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

Min Ni, Ashley Solmonson, Chunxiao Pan, Chendong Yang, Dan Li, Ashley Notzon, Ling Cai, Gerardo Guevara, Lauren G. Zacharias, Brandon Faubert, Hieu S. Vu, Lei Jiang, Bookyung Ko, Noriko Merida Morales, Jimin Pei, Gonçalo Vale, Dinesh Rakheja, Nick V. Grishin, Jeffrey G. McDonald, Garrett K. GotwayMarkey C. McNutt, Juan M. Pascual, Ralph J. DeBerardinis

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


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. 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.

Original languageEnglish (US)
Pages (from-to)1376-1386.e6
JournalCell Reports
Issue number5
StatePublished - Apr 30 2019
Externally publishedYes


  • 2-ketoacid dehydrogenase
  • epilepsy,developmental delay
  • fatty acid oxidation
  • genomics
  • inborn errors of metabolism
  • lactic acidosis
  • lipogenesis
  • lipoylation
  • metabolomics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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