Lack of mitochondrial trifunctional protein in mice causes neonatal hypoglycemia and sudden death
Lack of mitochondrial trifunctional protein in mice causes neonatal hypoglycemia and sudden death
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DOI：
10.1172/jci12590
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发表时间：
2001-06-01
影响因子：
15.9
通讯作者：
Strauss, AW
中科院分区：
文献类型：
--
作者：
Ibdah, JA;Paul, H;Strauss, AW
线粒体三功能蛋白（MTP）是由四个α亚基和四个P亚基组成的杂八聚体，其催化线粒体长链脂肪酸P-氧化的最后三个步骤。人类MTP缺乏会导致Reye样综合征、心肌病或突然意外死亡。我们使用基因靶向产生MTP a亚基无效等位基因，并产生缺乏MTP ex和P亚基的小鼠。与Mtpa（+/-）和Mtpa（+/+）同窝小鼠相比，Mtpa（-/-）胎儿积累长链脂肪酸代谢物并且具有低出生体重，Mtpa（-/-）小鼠在出生后6-36小时遭受新生儿低血糖和猝死。Mtpa（-/-）PUPS中的组织病理学变化的分析揭示了出生后肝脂肪变性的快速发展，并且随后，心肌细胞和血管肌细胞明显坏死和急性变性。该小鼠模型证明了完整的线粒体长链脂肪酸氧化对于胎儿发育和出生后的存活至关重要。MTP缺乏可导致胎儿生长迟缓、新生儿低血糖和猝死。
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 syndrome, cardiomyopathy, or sudden unexpected death. We used gene targeting to generate an MTP a subunit null allele and to produce mice that lack MTP ex and P 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.