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Principal Investigator: Trevor Stanley Tippetts
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $77,284
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <0-11 years old><1,2-Dithiolane-3-pentanoic acid><2-Keto-4-Hydroxyglutarate Dehydrogenase><2-Oxoglutarate Dehydrogenase><2-Oxoglutarate Dehydrogenase Complex><21+ years old><Acetyl CoA><Acetyl Coenzyme A><Acute><Adult><Adult Human><Amino Acids><Anabolism><Animals><Atrial Fibrillation><Auricular Fibrillation><Automobile Driving><Back><Blood Serum><Body Tissues><Bypass><Cardiac><Cardiac Abnormalities><Cardiac Chronotropism><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac development><Cardiocyte><Cardiomyopathies><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cellular Function><Cellular Physiology><Cellular Process><Cessation of life><Characteristics><Child><Child Youth><Children (0-21)><Citric Acid Cycle><Clinical Data><Consumption><D-Glucose><DNA Recombination><Death><Defect><Dehydrogenases><Development><Developmental Delay><Developmental Delay Disorders><Dextrose><Diet><Dietary Supplementation><Disease><Disorder><Distress><Dorsum><Dysfunction><Early Diagnosis><Early treatment><Echocardiogram><Echocardiography><Embryo><Embryonic><Energy Expenditure><Energy Metabolism><Environment><Enzyme Gene><Enzymes><Exhibits><FDA approved><Failure><Fatty Acids><Formulation><Functional disorder><Gatekeeping><Genetic Alteration><Genetic Change><Genetic Diseases><Genetic Recombination><Genetic defect><Germ Lines><Glucose><Glycolysis><Heart><Heart Abnormalities><Heart Muscle Cells><Heart Rate><Heart failure><Heart myocyte><Hereditary Metabolic Disorder><Hexadecanoates><Histologic Technics><Histologic Techniques><Histological Technics><Histological Techniques><Histology><Immunoblotting><Impairment><In Vitro><Inborn Errors of Metabolism><Infant Mortality><Infant Mortality Total><Infection><Inflammatory><Intermediary Metabolism><Intracellular Communication and Signaling><Investigation><Keto Acids><Ketoglutarate Dehydrogenase Complex><Ketone Bodies><Krebs Cycle><Lead><Lipids><Lipoic Acid><Lipopolysaccharides><Mendelian disease><Mendelian disorder><Mendelian genetic disorder><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolic dysfunction><Metabolism><Methods><Mice><Mice Mammals><Mitochondria><Modeling><Molecular><Murine><Mus><Mutation><Myocardial Diseases><Myocardial Disorder><Myocardiopathies><Nutrient><Nutritional><Organ><Organism><Oxidoreductase><Oxidoreductase Gene><Oxoglutarate Dehydrogenase><Palmitates><Pathogenicity><Pathologic><Pathology><Patients><Pb element><Phenotype><Physiopathology><Proteins><Protocol><Protocols documentation><Pyruvate><Recombination><Reductases><Regulation><S-acetate Coenzyme A><Sampling><Secondary to><Serum><Signal Transduction><Signal Transduction Systems><Signaling><Specific Child Development Disorders><Spirometry><Subcellular Process><TCA cycle><Tachycardia><Testing><Therapeutic><Thesaurismosis><Thioctic Acid><Tissues><Transthoracic Echocardiography><Tricarboxylic Acid Cycle><Variant><Variation><Western Blotting><Western Immunoblotting><Work><adulthood><alpha-Ketoglutarate Dehydrogenase><alpha-Ketoglutarate Dehydrogenase Complex><alpha-Lipoic Acid><aminoacid><biological signal transduction><biosynthesis><cardiac failure><cardiac function><cardiac metabolism><cardiogenesis><cardiometabolic><cardiometabolism><cardiomyocyte><circulating biomarkers><circulating markers><cofactor><data modeling><death among infants><death in first year of life><death in infancy><death in infants><developmental><diet supplementation><diets><driving><early detection><early therapy><epigenetic regulation><fat metabolism><fatty acid oxidation><feeding><flexibility><flexible><function of the heart><gatekeeper><genetic condition><genetic disorder><genome mutation><heart development><heart formation><heart function><heart metabolism><heart sonography><heavy metal Pb><heavy metal lead><improved><in vivo><inborn metabolism disorder><infant death><infant demise><infantile death><ketoacid><kids><lipid metabolism><lipoate><living system><metabolic phenotype><metabolism disorder><metabolism measurement><metabolomics><metabonomics><metabotype><mitochondrial><model of data><model the data><modeling of the data><monogenic disease><monogenic disorder><mortality in infants><mouse model><murine model><mutant><myocardium disease><myocardium disorder><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><nutritious><oxidation><pathophysiology><post-natal period><postnatal period><premature><prematurity><programs><protein blotting><pyruvate dehydrogenase><response><single-gene disease><single-gene disorder><stable isotope><stressor><succinyl-CoA><succinyl-coenzyme A><youngster>