Uncovering the mechanistic drivers of hepatic dysfunction in LIPT1 deficiency

PROJECT SUMMARY/ABSTRACT Inborn errors of metabolism (IEMs) are genetic diseases that often cause severe illness and death in infancy or early childhood. IEMs represent the largest subset of genetic diseases in children, numbering over 1000, with a combined incidence greater than 1 in 1000. For some IEMs, early identification and intervention permit normal development, but in many cases, an incomplete understanding of IEM pathophysiology limits therapeutic options. Defects in lipoic acid (LA) metabolism represent a recently described category of IEM that causes complex metabolic disease, liver injury, and neurodevelopmental delay. Little is known about the mechanistic drivers of pathology in patients with these defects, and identification of key accumulated or deficient metabolites in vivo holds promise to inform therapeutic intervention. Lipoylation, or the addition of an LA moiety to a target protein, is required for the function of specific metabolic enzymes referred to as 2-ketoacid dehydrogenases. These enzymes are critical contributors to central carbon metabolism and include pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (α-KGDH). Lipoyltransferase-1 (LIPT1) catalyzes the transfer of an LA moiety to the 2-ketoacid dehydrogenases. LIPT1 deficiency in patients results in severe illness with restricted growth and neurodevelopmental delay. In healthy individuals, metabolic flexibility in the liver permits mobilization of energy stores during growth and development to maintain homeostasis. Hospitalizations and deaths in patients with IEMs often occur during periods of homeostatic decompensation. I hypothesize that impaired central carbon metabolism in LIPT1 deficiency restricts hepatic metabolic flexibility, destabilizing maintenance of homeostasis. Preliminary data reveal that knockout of Lipt1 in mouse livers results in acute weight loss and death 6-8 weeks after induction, while mice with developmental loss of Lipt1 in the livers display restricted growth with ~40% lethality by 20 weeks of age. With these novel, complementary models, this proposal will dissect the impact of developmental loss of lipoylation from the role of lipoylation in healthy liver physiology. If successful, it will define the metabolic alterations driven by lipoylation loss and attenuate these alterations with targeted dietary intervention to bypass blockades at both PDH and α-KGDH.