The SLC25 Mitochondrial Carrier Family: Structure and Mechanism.
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ABSTRACT:
SUBMITTER: Ruprecht JJ
PROVIDER: S-EPMC7611774 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Members of the mitochondrial carrier family (SLC25) transport a variety of compounds across the inner membrane of mitochondria. These transport steps provide building blocks for the cell and link the pathways of the mitochondrial matrix and cytosol. An increasing number of diseases and pathologies has been associated with their dysfunction. In this review, the molecular basis of these diseases is explained based on our current understanding of their transport mechanism.
| S-EPMC7611780 | biostudies-literature
Project description: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.
| S-EPMC7226361 | biostudies-literature
Project description:Solute carrier family 25 (SLC25) encodes transport proteins at the inner mitochondrial membrane and functions as carriers for metabolites. Although SLC25 genetic variants correlate with human metabolic diseases, their roles in colon cancer remain unknown. Cases of colon cancer were retrieved from The Cancer Genome Atlas, and the transcriptionally differentially expressed members (DEMs) of SLC25 were identified. DNA level alterations, clinicopathological characteristics, and clinical survival were also investigated. A risk score model based on the DEMs was constructed to further evaluate their prognostic values in a clinical setting. The results were preliminarily validated using bioinformatic analysis of datasets from the Gene Expression Omnibus, immunohistochemical evaluations in clinical specimens, and functional experiments in colon cancer-derived cell lines. Thirty-seven DEMs were identified among 53 members of SLC25. Eight of 37 DEMs were introduced into a risk score model using integrated LASSO regression and multivariate Cox regression. Validated by GSE395282 and GSE175356, DEMs with high-risk scores were associated with the phenotypes of increasing tumor immune infiltration and decreasing glycolysis and apoptosis contents. SLC25A5 was downregulated in cancer, and its upregulation was related to better overall survival in patients from public datasets and in clinical cases. High SLC25A5 expression was an independent prognostic factor for 79 patients after surgical treatment. A negative correlation between CD8 and SLC25A5 was determined in specimens from 106 patients with advanced colon cancer. SLC25A5 attenuated cell proliferation, upregulated the expression of programmed cell death-related signatures, and exerted its biological function by inhibiting the MAPK signaling pathway. Our study reveals that mitochondrial SLC25 has prognostic value in patients with colon cancer. The bioinformatic analyses by following verification in situ and in vitro provide direction for further functional and mechanistic studies on the identified member of SLC25.
| S-EPMC8921248 | biostudies-literature
Project description:Members of the SLC25 mitochondrial carrier family link cytosolic and mitochondrial metabolism and support cellular maintenance and growth by transporting compounds across the mitochondrial inner membrane. Their monomeric or dimeric state and kinetic mechanism have been a matter of long-standing debate. It is believed by some that they exist as homodimers and transport substrates with a sequential kinetic mechanism, forming a ternary complex where both exchanged substrates are bound simultaneously. Some studies, in contrast, have provided evidence indicating that the mitochondrial ADP/ATP carrier (SLC25A4) functions as a monomer, has a single substrate binding site, and operates with a ping-pong kinetic mechanism, whereby ADP is imported before ATP is exported. Here we reanalyze the oligomeric state and kinetic properties of the human mitochondrial citrate carrier (SLC25A1), dicarboxylate carrier (SLC25A10), oxoglutarate carrier (SLC25A11), and aspartate/glutamate carrier (SLC25A13), all previously reported to be dimers with a sequential kinetic mechanism. We demonstrate that they are monomers, except for dimeric SLC25A13, and operate with a ping-pong kinetic mechanism in which the substrate import and export steps occur consecutively. These observations are consistent with a common transport mechanism, based on a functional monomer, in which a single central substrate-binding site is alternately accessible.
| S-SCDT-10_1038-S44318-024-00150-0 | biostudies-other
Project description:Many bacterial effector proteins that are delivered to host cells during infection are enzymes targeting host cell signalling. Recently, Legionella pneumophila effector Lpg1137 was experimentally characterised as a serine protease that cleaves human syntaxin 17. We present strong bioinformatic evidence that Lpg1137 is a homologue of mitochondrial carrier proteins and is not related to known serine proteases. We also discuss how this finding can be reconciled with the apparently contradictory experimental results.
