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Mitochondrial Transport Proteins
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Mitochondrial Transport Proteins

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 130731

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Prof. Dr. Ferdinando Palmieri

E-Mail Website
Guest Editor
Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70125 Bari, Italy
Interests: functional proteomics; membrane proteins; membrane transport; mitochondrial carrier biogenesis; mitochondrial carrier diseases; mitochondrial carrier identification; mitochondrial carrier transcriptional regulation; mitochondrial transport proteins; structure/function relationship; transport mechanism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear  Colleagues,

A Special Issue on “Mitochondrial transport proteins” is beeing prepared for the journal Biomolecules.

Mitochondrial transporters are  membrane-inserted proteins that provide a link between metabolic reactions occurring in the mitochondrial matrix and outside the organelles by catalyzing the translocation of numerous solutes across the mitochondrial membrane. They include the mitochondrial carrier family members, the proteins involved in pyruvate transport, ABC transporters and channels, and are, therefore, essential for many biological processes and for cell homeostasis. Identification and functional studies of a large number of mitochondrial transporters have been performed over the years using both in vitro and in vivo systems. The few solved structures of these transporters have recently paved the way for further investigations. Furthermore, alterations in their function are responsible for several diseases. Original manuscripts and reviews dealing with any aspect of mitochondrial transport and related pathophysiology are very welcome.

Dr. Ferdinando Palmieri
Guest Editor

Manuscript Submission Information

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Keywords

  • mitochondrial transport proteins (MTPs)
  • mitochondrial carriers
  • MTP import
  • MTP diseases
  • MTPs in pathophysiology
  • MTF structure
  • MTF functional properties
  • MTF structure/function relationships
  • MTF tissue distribution
  • MTF metabolic roles
  • regulation of MTP transcription

Published Papers (23 papers)

