To address this hypothesis, we will focus on three specific aims.

First, we will determine the molecular metabolic mechanisms underlying the effects of L2HG on glycolysis and PPP activity. In particular, we will focus on the unique role of a specific phosphofructokinase-2 isoform, PFKFB4, as a key regulatory determinant of increased flux through the PPP in hypoxia.

Second, we will determine the effect of this L2HG-induced increased PPP activity in hypoxia on cellular redox potential and intra- and extracellular ROS elimination. Here, we will focus on PPP-derived NADPH and GSH as key cofactors in NADPH oxidase and glutathione peroxidase activities, respectively, in order to enhance elimination of excess ROS.

Third, we will study the effects of L2HG in hypoxia or ischemia on cellular and cardiac function, respectively, using unique cellular and genetic murine models. Taken together, these studies should provide insights into the mechanisms by which L2HG promotes metabolic remodeling to preserve cell and cardiac function in oxygen-limited states.

Brigham & Womens Hospital

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Massachusetts United States

State-Wide

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 453% from $621,648 to $3,437,123.