| S-EPMC5621508 | biostudies-literature
Project description:Subcellular compartmentation is a fundamental property of eukaryotic cells. Communication and metabolic and regulatory interconnectivity between organelles require that solutes can be transported across their surrounding membranes. Indeed, in mammals, there are hundreds of genes encoding solute carriers (SLCs) which mediate the selective transport of molecules such as nucleotides, amino acids, and sugars across biological membranes. Research over many years has identified the localization and preferred substrates of a large variety of SLCs. Of particular interest has been the SLC25 family, which includes carriers embedded in the inner membrane of mitochondria to secure the supply of these organelles with major metabolic intermediates and coenzymes. The substrate specificity of many of these carriers has been established in the past. However, the route by which animal mitochondria are supplied with NAD+ had long remained obscure. Only just recently, the existence of a human mitochondrial NAD+ carrier was firmly established. With the realization that SLC25A51 (or MCART1) represents the major mitochondrial NAD+ carrier in mammals, a long-standing mystery in NAD+ biology has been resolved. Here, we summarize the functional importance and structural features of this carrier as well as the key observations leading to its discovery.
| S-EPMC8231866 | biostudies-literature
Project description:The transfer of metabolites through the mitochondrial membranes is a vital process that is highly controlled and regulated by the inner membrane. A variety of metabolites, nucleotides, and cofactors are transported across the inner mitochondrial membrane (IMM) by a superfamily of membrane transporters which are known as the mitochondrial carrier family (MCF) or the solute carrier family 25 (SLC25 protein family). In humans, the MCF has 53 members encoded by nuclear genes. Members of the SLC25 family of transporters, which is the largest group of solute carriers, are also known as mitochondrial carriers (MCs). Because MCs are nuclear-coded proteins, they must be imported into the IMM. When compared with normal cells, the mitochondria of cancer cells exhibit significantly increased transmembrane potentials and a number of their transporters are altered. SLC25 members were identified as potential biomarkers for various cancers. The objective of this review is to summarize what is currently known about the involvement of mitochondrial SLC25 carriers in associated diseases. This review suggests that the SLC25 family could be used for the development of novel points of attack for targeted cancer therapy.
| S-EPMC7288124 | biostudies-literature
Project description:The mitochondrion relies on compartmentalization of certain enzymes, ions and metabolites for the sake of efficient metabolism. In order to fulfil its activities, a myriad of carriers are properly expressed, targeted and folded in the inner mitochondrial membrane. Among these carriers, the six-transmembrane-helix mitochondrial SLC25 (solute carrier family 25) proteins facilitate transport of solutes with disparate chemical identities across the inner mitochondrial membrane. Although their proper function replenishes building blocks needed for metabolic reactions, dysfunctional SLC25 proteins are involved in pathological states. It is the purpose of the present review to cover the current knowledge on the role of SLC25 transporters in health and disease.
| S-EPMC3806213 | biostudies-literature
Project description:The transportation of solutes across the inner membrane of the mitochondria is catalyzed by a nuclear-coded family of transport proteins called mitochondrial carriers (MCs). Sequences from dictyostelid genome projects have facilitated analysis of the evolution of the dictyostelid mitochondrial carrier family (MCF). The average evolutionary distances between various regions in the MCF shows that the transmembrane region (TR) and conical pit region (CPR) are the only two conserved structural regions. A phylogenetic tree built using the concatenated orthologous TR and CPR sequences of 7 MCs showed that dictyostelids are similar to metazoans in this way. A close evolutionary relationship was observed between dictyostelids and metazoans in 4 MCs known to be related to ADP/ATP transport (MAA). This was further evidenced by the fact that dictyostelids have undergone gene expansion similar to that of metazoans during the evolution of MAA. Sequence logo analysis of CPR in MAA showed that dictyostelids have motifs similar to those of Metazoa. Combined with the conserved substrate binding site of 7 MCs in eukaryotes, it is postulated that dictyostelids are closely related to Metazoa with respect to the evolution of MAA.
| S-EPMC5007236 | biostudies-literature
Project description:BACKGROUND:Development of anxiety- and depression-like states under chronic social defeat stress in mice has been shown by many experimental studies. In this article, the differentially expressed Slc25* family genes encoding mitochondrial carrier proteins were analyzed in the brain of depressive (defeated) mice versus aggressive mice winning in everyday social confrontations. The collected samples of brain regions were sequenced at JSC Genoanalytica ( http://genoanalytica.ru/ , Moscow, Russia). RESULTS:Changes in the expression of the 20 Slc25* genes in the male mice were brain region- and social experience (positive or negative)-specific. In particular, most Slc25* genes were up-regulated in the hypothalamus of defeated and aggressive mice and in the hippocampus of defeated mice. In the striatum of defeated mice and in the ventral tegmental area of aggressive mice expression of mitochondrial transporter genes changed specifically. Significant correlations between expression of most Slc25* genes and mitochondrial Mrps and Mrpl genes were found in the brain regions. CONCLUSION:Altered expression of the Slc25* genes may serve as a marker of mitochondrial dysfunction in brain, which accompanies the development of many neurological and psychoemotional disorders.
| S-EPMC6288882 | biostudies-literature