Project Summary Metabolism is essential for normal cellular function and dynamically changes to meet organism and tissue needs. Cardiac function and metabolism are closely intertwined. Fatty acid oxidation serves as the primary means to provide energy in normal conditions. In heart failure, cardiomyocytes lose this metabolic flexibility and become more reliant on glycolysis. Despite extensive work to understand the metabolic underpinnings of heart failure, more investigation is needed to dissect the underlying mechanisms of this disease. A class of metabolic diseases collectively known as inborn errors of metabolism (IEMs) provide a window into pathophysiology, including heart failure, due to their well-defined causes. Pathology arising from IEMs can be tracked back to a single mutation, providing a direct and tractable method of studying the disease. Lipoic acid deficiencies are a novel class of IEMs that cause metabolic decompensation, severe neurodevelopmental delays, and early death. Lipoyltransferase-1 (LIPT1) catalyzes the final step in de novo lipoic acid synthesis by transferring the lipoate moiety to 2-ketoacid dehydrogenases such as pyruvate dehydrogenase (PDH), oxoglutarate dehydrogenase (OGDH), and branched-chain ketoacid dehydrogenase (BCKDH). The Genetic and Metabolic Disease Program (GMDP) at UT southwestern has unique access to patient samples and clinical data. A LIPT1 deficient patient presented with neurodevelopmental delays and numerous unexpected metabolic phenotypes, including elevated serum 2-hydroxyglutarate (2HG), a metabolite with wide ranging impacts on cell signaling and epigenetic regulation. The patient also displayed altered cardiac function, including impaired systolic function and tachycardia secondary to atrial fibrillation, worsened by acute episodes of metabolic decompensation. We intend to characterize the underlying causes of cardiometabolic distress using novel mice to model cardiac LIPT1 deficiency. Mice lacking LIPT1 in the heart die within 6-7 weeks with severe systolic dysfunction and elevated levels of 2HG. The central hypothesis of this proposal is that LIPT1 deficiency pathologically limits cardiometabolic flexibility leading to deleterious metabolite accumulation, including 2HG, and impaired cardiac development and function. If successful, this proposal will generate a definitive assessment of cardiac LIPT1 deficiency in mice providing a detailed understanding of the metabolic consequences of this specific IEM. More broadly, this proposal will increase our understanding of the consequences of limited metabolic flexibility in cardiac tissue, a hallmark of heart failure. The appropriate usage of both patient data and mouse models will increase the disease relevance of the work discussed in this proposal.