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, Goncalo Dias do Vale, Dinesh Rakheja, Nick V Grishin, Jeffrey G McDonald, Garrett K GotwayMarkey C. McNutt, Juan M Pascual, Ralph J DeBerardinis

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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
Volume27
Issue number5
DOIs
StatePublished - Apr 30 2019

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Functional assessment
Inborn Errors Metabolism
Metabolomics
Genomics
Metabolism
Lipoylation
Lactic Acidosis
Oxidoreductases
Lipogenesis
Glutamine
Epilepsy
Heterozygote
Isotopes
Fibroblasts
Alleles
Phenotype
Lipids
Amino Acids
Mutation
Defects

Keywords

  • 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)

Cite this

Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans. / 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; Dias do Vale, Goncalo; Rakheja, Dinesh; Grishin, Nick V; McDonald, Jeffrey G; Gotway, Garrett K; McNutt, Markey C.; Pascual, Juan M; DeBerardinis, Ralph J.

In: Cell Reports, Vol. 27, No. 5, 30.04.2019, p. 1376-1386.e6.

Research output: Contribution to journalArticle

Ni, M, Solmonson, A, Pan, C, Yang, C, Li, D, Notzon, A, Cai, L, Guevara, G, Zacharias, LG, Faubert, B, Vu, HS, Jiang, L, Ko, B, Morales, NM, Pei, J, Dias do Vale, G, Rakheja, D, Grishin, NV, McDonald, JG, Gotway, GK, McNutt, MC, Pascual, JM & DeBerardinis, RJ 2019, 'Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans', Cell Reports, vol. 27, no. 5, pp. 1376-1386.e6. https://doi.org/10.1016/j.celrep.2019.04.005
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 ; Dias do Vale, Goncalo ; Rakheja, Dinesh ; Grishin, Nick V ; McDonald, Jeffrey G ; Gotway, Garrett K ; McNutt, Markey C. ; Pascual, Juan M ; DeBerardinis, Ralph J. / Functional Assessment of Lipoyltransferase-1 Deficiency in Cells, Mice, and Humans. In: Cell Reports. 2019 ; Vol. 27, No. 5. pp. 1376-1386.e6.
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AU - Solmonson, Ashley

AU - Pan, Chunxiao

AU - Yang, Chendong

AU - Li, Dan

AU - Notzon, Ashley

AU - Cai, Ling

AU - Guevara, Gerardo

AU - Zacharias, Lauren G.

AU - Faubert, Brandon

AU - Vu, Hieu S.

AU - Jiang, Lei

AU - Ko, Bookyung

AU - Morales, Noriko Merida

AU - Pei, Jimin

AU - Dias do Vale, Goncalo

AU - Rakheja, Dinesh

AU - Grishin, Nick V

AU - McDonald, Jeffrey G

AU - Gotway, Garrett K

AU - McNutt, Markey C.

AU - Pascual, Juan M

AU - DeBerardinis, Ralph J

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N2 - 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.

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