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Research

Jump to: Review

22 pages, 49097 KiB  
Article
Mitochondrial Carriers Regulating Insulin Secretion Profiled in Human Islets upon Metabolic Stress
by Cecilia Jimenez-Sánchez, Thierry Brun and Pierre Maechler
Biomolecules 2020, 10(11), 1543; https://doi.org/10.3390/biom10111543 - 12 Nov 2020
Cited by 9 | Viewed by 2699
Abstract
Chronic exposure of β-cells to nutrient-rich metabolic stress impairs mitochondrial metabolism and its coupling to insulin secretion. We exposed isolated human islets to different metabolic stresses for 3 days: 0.4 mM oleate or 0.4 mM palmitate at physiological 5.5 mM glucose (lipotoxicity), high [...] Read more.
Chronic exposure of β-cells to nutrient-rich metabolic stress impairs mitochondrial metabolism and its coupling to insulin secretion. We exposed isolated human islets to different metabolic stresses for 3 days: 0.4 mM oleate or 0.4 mM palmitate at physiological 5.5 mM glucose (lipotoxicity), high 25 mM glucose (glucotoxicity), and high 25 mM glucose combined with 0.4 mM oleate and/or palmitate (glucolipotoxicity). Then, we profiled the mitochondrial carriers and associated genes with RNA-Seq. Diabetogenic conditions, and in particular glucotoxicity, increased expression of several mitochondrial solute carriers in human islets, such as the malate carrier DIC, the α-ketoglutarate-malate exchanger OGC, and the glutamate carrier GC1. Glucotoxicity also induced a general upregulation of the electron transport chain machinery, while palmitate largely counteracted this effect. Expression of different components of the TOM/TIM mitochondrial protein import system was increased by glucotoxicity, whereas glucolipotoxicity strongly upregulated its receptor subunit TOM70. Expression of the mitochondrial calcium uniporter MCU was essentially preserved by metabolic stresses. However, glucotoxicity altered expression of regulatory elements of calcium influx as well as the Na+/Ca2+ exchanger NCLX, which mediates calcium efflux. Overall, the expression profile of mitochondrial carriers and associated genes was modified by the different metabolic stresses exhibiting nutrient-specific signatures. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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23 pages, 7790 KiB  
Article
Glucose-Induced Expression of DAPIT in Pancreatic β-Cells
by Alberto Leguina-Ruzzi, Anežka Vodičková, Blanka Holendová, Vojtěch Pavluch, Jan Tauber, Hana Engstová, Andrea Dlasková and Petr Ježek
Biomolecules 2020, 10(7), 1026; https://doi.org/10.3390/biom10071026 - 10 Jul 2020
Cited by 5 | Viewed by 2743
Abstract
Transcript levels for selected ATP synthase membrane FO-subunits—including DAPIT—in INS-1E cells were found to be sensitive to lowering glucose down from 11 mM, in which these cells are routinely cultured. Depending on conditions, the diminished mRNA levels recovered when glucose was [...] Read more.
Transcript levels for selected ATP synthase membrane FO-subunits—including DAPIT—in INS-1E cells were found to be sensitive to lowering glucose down from 11 mM, in which these cells are routinely cultured. Depending on conditions, the diminished mRNA levels recovered when glucose was restored to 11 mM; or were elevated during further 120 min incubations with 20-mM glucose. Asking whether DAPIT expression may be elevated by hyperglycemia in vivo, we studied mice with hyaluronic acid implants delivering glucose for up to 14 days. Such continuous two-week glucose stimulations in mice increased DAPIT mRNA by >5-fold in isolated pancreatic islets (ATP synthase F1α mRNA by 1.5-fold). In INS-1E cells, the glucose-induced ATP increment vanished with DAPIT silencing (6% of ATP rise), likewise a portion of the mtDNA-copy number increment. With 20 and 11-mM glucose the phosphorylating/non-phosphorylating respiration rate ratio diminished to ~70% and 96%, respectively, upon DAPIT silencing, whereas net GSIS rates accounted for 80% and 90% in USMG5/DAPIT-deficient cells. Consequently, the sufficient DAPIT expression and complete ATP synthase assembly is required for maximum ATP synthesis and mitochondrial biogenesis, but not for insulin secretion as such. Elevated DAPIT expression at high glucose further increases the ATP synthesis efficiency. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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13 pages, 1670 KiB  
Article
Transport of Ca2+ and Ca2+-Dependent Permeability Transition in the Liver and Heart Mitochondria of Rats with Different Tolerance to Acute Hypoxia
by Konstantin N. Belosludtsev, Mikhail V. Dubinin, Eugeny Yu. Talanov, Vlada S. Starinets, Kirill S. Tenkov, Nadezhda M. Zakharova and Natalia V. Belosludtseva
Biomolecules 2020, 10(1), 114; https://doi.org/10.3390/biom10010114 - 09 Jan 2020
Cited by 16 | Viewed by 3341
Abstract
The work examines the kinetic parameters of Ca2+ uptake via the mitochondrial calcium uniporter complex (MCUC) and the opening of the Ca2+-dependent permeability transition pore (MPT pore) in the liver and heart mitochondria of rats with high resistance (HR) and [...] Read more.
The work examines the kinetic parameters of Ca2+ uptake via the mitochondrial calcium uniporter complex (MCUC) and the opening of the Ca2+-dependent permeability transition pore (MPT pore) in the liver and heart mitochondria of rats with high resistance (HR) and low resistance (LR) to acute hypoxia. We found that the rate of Ca2+ uptake by mitochondria of the liver and heart in HR rats is higher than that in LR rats, which is associated with a higher level of the channel-forming subunit MCU in liver mitochondria of HR rats and a lower content of the dominant-negative channel subunit MCUb in heart mitochondria of HR rats. It was shown that the liver mitochondria of HR rats are more resistant to the induction of the MPT pore than those of LR rats (the calcium retention capacity of liver mitochondria of HR rats was found to be 1.3 times greater than that of LR rats). These data correlate with the fact that the level of F0F1-ATP synthase, a possible structural element of the MPT pore, in the liver mitochondria of HR rats is lower than in LR rats. In heart mitochondria of rats of the two phenotypes, no statistically significant difference in the formation of the MPT pore was revealed. The paper discusses how changes in the expression of the MCUC subunits and the putative components of the MPT pore can affect Ca2+ homeostasis of mitochondria in animals with originally different tolerance to hypoxia and in hypoxia-induced tissue injury. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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Review

