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

Mitochondrial trifunctional protein (MTP) is a hetero-octamer of four a and four P subunits that catalyzes the final three steps of mitochondrial long chain fatty acid P-oxidation. Human MTP deficiency causes Reye-like syndro me, cardiomyopathy, or sudden unexpected death. We used gene targeting to g enerate an MTP a subunit null allele and to produce mice that lack MTP ex a nd P subunits. The Mtpa(-/-) fetuses accumulate long chain fatty acid metab olites 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 Mtp a(-/-) PUPS revealed rapid development of hepatic steatosis after birth and , later, significant necrosis and acute degeneration of the cardiac and dia phragmatic myocytes. This mouse model documents that intact mitochondrial l ong chain fatty acid oxidation is essential for fetal development and for s urvival after birth. Deficiency of MTP causes fetal growth retardation, neo natal hypoglycemia, and sudden death.