Department of Biosciences, Biotechnologies and Biopharmaceutics, Laboratory of Biochemistry and Molecular Biology, University of Bari Aldo Moro, via E. Orabona 4, 70125 Bari, Italy.
Department of Sciences, University of Basilicata, via Ateneo Lucano 10, 85100 Potenza, Italy.
Biomolecules. 2020 Apr 23;10(4):655. doi: 10.3390/biom10040655.
In the 1980s, after the mitochondrial DNA (mtDNA) had been sequenced, several diseases resulting from mtDNA mutations emerged. Later, numerous disorders caused by mutations in the nuclear genes encoding mitochondrial proteins were found. A group of these diseases are due to defects of mitochondrial carriers, a family of proteins named solute carrier family 25 (SLC25), that transport a variety of solutes such as the reagents of ATP synthase (ATP, ADP, and phosphate), tricarboxylic acid cycle intermediates, cofactors, amino acids, and carnitine esters of fatty acids. The disease-causing mutations disclosed in mitochondrial carriers range from point mutations, which are often localized in the substrate translocation pore of the carrier, to large deletions and insertions. The biochemical consequences of deficient transport are the compartmentalized accumulation of the substrates and dysfunctional mitochondrial and cellular metabolism, which frequently develop into various forms of myopathy, encephalopathy, or neuropathy. Examples of diseases, due to mitochondrial carrier mutations are: combined D-2- and L-2-hydroxyglutaric aciduria, carnitine-acylcarnitine carrier deficiency, hyperornithinemia-hyperammonemia-homocitrillinuria (HHH) syndrome, early infantile epileptic encephalopathy type 3, Amish microcephaly, aspartate/glutamate isoform 1 deficiency, congenital sideroblastic anemia, Fontaine progeroid syndrome, and citrullinemia type II. Here, we review all the mitochondrial carrier-related diseases known until now, focusing on the connections between the molecular basis, altered metabolism, and phenotypes of these inherited disorders.
20 世纪 80 年代，在线粒体 DNA（mtDNA）测序之后，出现了几种由 mtDNA 突变引起的疾病。后来，发现了许多由编码线粒体蛋白的核基因突变引起的疾病。这些疾病中有一类是由于线粒体载体蛋白缺陷引起的，线粒体载体蛋白属于溶质载体家族 25（SLC25），可转运多种溶质，如 ATP 合酶的试剂（ATP、ADP 和磷酸盐）、三羧酸循环中间产物、辅酶、氨基酸和脂肪酸的肉碱酯。在线粒体载体中发现的致病突变范围从点突变（通常定位于载体的底物转运孔内）到大片段缺失和插入。转运缺陷的生化后果是底物的区室化积累和功能失调的线粒体和细胞代谢，这经常发展为各种形式的肌病、脑病或神经病。由于线粒体载体突变引起的疾病的例子包括：D-2-和 L-2-羟基戊二酸尿症、肉碱酰基辅酶 A 载体缺乏症、高鸟氨酸血症-高氨血症-同型瓜氨酸尿症（HHH）综合征、早发性婴儿癫痫性脑病 3 型、阿米什小颅畸形、天冬氨酸/谷氨酸同工酶 1 缺乏症、先天性铁粒幼细胞性贫血、Fontaine 进行性老化综合征和瓜氨酸血症 II 型。在这里，我们回顾了迄今为止已知的所有与线粒体载体相关的疾病，重点关注这些遗传性疾病的分子基础、代谢改变和表型之间的联系。
