The SLC3 and SLC7 families of amino acid transporters Fotiadis, Dimitrios; Kanai, Yoshikatsu; Palacín, Manuel
Molecular aspects of medicine,
April-June 2013, 2013 Apr-Jun, 2013-4-00, 20130401, Letnik:
34, Številka:
2-3
Journal Article
Recenzirano
Amino acids are necessary for all living cells and organisms. Specialized transporters mediate the transfer of amino acids across plasma membranes. Malfunction of these proteins can affect whole-body ...homoeostasis giving raise to diverse human diseases. Here, we review the main features of the SLC3 and SLC7 families of amino acid transporters. The SLC7 family is divided into two subfamilies, the cationic amino acid transporters (CATs), and the L-type amino acid transporters (LATs). The latter are the light or catalytic subunits of the heteromeric amino acid transporters (HATs), which are associated by a disulfide bridge with the heavy subunits 4F2hc or rBAT. These two subunits are glycoproteins and form the SLC3 family. Most CAT subfamily members were functionally characterized and shown to function as facilitated diffusers mediating the entry and efflux of cationic amino acids. In certain cells, CATs play an important role in the delivery of l-arginine for the synthesis of nitric oxide. HATs are mostly exchangers with a broad spectrum of substrates and are crucial in renal and intestinal re-absorption and cell redox balance. Furthermore, the role of the HAT 4F2hc/LAT1 in tumor growth and the application of LAT1 inhibitors and PET tracers for reduction of tumor progression and imaging of tumors are discussed. Finally, we describe the link between specific mutations in HATs and the primary inherited aminoacidurias, cystinuria and lysinuric protein intolerance.
Institute for Research in Biomedicine (IRB Barcelona), CIBER de Diabetes y Enfermedades Metabólicas Asociadas, and Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de ...Barcelona, Barcelona, Spain
The meaning of the word mitochondrion (from the Greek mitos , meaning thread, and chondros , grain) illustrates that the heterogeneity of mitochondrial morphology has been known since the first descriptions of this organelle. Such a heterogeneous morphology is explained by the dynamic nature of mitochondria. Mitochondrial dynamics is a concept that includes the movement of mitochondria along the cytoskeleton, the regulation of mitochondrial architecture (morphology and distribution), and connectivity mediated by tethering and fusion/fission events. The relevance of these events in mitochondrial and cell physiology has been partially unraveled after the identification of the genes responsible for mitochondrial fusion and fission. Furthermore, during the last decade, it has been identified that mutations in two mitochondrial fusion genes ( MFN2 and OPA1 ) cause prevalent neurodegenerative diseases (Charcot-Marie Tooth type 2A and Kjer disease/autosomal dominant optic atrophy). In addition, other diseases such as type 2 diabetes or vascular proliferative disorders show impaired MFN2 expression. Altogether, these findings have established mitochondrial dynamics as a consolidated area in cellular physiology. Here we review the most significant findings in the field of mitochondrial dynamics in mammalian cells and their implication in human pathologies.
Aging is associated with a decline in mitochondrial function and the accumulation of abnormal mitochondria. However, the precise mechanisms by which aging promotes these mitochondrial alterations and ...the role of the latter in aging are still not fully understood. Mitochondrial dynamics is a key process regulating mitochondrial function and quality. Altered expression of some mitochondrial dynamics proteins has been recently associated with aging and with age-related alterations in yeast, Caenorhabditis elegans , mice, and humans. Here, we review the link between alterations in mitochondrial dynamics, aging, and age-related impairment. We propose that the dysregulation of mitochondrial dynamics leads to age-induced accumulation of unhealthy mitochondria and contributes to alterations linked to aging, such as diabetes and neurodegeneration.
In humans, more than 50 transporters are responsible for the traffic and balance of amino acids within and between cells and tissues, and half of them have been associated with disease 1. Covering ...all common amino acids, Heteromeric Amino acid Transporters (HATs) are one class of such transporters. This review first highlights structural and functional studies that solved the atomic structure of HATs and revealed molecular clues on substrate interaction. Moreover, this review focuses on HATs that have a role in the central nervous system (CNS) and that are related to neurological diseases, including: (i) LAT1/CD98hc and its role in the uptake of branched chain amino acids trough the blood brain barrier and autism. (ii) LAT2/CD98hc and its potential role in the transport of glutamine between plasma and cerebrospinal fluid. (iii) y
+
LAT2/CD98hc that is emerging as a key player in hepatic encephalopathy. xCT/CD98hc as a potential therapeutic target in glioblastoma, and (iv) Asc-1/CD98hc as a potential therapeutic target in pathologies with alterations in NMDA glutamate receptors.
