Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans

• Published in: Cell reports (Cambridge) Vol. 27; no. 5; pp. 1376 - 1386.e6
• Main Authors: Ni, Min, Solmonson, Ashley, Pan, Chunxiao, Yang, Chendong, Li, Dan, Notzon, Ashley, Cai, Ling, Guevara, Gerardo, Zacharias, Lauren G., Faubert, Brandon, Vu, Hieu S., Jiang, Lei, Ko, Bookyung, Morales, Noriko Merida, Pei, Jimin, Vale, Gonçalo, Rakheja, Dinesh, Grishin, Nick V., McDonald, Jeffrey G., Gotway, Garrett K., McNutt, Markey C., Pascual, Juan M., DeBerardinis, Ralph J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.04.2019; Elsevier
• Subjects: 2-ketoacid dehydrogenase; epilepsy,developmental delay; fatty acid oxidation; genomics; inborn errors of metabolism; lactic acidosis; lipogenesis; lipoylation; metabolomics; inborn errors of metabolism; metabolomics; lactic acidosis; genomics; lipogenesis; fatty acid oxidation; 2-ketoacid dehydrogenase; lipoylation; epilepsy,developmental delay
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.04.005

Inborn errors of metabolism (IEMs) link metabolic defects to human phenotypes. Modern genomics has accelerated IEM discovery, but assessing the impact of genomic variants is still challenging. Here, we integrate genomics and metabolomics to identify a cause of lactic acidosis and epilepsy. The proband is a compound heterozygote for variants in LIPT1, which encodes the lipoyltransferase required for 2-ketoacid dehydrogenase (2KDH) function. Metabolomics reveals abnormalities in lipids, amino acids, and 2-hydroxyglutarate consistent with loss of multiple 2KDHs. Homozygous knockin of a LIPT1 mutation reduces 2KDH lipoylation in utero and results in embryonic demise. In patient fibroblasts, defective 2KDH lipoylation and function are corrected by wild-type, but not mutant, LIPT1 alleles. Isotope tracing reveals that LIPT1 supports lipogenesis and balances oxidative and reductive glutamine metabolism. Altogether, the data extend the role of LIPT1 in metabolic regulation and demonstrate how integrating genomics and metabolomics can uncover broader aspects of IEM pathophysiology. [Display omitted] •Human LIPT1 mutations impair 2-ketoacid dehydrogenase lipoylation and activity•LIPT1 deficiency increases 2-HG and depletes structural lipids in plasma•LIPT1 deficiency impedes lipogenesis but increases fatty acid oxidation•LIPT1 regulates the balance between oxidative and reductive glutamine metabolism Ni et al. investigate human LIPT1 deficiency, which results in developmental delay, epilepsy, and broad metabolic abnormalities, including lactic acidosis, L- and D-2-hydroxyglutaric aciduria, defective lipogenesis, and an altered balance between oxidative and reductive glutamine metabolism.