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17 pages, 1058 KiB  
Review
Routes for Potassium Ions across Mitochondrial Membranes: A Biophysical Point of View with Special Focus on the ATP-Sensitive K+ Channel
by Yevheniia Kravenska, Vanessa Checchetto and Ildiko Szabo
Biomolecules 2021, 11(8), 1172; https://doi.org/10.3390/biom11081172 - 08 Aug 2021
Cited by 11 | Viewed by 3200
Abstract
Potassium ions can cross both the outer and inner mitochondrial membranes by means of multiple routes. A few potassium-permeable ion channels exist in the outer membrane, while in the inner membrane, a multitude of different potassium-selective and potassium-permeable channels mediate K+ uptake [...] Read more.
Potassium ions can cross both the outer and inner mitochondrial membranes by means of multiple routes. A few potassium-permeable ion channels exist in the outer membrane, while in the inner membrane, a multitude of different potassium-selective and potassium-permeable channels mediate K+ uptake into energized mitochondria. In contrast, potassium is exported from the matrix thanks to an H+/K+ exchanger whose molecular identity is still debated. Among the K+ channels of the inner mitochondrial membrane, the most widely studied is the ATP-dependent potassium channel, whose pharmacological activation protects cells against ischemic damage and neuronal injury. In this review, we briefly summarize and compare the different hypotheses regarding the molecular identity of this patho-physiologically relevant channel, taking into account the electrophysiological characteristics of the proposed components. In addition, we discuss the characteristics of the other channels sharing localization to both the plasma membrane and mitochondria. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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15 pages, 21732 KiB  
Review
Welcome to the Family: Identification of the NAD+ Transporter of Animal Mitochondria as Member of the Solute Carrier Family SLC25
by Mathias Ziegler, Magnus Monné, Andrey Nikiforov, Gennaro Agrimi, Ines Heiland and Ferdinando Palmieri
Biomolecules 2021, 11(6), 880; https://doi.org/10.3390/biom11060880 - 14 Jun 2021
Cited by 18 | Viewed by 5141
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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23 pages, 2265 KiB  
Review
From the Identification to the Dissection of the Physiological Role of the Mitochondrial Calcium Uniporter: An Ongoing Story
by Giorgia Pallafacchina, Sofia Zanin and Rosario Rizzuto
Biomolecules 2021, 11(6), 786; https://doi.org/10.3390/biom11060786 - 23 May 2021
Cited by 18 | Viewed by 4123
Abstract
The notion of mitochondria being involved in the decoding and shaping of intracellular Ca2+ signals has been circulating since the end of the 19th century. Despite that, the molecular identity of the channel that mediates Ca2+ ion transport into mitochondria remained [...] Read more.
The notion of mitochondria being involved in the decoding and shaping of intracellular Ca2+ signals has been circulating since the end of the 19th century. Despite that, the molecular identity of the channel that mediates Ca2+ ion transport into mitochondria remained elusive for several years. Only in the last decade, the genes and pathways responsible for the mitochondrial uptake of Ca2+ began to be cloned and characterized. The gene coding for the pore-forming unit of the mitochondrial channel was discovered exactly 10 years ago, and its product was called mitochondrial Ca2+ uniporter or MCU. Before that, only one of its regulators, the mitochondria Ca2+ uptake regulator 1, MICU1, has been described in 2010. However, in the following years, the scientific interest in mitochondrial Ca2+ signaling regulation and physiological role has increased. This shortly led to the identification of many of its components, to the description of their 3D structure, and the characterization of the uniporter contribution to tissue physiology and pathology. In this review, we will summarize the most relevant achievements in the history of mitochondrial Ca2+ studies, presenting a chronological overview of the most relevant and landmarking discoveries. Finally, we will explore the impact of mitochondrial Ca2+ signaling in the context of muscle physiology, highlighting the recent advances in understanding the role of the MCU complex in the control of muscle trophism and metabolism. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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20 pages, 3429 KiB  
Review
The Mitochondrial Carnitine Acyl-carnitine Carrier (SLC25A20): Molecular Mechanisms of Transport, Role in Redox Sensing and Interaction with Drugs
by Annamaria Tonazzi, Nicola Giangregorio, Lara Console, Ferdinando Palmieri and Cesare Indiveri
Biomolecules 2021, 11(4), 521; https://doi.org/10.3390/biom11040521 - 31 Mar 2021
Cited by 26 | Viewed by 6176
Abstract
The SLC25A20 transporter, also known as carnitine acyl-carnitine carrier (CAC), catalyzes the transport of short, medium and long carbon chain acyl-carnitines across the mitochondrial inner membrane in exchange for carnitine. The 30-year story of the protein responsible for this function started with its [...] Read more.