How the complex environment of a membrane protein interplays with its structure and function is illustrated in the review by Jimenez-Munguia on interferon-induced transmembrane protein 3 (IFITM3), an ...antiviral protein that blocks fusion of the viral membrane with the host cell. In their review, they touch upon the possibility of IFITM3 adopting different topologies which overlays with the dependence of its activity on the local lipid composition of the membrane, thus making for an intricate mechanistic question which is yet to be understood in complete molecular detail.
Amino acids are essential building blocks of all mammalian cells. In addition to their role in protein synthesis, amino acids play an important role as energy fuels, precursors for a variety of ...metabolites and as signalling molecules. Disorders associated with the malfunction of amino acid transporters reflect the variety of roles that they fulfil in human physiology. Mutations of brain amino acid transporters affect neuronal excitability. Mutations of renal and intestinal amino acid transporters affect whole-body homoeostasis, resulting in malabsorption and renal problems. Amino acid transporters that are integral parts of metabolic pathways reduce the function of these pathways. Finally, amino acid uptake is essential for cell growth, thereby explaining their role in tumour progression. The present review summarizes the involvement of amino acid transporters in these roles as illustrated by diseases resulting from transporter malfunction.
Mitochondrial dysfunction has been reported in skeletal muscle of obese subjects and of type 2 diabetic patients. Reduced mitochondrial mass and defective activity have been proposed to explain this ...dysfunction. Alterations in mitochondrial function may be crucial to explain the metabolic changes and insulin resistance that characterize both obesity and type 2 diabetes. Consequently, the identification of the primary mechanisms involved is of great relevance.
Mitochondrial dynamics refers to the movement of mitochondria along the cytoskeleton and also to the regulation of mitochondrial morphology and distribution, which depend on fusion and fission events. In recent years, some of the proteins that participate in mitochondrial fusion and fission have been identified in mammalian cells. Recent evidence indicates that proteins participating in these processes are also involved in metabolism. The mitochondrial fusion protein mitofusin 2 stimulates respiration, substrate oxidation and the expression of subunits that participate in respiratory complexes in cultured cells. In this regard, skeletal muscle of obese subjects and of type 2 diabetic patients shows reduced mitofusin 2 expression. Therefore, alterations in the activity of the proteins involved in mitochondrial dynamics, and particularly mitofusin 2, may participate in the reduced mitochondrial function present in skeletal muscle in obesity and in type 2 diabetes.
Mitochondrial dysfunction and accumulation of damaged mitochondria are considered major contributors to aging. However, the molecular mechanisms responsible for these mitochondrial alterations remain ...unknown. Here, we demonstrate that mitofusin 2 (Mfn2) plays a key role in the control of muscle mitochondrial damage. We show that aging is characterized by a progressive reduction in Mfn2 in mouse skeletal muscle and that skeletal muscle Mfn2 ablation in mice generates a gene signature linked to aging. Furthermore, analysis of muscle Mfn2‐deficient mice revealed that aging‐induced Mfn2 decrease underlies the age‐related alterations in metabolic homeostasis and sarcopenia. Mfn2 deficiency reduced autophagy and impaired mitochondrial quality, which contributed to an exacerbated age‐related mitochondrial dysfunction. Interestingly, aging‐induced Mfn2 deficiency triggers a ROS‐dependent adaptive signaling pathway through induction of HIF1α transcription factor and BNIP3. This pathway compensates for the loss of mitochondrial autophagy and minimizes mitochondrial damage. Our findings reveal that Mfn2 repression in muscle during aging is a determinant for the inhibition of mitophagy and accumulation of damaged mitochondria and triggers the induction of a mitochondrial quality control pathway.
Synopsis
Reduced muscle mitochondrial fusion protein Mfn2 is a determinant for age‐induced decay of mitochondrial function and quality, contributing to age‐associated metabolic alterations and sarcopenia.
