Lack of mitochondrial trifunctional protein in mice causes neonatal hypoglycemia and sudden death

Jamal A. Ibdah, Hyacinth Paul, Yiwen Zhao, Scott Binford, Ken Salleng, Mark Cline, Dietrich Matern, Michael J. Bennett, Piero Rinaldo, Arnold W. Strauss

Research output: Contribution to journalArticlepeer-review

121 Scopus citations

Abstract

Mitochondrial trifunctional protein (MTP) is a hetero-octamer of four α and four β subunits that catalyzes the final three steps of mitochondrial long chain fatty acid β-oxidation. Human MTP deficiency causes Reye-like syndrome, cardiomyopathy, or sudden unexpected death. We used gene targeting to generate an MTP α subunit null allele and to produce mice that lack MTP α and β subunits. The Mtpa-/- fetuses accumulate long chain fatty acid metabolites and have low birth weight compared with the Mtpa+/- and Mtpa+/+ littermates. Mtpa-/- mice suffer neonatal hypoglycemia and sudden death 6-36 hours after birth. Analysis of the histopathological changes in the Mtpa-/- pups revealed rapid development of hepatic steatosis after birth and, later, significant necrosis and acute degeneration of the cardiac and diaphragmatic myocytes. This mouse model documents that intact mitochondrial long chain fatty acid oxidation is essential for fetal development and for survival after birth. Deficiency of MTP causes fetal growth retardation, neonatal hypoglycemia, and sudden death.

Original languageEnglish (US)
Pages (from-to)1403-1409
Number of pages7
JournalJournal of Clinical Investigation
Volume107
Issue number11
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Medicine(all)

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