The SLC25A20 transporter, also known as carnitine acyl-carnitine carrier (CAC), catalyzes the transport of short, medium and long carbon chain acyl-carnitines across the mitochondrial inner membrane in exchange for carnitine. The 30-year story of the protein responsible for this function started with its purification from rat liver mitochondria. Even though its 3D structure is not yet available, CAC is one of the most deeply characterized transport proteins of the inner mitochondrial membrane. Other than functional, kinetic and mechanistic data, post-translational modifications regulating the transport activity of CAC have been revealed. CAC interactions with drugs or xenobiotics relevant to human health and toxicology and the response of the carrier function to dietary compounds have been discovered. Exploiting combined approaches of site-directed mutagenesis with chemical targeting and bioinformatics, a large set of data on structure/function relationships have been obtained, giving novel information on the molecular mechanism of the transport catalyzed by this protein. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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17 pages, 4629 KiB  
Review
The Mitochondrial Citrate Carrier SLC25A1/CIC and the Fundamental Role of Citrate in Cancer, Inflammation and Beyond
by Rami Mosaoa, Anna Kasprzyk-Pawelec, Harvey R. Fernandez and Maria Laura Avantaggiati
Biomolecules 2021, 11(2), 141; https://doi.org/10.3390/biom11020141 - 22 Jan 2021
Cited by 32 | Viewed by 8743
Abstract
The mitochondrial citrate/isocitrate carrier, CIC, has been shown to play an important role in a growing list of human diseases. CIC belongs to a large family of nuclear-encoded mitochondrial transporters that serve the fundamental function of allowing the transit of ions and metabolites [...] Read more.
The mitochondrial citrate/isocitrate carrier, CIC, has been shown to play an important role in a growing list of human diseases. CIC belongs to a large family of nuclear-encoded mitochondrial transporters that serve the fundamental function of allowing the transit of ions and metabolites through the impermeable mitochondrial membrane. Citrate is central to mitochondrial metabolism and respiration and plays fundamental activities in the cytosol, serving as a metabolic substrate, an allosteric enzymatic regulator and, as the source of Acetyl-Coenzyme A, also as an epigenetic modifier. In this review, we highlight the complexity of the mechanisms of action of this transporter, describing its involvement in human diseases and the therapeutic opportunities for targeting its activity in several pathological conditions. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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12 pages, 809 KiB  
Review
Renaissance of VDAC: New Insights on a Protein Family at the Interface between Mitochondria and Cytosol
by Vito De Pinto
Biomolecules 2021, 11(1), 107; https://doi.org/10.3390/biom11010107 - 15 Jan 2021
Cited by 33 | Viewed by 3570
Abstract
It has become impossible to review all the existing literature on Voltage-Dependent Anion selective Channel (VDAC) in a single article. A real Renaissance of studies brings this protein to the center of decisive knowledge both for cell physiology and therapeutic application. This review, [...] Read more.
It has become impossible to review all the existing literature on Voltage-Dependent Anion selective Channel (VDAC) in a single article. A real Renaissance of studies brings this protein to the center of decisive knowledge both for cell physiology and therapeutic application. This review, after highlighting the similarities between the cellular context and the study methods of the solute carriers present in the inner membrane and VDAC in the outer membrane of the mitochondria, will focus on the isoforms of VDAC and their biochemical characteristics. In particular, the possible reasons for their evolutionary onset will be discussed. The variations in their post-translational modifications and the differences between the regulatory regions of their genes, probably the key to understanding the current presence of these genes, will be described. Finally, the situation in the higher eukaryotes will be compared to that of yeast, a unicellular eukaryote, where there is only one active isoform and the role of VDAC in energy metabolism is better understood. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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19 pages, 3119 KiB  
Review
Sequence Features of Mitochondrial Transporter Protein Families
by Gergely Gyimesi and Matthias A. Hediger
Biomolecules 2020, 10(12), 1611; https://doi.org/10.3390/biom10121611 - 28 Nov 2020
Cited by 20 | Viewed by 5484
Abstract
Mitochondrial carriers facilitate the transfer of small molecules across the inner mitochondrial membrane (IMM) to support mitochondrial function and core cellular processes. In addition to the classical SLC25 (solute carrier family 25) mitochondrial carriers, the past decade has led to the discovery of [...] Read more.