Aging is characterized by a reduction of Mfn2 protein expression in skeletal muscle.
Reduction in Mfn2 impairs mitochondrial quality control and mitochondrial function in skeletal muscle.
Mfn2‐deficient mice show unhealthy aging characterized by impaired metabolic homeostasis and sarcopenia.
Reduction in Mfn2 triggers a mitochondrial retrograde signalling pathway in order to minimize mitochondrial damage.
Reduced muscle mitochondrial fusion protein Mfn2 is a determinant for age‐induced decay of mitochondrial function and quality, contributing to age‐associated metabolic alterations and sarcopenia.
L-amino acid transporters (LATs) play key roles in human physiology and are implicated in several human pathologies. LATs are asymmetric amino acid exchangers where the low apparent affinity ...cytoplasmic side controls the exchange of substrates with high apparent affinity on the extracellular side. Here, we report the crystal structures of an LAT, the bacterial alanine-serine-cysteine exchanger (BasC), in a non-occluded inward-facing conformation in both apo and substrate-bound states. We crystallized BasC in complex with a nanobody, which blocks the transporter from the intracellular side, thus unveiling the sidedness of the substrate interaction of BasC. Two conserved residues in human LATs, Tyr 236 and Lys 154, are located in equivalent positions to the Na1 and Na2 sites of sodium-dependent APC superfamily transporters. Functional studies and molecular dynamics (MD) calculations reveal that these residues are key for the asymmetric substrate interaction of BasC and in the homologous human transporter Asc-1.
Evidence for a Mitochondrial Regulatory Pathway Defined by Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α, Estrogen-Related
Receptor-α, and Mitofusin 2
Francesc X. Soriano 1 ,
Marc Liesa ...1 ,
Daniel Bach 1 ,
David C. Chan 2 ,
Manuel Palacín 1 and
Antonio Zorzano 1
1 Institute for Research in Biomedicine (IRB), Scientific Park of Barcelona, and Department of Biochemistry and Molecular Biology,
Faculty of Biology, University of Barcelona, Barcelona, Spain
2 Division of Biology, California Institute of Technology, Pasadena, California
Address correspondence and reprint requests to Antonio Zorzano, Institute for Research in Biomedicine, IRB-Parc Científic
de Barcelona,Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
E-mail: azorzano{at}pcb.ub.es
Abstract
Mitofusin 2 (Mfn2) is a mitochondrial membrane protein that participates in mitochondrial fusion and regulates mitochondrial
metabolism in mammalian cells. Here, we show that Mfn2 gene expression is induced in skeletal muscle and brown adipose tissue
by conditions associated with enhanced energy expenditure, such as cold exposure or β 3 -adrenergic agonist treatment. In keeping with the role of peroxisome proliferator–activated receptor-γ coactivator (PGC)-1α
on energy expenditure, we demonstrate a stimulatory effect of PGC-1α on Mfn2 mRNA and protein expression in muscle cells.
PGC-1α also stimulated the activity of the Mfn2 promoter, which required the integrity of estrogen-related receptor-α (ERRα)-binding elements located at −413/−398. ERRα
also activated the transcriptional activity of the Mfn2 promoter, and the effects were synergic with those of PGC-1α. Mfn2 loss of function reduced the stimulatory effect of PGC-1α
on mitochondrial membrane potential. Exposure to cold substantially increased Mfn2 gene expression in skeletal muscle from
heterozygous Mfn2 knock-out mice, which occurred in the presence of higher levels of PGC-1α mRNA compared with control mice.
Our results indicate the existence of a regulatory pathway involving PGC-1α, ERRα, and Mfn2. Alterations in this regulatory
pathway may participate in the pathophysiology of insulin-resistant conditions and type 2 diabetes.
Footnotes
D.B. is currently affiliated with the School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
ERRα, estrogen-related receptor-α; COX-II, cytochrome c oxidase subunit-II; MEF2, myocyte enhancer factor-2; Mfn2, mitofusin
2; PGC, peroxisome proliferator–activated receptor-γ coactivator.
DOI: 10.2337/db05-0509
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted February 21, 2006.
Received April 22, 2005.
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