Abstract
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.
Highlights
Mitochondrial diseases are caused by mutations in either the mitochondrial or nuclear genome
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 levels of transport activity of the recombinant S-adenosylmethionine carrier (SAMC) variants harboring the three missense mutations associated with SLC25A26 deficiency seem to be related to their position in the SAMC homology model. p.Ala102Val and p.Pro199Leu, which cause almost depleted transport activity compared to the wild-type carrier protein and are found inside the substrate translocation pore (Figure 2, at position 126) and in the third signature motif sequence (SMS), respectively, and p.Val148Gly, which causes a marked decrease in activity (15% of the wild-type protein), is found outside the pore [159]
Summary
Mitochondrial diseases are caused by mutations in either the mitochondrial or nuclear genome. The disease-causing mutations in the mtDNA primarily involve core subunits of the respiratory chain and oxidative phosphorylation complexes as well as gene products involved in mitochondrial translation. These defects give rise to, for example, Leigh syndrome, LHON (Leber hereditary optic neuropathy), MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes syndrome), MERRF (myoclonic epilepsy with ragged fibers), and NARP (neurogenic muscle weakness ataxia and retinitis pigmentosa) [3,4]. Among the mitochondrial diseases caused by mutations in nuclear genes are: Friedreich’s ataxia, dominant optic atrophy, Barth syndrome, Rett syndrome, spastic paraplegia, coenzyme Q10 deficiency, and progressive external ophthalmoplegia [3,4]. Particular emphasis is given to the location and relevance of the mutations within the structure of the transporters and to the pathogenic mechanisms underlying the symptoms characteristic of the diseases
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