Mitochondrial carriers facilitate the transfer of small molecules across the inner mitochondrial membrane (IMM) to support mitochondrial function and core cellular processes. In addition to the classical SLC25 (solute carrier family 25) mitochondrial carriers, the past decade has led to the discovery of additional protein families with numerous members that exhibit IMM localization and transporter-like properties. These include mitochondrial pyruvate carriers, sideroflexins, and mitochondrial cation/H+ exchangers. These transport proteins were linked to vital physiological functions and disease. Their structures and transport mechanisms are, however, still largely unknown and understudied. Protein sequence analysis per se can often pinpoint hotspots that are of functional or structural importance. In this review, we summarize current knowledge about the sequence features of mitochondrial transporters with a special focus on the newly included SLC54, SLC55 and SLC56 families of the SLC solute carrier superfamily. Taking a step further, we combine sequence conservation analysis with transmembrane segment and secondary structure prediction methods to extract residue positions and sequence motifs that likely play a role in substrate binding, binding site gating or structural stability. We hope that our review will help guide future experimental efforts by the scientific community to unravel the transport mechanisms and structures of these novel mitochondrial carriers. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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40 pages, 2958 KiB  
Review
VDAC1 at the Intersection of Cell Metabolism, Apoptosis, and Diseases
by Varda Shoshan-Barmatz, Anna Shteinfer-Kuzmine and Ankit Verma
Biomolecules 2020, 10(11), 1485; https://doi.org/10.3390/biom10111485 - 26 Oct 2020
Cited by 94 | Viewed by 8953
Abstract
The voltage-dependent anion channel 1 (VDAC1) protein, is an important regulator of mitochondrial function, and serves as a mitochondrial gatekeeper, with responsibility for cellular fate. In addition to control over energy sources and metabolism, the protein also regulates epigenomic elements and apoptosis via [...] Read more.
The voltage-dependent anion channel 1 (VDAC1) protein, is an important regulator of mitochondrial function, and serves as a mitochondrial gatekeeper, with responsibility for cellular fate. In addition to control over energy sources and metabolism, the protein also regulates epigenomic elements and apoptosis via mediating the release of apoptotic proteins from the mitochondria. Apoptotic and pathological conditions, as well as certain viruses, induce cell death by inducing VDAC1 overexpression leading to oligomerization, and the formation of a large channel within the VDAC1 homo-oligomer. This then permits the release of pro-apoptotic proteins from the mitochondria and subsequent apoptosis. Mitochondrial DNA can also be released through this channel, which triggers type-Ι interferon responses. VDAC1 also participates in endoplasmic reticulum (ER)-mitochondria cross-talk, and in the regulation of autophagy, and inflammation. Its location in the outer mitochondrial membrane, makes VDAC1 ideally placed to interact with over 100 proteins, and to orchestrate the interaction of mitochondrial and cellular activities through a number of signaling pathways. Here, we provide insights into the multiple functions of VDAC1 and describe its involvement in several diseases, which demonstrate the potential of this protein as a druggable target in a wide variety of pathologies, including cancer. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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20 pages, 1979 KiB  
Review
Characterization of In Vivo Function(s) of Members of the Plant Mitochondrial Carrier Family
by Adriano Nunes-Nesi, João Henrique F. Cavalcanti and Alisdair R. Fernie
Biomolecules 2020, 10(9), 1226; https://doi.org/10.3390/biom10091226 - 24 Aug 2020
Cited by 11 | Viewed by 3189
Abstract
Although structurally related, mitochondrial carrier family (MCF) proteins catalyze the specific transport of a range of diverse substrates including nucleotides, amino acids, dicarboxylates, tricarboxylates, cofactors, vitamins, phosphate and H+. Despite their name, they do not, however, always localize to the mitochondria, [...] Read more.
Although structurally related, mitochondrial carrier family (MCF) proteins catalyze the specific transport of a range of diverse substrates including nucleotides, amino acids, dicarboxylates, tricarboxylates, cofactors, vitamins, phosphate and H+. Despite their name, they do not, however, always localize to the mitochondria, with plasma membrane, peroxisomal, chloroplast and thylakoid and endoplasmic reticulum localizations also being reported. The existence of plastid-specific MCF proteins is suggestive that the evolution of these proteins occurred after the separation of the green lineage. That said, plant-specific MCF proteins are not all plastid-localized, with members also situated at the endoplasmic reticulum and plasma membrane. While by no means yet comprehensive, the in vivo function of a wide range of these transporters is carried out here, and we discuss the employment of genetic variants of the MCF as a means to provide insight into their in vivo function complementary to that obtained from studies following their reconstitution into liposomes. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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19 pages, 2458 KiB  
Review
Mitochondrial Potassium Channels as Druggable Targets
by Antoni Wrzosek, Bartłomiej Augustynek, Monika Żochowska and Adam Szewczyk
Biomolecules 2020, 10(8), 1200; https://doi.org/10.3390/biom10081200 - 18 Aug 2020
Cited by 45 | Viewed by 5606
