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

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.

Drosophila melanogaster Mitochondrial Carriers: Similarities and Differences with the Human Carriers

“…The first studies on CIC were performed in intact mitochondria, then the protein was purified from several sources, functionally reconstituted into proteoliposomes and kinetically characterized [ 3 , 35 ]. This carrier catalyzes an obligatory electroneutral exchange of a tricarboxylate—such as citrate, isocitrate and cis-aconitate—for another tricarboxylate, a dicarboxylate (i.e., succinate or l -malate) or PEP [ 2 ]. Its transport activity is strongly and specifically inhibited by 1,2,3-benzenetricarboxylic acid (1,2,3-BTA), which is a substrate analog, even if other inhibitors are effective [ 3 , 35 ].…”

“…MCs represent an important link between metabolic reactions occurring inside mitochondria and those taking place outside them. Mitochondrial carriers are essential in many biochemical processes, such as the citric acid cycle, oxidative phosphorylation, the transfer of NADH and NADPH reducing equivalents, gluconeogenesis, and amino acid and fatty acid metabolism, as well as in mitochondrial duplication, transcription and translation processes, calcium-mediated cell signaling pathways and insulin secretion [ 1 , 2 , 3 ].…”

“…The first carrier whose primary structure has been determined is the adenine nucleotide carrier; subsequently, the amino acid sequences of the uncoupling protein, phosphate carrier, α-ketoglutarate/malate carrier tricarboxylic acid carrier, α-ketoglutarate/malate carrier, tricarboxylic acid carrier and carnitine/acylcarnitine carrier have been determined using proteins purified from mitochondria [ 2 , 3 , 6 , 7 , 8 ]. Some carriers (e.g., those carrying adenine nucleotides, phosphate, pyruvate and glutamate) are present in all mitochondria.…”

“…Some carriers (e.g., those carrying adenine nucleotides, phosphate, pyruvate and glutamate) are present in all mitochondria. Others are tissue-specific and have a limited distribution, reflecting their importance in particular metabolic functions, such as urea or fatty acid synthesis [ 2 ]. Few members are instead located in other cell organelles including chloroplasts, peroxisomes and mitosomes [ 9 , 10 ].…”

“…Furthermore, the amino- and carboxy-terminal regions of the polypeptide chain protrude into the intermembrane space, as demonstrated by transmembrane topography studies [ 12 ]. In humans, 53 hypothetical genes have been identified encoding mitochondrial transport proteins to date; they are grouped in a single family called solute carrier family 25 (SLC25) [ 2 ]. The SLC25 family belongs to the largest human solute-carrier (SLC) superfamily, organized into 65 gene families and including over 400 membrane proteins catalyzing the transport of metabolites across biological membranes [ 13 , 14 ].…”