Abstract Body: Introduction. Metabolism is essential for cellular function and adapts to tissue needs. Healthy hearts primarily rely on fatty acid oxidation for energy; however, failing hearts shift toward glycolysis. Inborn errors of metabolism (IEMs) are monogenic disorders affecting metabolic enzymes. All IEMs stem from specific enzyme variants, providing a direct molecular path to study phenotypes like heart failure. Lipoyltransferase-1 (LIPT1) transfers lipoic acid to 2-ketoacid dehydrogenases (2KDHs) such as pyruvate dehydrogenase and oxoglutarate dehydrogenase (OGDH). Lipoylated 2KDH enzymes are essential for the oxidation of fuels for mitochondrial metabolism. Patients with LIPT1 deficiency present with impaired cardiac function and developmental devastation. We assessed the hypothesis that LIPT1 is required for cardiac function and whether novel nutrients can improve cardiac outcomes.
Methods and Results. We specifically knocked out Lipt1 in the heart in mice. Mouse late-gestation LIPT1 knockout (e.g., Myh6-Cre) leads to death by 6 weeks of age with systolic dysfunction and dilated hypertrophic cardiomyopathy (n=10-20/group, control heart mass=.091, LIPT1 KO= .221, SE=.018, p<.001) while LIPT1 depletion in early-gestation (e.g., Nkx2.5-Cre) leads to embryonic demise in utero, indicating a temporal window where LIPT1 is required for cardiac development (n=20 litters of mice). Heart metabolomics revealed an accumulation of metabolites upstream of lipoylated protein complexes in both early- and late-gestation knockouts of cardiac LIPT1 (n=6/group). Interestingly, lipoylation depletion leads to D-2-hydroxyglutarate accumulation (n=6/group, FC=23.8, p<.001) and depleted histone methylation. Histology of Lipt1 deficient hearts shows enlarged cardiomyocytes and collagen accumulation (n=6 mice/group).
Propionate is an alternative fuel source for the TCA cycle that does not rely on lipoylated enzymes. Infusion of [U-¹³C]propionate is equally metabolized into TCA cycle intermediates downstream of OGDH in both LIPT1 deficient and replete hearts (n=6/group, p>.6). Finally, dietary supplementation of propionate extends lifespan of Myh6-Cre driven LIPT1 deficient mice up to 2 weeks (n=6/group, p<.01).
Conclusions: Lipoylation is necessary for cardiac function. LIPT1 loss disrupts metabolism and leads to death in mice. Supplementing mice with propionate, bypassing enzyme blockades, partially extends the lifespan of late-gestation heart-specific LIPT1 knockout mice.