Mitochondrial transporters of the SLC25 family and associated diseases: a review
Mitochondrial transporters of the SLC25 family and associated diseases: a review
复制标题
DOI：
10.1007/s10545-014-9708-5
复制
发表时间：
2014-07-01
影响因子：
4.2
通讯作者：
Palmieri, Ferdinando
中科院分区：
文献类型：
--
作者：
Palmieri, Ferdinando
迄今为止，14种与SLC 25家族线粒体转运蛋白相关的遗传性疾病（包括表型）已在生物化学和遗传学上得到了很好的表征。它们是由编码线粒体载体的SLC 25核基因突变引起的罕见代谢紊乱，线粒体载体是人类中53种蛋白质的超家族，可将各种溶质穿梭于线粒体膜。线粒体载体在它们运输的底物的性质和大小、运输模式和驱动力方面变化很大。然而，它们在分子水平上的底物转运机制被认为基本相同。本文就SLC 25线粒体载体的主要结构和功能特性以及已知的与载体相关的疾病作一综述。这些疾病中的两种，ADP/ATP载体缺乏症和磷酸盐载体缺乏症，是由两种线粒体载体的缺陷引起的，这两种线粒体载体为线粒体提供ADP和磷酸盐，氧化磷酸化的底物;因此，这些疾病的特征在于线粒体的能量产生缺陷。参与其他细胞功能的SLC 25载体基因的突变导致肉毒碱/酰基肉毒碱载体缺乏、HHH综合征、天冬氨酸/谷氨酸同种型1和2缺乏、先天性阿米什小头畸形、伴有双侧纹状体坏死的神经病、先天性铁粒幼细胞性贫血、新生儿癫痫性脑病和柠檬酸盐载体缺乏;这些疾病的特征在于依赖于缺陷载体在中间代谢中的作用的特定代谢功能障碍。
To date, 14 inherited diseases (including phenotypes) associated to mitochondrial transporters of the SLC25 family have been well characterized biochemically and genetically. They are rare metabolic disorders caused by mutations in the SLC25 nuclear genes that encode mitochondrial carriers, a superfamily of 53 proteins in humans that shuttle a variety of solutes across the mitochondrial membrane. Mitochondrial carriers vary considerably in the nature and size of the substrates they transport, the modes of transport and driving forces. However, their substrate translocation mechanism at the molecular level is thought to be basically the same. Herein, the main structural and functional properties of the SLC25 mitochondrial carriers and the known carrier-related diseases are presented. Two of these disorders, ADP/ATP carrier deficiency and phosphate carrier deficiency, are caused by defects of the two mitochondrial carriers that provide mitochondria with ADP and phosphate, the substrates of oxidative phosphorylation; these disorders therefore are characterized by defective energy production by mitochondria. The mutations of SLC25 carrier genes involved in other cellular functions cause carnitine/acylcarnitine carrier deficiency, HHH syndrome, aspartate/glutamate isoform 1 and 2 deficiencies, congenital Amish microcephaly, neuropathy with bilateral striatal necrosis, congenital sideroblastic anemia, neonatal epileptic encephalopathy, and citrate carrier deficiency; these disorders are characterized by specific metabolic dysfunctions depending on the role of the defective carrier in intermediary metabolism.