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Review
. 2020 Apr 23;10(4):655.
doi: 10.3390/biom10040655.

Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review

Ferdinando Palmieri  1 , Pasquale Scarcia  1 , Magnus Monné  1   2
Affiliations
Review

Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review

Ferdinando Palmieri et al. Biomolecules. .

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.

Keywords: SLC25.; disease; error of metabolism; membrane transport; mitochondrial carrier; mitochondrial carrier disease; mitochondrial disease; mitochondrial transporter; mutation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Multiple sequence alignment of mitochondrial carriers showing the position of disease-causing point mutations. The protein sequences of the 18 MCs found to have disease-causing point mutations are aligned against the sequences of bovine AAC1 (bAAC1 with numbering) and Thermothelomyces thermophila AAC2 (tAAC2) whose 3D-structures have been determined (Figure 2). Sequences of the transmembrane helices are underlined, the conserved residues of the SMSs are in bold, the charged residues of the cytoplasmic gate are in italics, and the contact points I, II, and III residues on the first, second, and third row of the alignment, respectively, are boxed. The numbers inside the alignment indicate missing residues. One color for each MC indicates the positions of the single point mutations associated with disease, and the top color in each position in the alignment corresponds to the colored positions in Figure 2.
Figure 2
Figure 2
Structural positions of disease-causing point mutations in mitochondrial carriers. The bovine AAC1 structure (in the c-state, gray) and the thermophile AAC2 structure (in the m-state, pink) are viewed from the membrane plane (A,C) and the intermembrane space side (B,D). In all the panels, the α-carbons of the mutated positions are indicated as spheres colored as the top color of the mutations in the same position shown in the alignment of Figure 1. The numbering is that of bovine AAC1 (Figure 1) with the residue side chains exposed to the substrate translocation pore in B and D or outside the pore in A and C.
Figure 3
Figure 3
Metabolic roles of the mitochondrial carriers associated with diseases. When known, the substrate species transported by the carriers are shown. The carriers for carboxylates, amino acids, and nucleotides are colored in green, red, and blue, respectively, whereas the remaining MCs are colored in light lime. Enzymes are abbreviated in green. Other abbreviations are: 2-OA, 2-oxoacid; 2-AA, 2-aminoadipate; 2-OA, 2-oxoadipate; 2-OG, 2-oxoglutarate; 2-OGDH, 2-oxoglutarate dehydrogease; 5-ALA, 5-aminolevulinic acid; Ac, acyl; BCKDH, branched chain ketoacid dehydrogenase; CPi, carbamoylphosphate; D-2HG, D-2-hydroxyglutarate; dPCoA, dephospho-CoA; EF, EF hand Ca2+-binding domains; GDH, glutamate dehydrogenase; HOATH, hydroxy-oxoacid transhydrogenase; ICDH-2, isocitrate dehydrogenase 2; L-2-HG, L-2-hydroxyglutarate; MDH, malate dehydrogenase; PDH, pyruvate dehydrogenase; SAHC, S-adenosylhomocysteine; SAM, S-adenosylmethionine; TCA, tricarboxylic acid; THF, tetrahydrofolate; TMP, thiamine monophosphate; TPP, thiamine pyrophosphate.
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