Abstract
Mitochondrial potassium channels have been described as important factors in cell pro-life and death phenomena. The activation of mitochondrial potassium channels, such as ATP-regulated or calcium-activated large conductance potassium channels, may have cytoprotective effects in cardiac or neuronal tissue. It has also been [...] Read more.
Mitochondrial potassium channels have been described as important factors in cell pro-life and death phenomena. The activation of mitochondrial potassium channels, such as ATP-regulated or calcium-activated large conductance potassium channels, may have cytoprotective effects in cardiac or neuronal tissue. It has also been shown that inhibition of the mitochondrial Kv1.3 channel may lead to cancer cell death. Hence, in this paper, we examine the concept of the druggability of mitochondrial potassium channels. To what extent are mitochondrial potassium channels an important, novel, and promising drug target in various organs and tissues? The druggability of mitochondrial potassium channels will be discussed within the context of channel molecular identity, the specificity of potassium channel openers and inhibitors, and the unique regulatory properties of mitochondrial potassium channels. Future prospects of the druggability concept of mitochondrial potassium channels will be evaluated in this paper. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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13 pages, 726 KiB  
Review
Proteomic and Bioinformatic Profiling of Transporters in Higher Plant Mitochondria
by Ian Max Møller, R. Shyama Prasad Rao, Yuexu Jiang, Jay J. Thelen and Dong Xu
Biomolecules 2020, 10(8), 1190; https://doi.org/10.3390/biom10081190 - 16 Aug 2020
Cited by 9 | Viewed by 2888
Abstract
To function as a metabolic hub, plant mitochondria have to exchange a wide variety of metabolic intermediates as well as inorganic ions with the cytosol. As identified by proteomic profiling or as predicted by MU-LOC, a newly developed bioinformatics tool, Arabidopsis thaliana mitochondria [...] Read more.
To function as a metabolic hub, plant mitochondria have to exchange a wide variety of metabolic intermediates as well as inorganic ions with the cytosol. As identified by proteomic profiling or as predicted by MU-LOC, a newly developed bioinformatics tool, Arabidopsis thaliana mitochondria contain 128 or 143 different transporters, respectively. The largest group is the mitochondrial carrier family, which consists of symporters and antiporters catalyzing secondary active transport of organic acids, amino acids, and nucleotides across the inner mitochondrial membrane. An impressive 97% (58 out of 60) of all the known mitochondrial carrier family members in Arabidopsis have been experimentally identified in isolated mitochondria. In addition to many other secondary transporters, Arabidopsis mitochondria contain the ATP synthase transporters, the mitochondria protein translocase complexes (responsible for protein uptake across the outer and inner membrane), ATP-binding cassette (ABC) transporters, and a number of transporters and channels responsible for allowing water and inorganic ions to move across the inner membrane driven by their transmembrane electrochemical gradient. A few mitochondrial transporters are tissue-specific, development-specific, or stress-response specific, but this is a relatively unexplored area in proteomics that merits much more attention. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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16 pages, 5690 KiB  
Review
Peroxisomal Cofactor Transport
by Anastasija Plett, Lennart Charton and Nicole Linka
Biomolecules 2020, 10(8), 1174; https://doi.org/10.3390/biom10081174 - 12 Aug 2020
Cited by 14 | Viewed by 4040
Abstract
Peroxisomes are eukaryotic organelles that are essential for growth and development. They are highly metabolically active and house many biochemical reactions, including lipid metabolism and synthesis of signaling molecules. Most of these metabolic pathways are shared with other compartments, such as Endoplasmic reticulum [...] Read more.
Peroxisomes are eukaryotic organelles that are essential for growth and development. They are highly metabolically active and house many biochemical reactions, including lipid metabolism and synthesis of signaling molecules. Most of these metabolic pathways are shared with other compartments, such as Endoplasmic reticulum (ER), mitochondria, and plastids. Peroxisomes, in common with all other cellular organelles are dependent on a wide range of cofactors, such as adenosine 5′-triphosphate (ATP), Coenzyme A (CoA), and nicotinamide adenine dinucleotide (NAD). The availability of the peroxisomal cofactor pool controls peroxisome function. The levels of these cofactors available for peroxisomal metabolism is determined by the balance between synthesis, import, export, binding, and degradation. Since the final steps of cofactor synthesis are thought to be located in the cytosol, cofactors must be imported into peroxisomes. This review gives an overview about our current knowledge of the permeability of the peroxisomal membrane with the focus on ATP, CoA, and NAD. Several members of the mitochondrial carrier family are located in peroxisomes, catalyzing the transfer of these organic cofactors across the peroxisomal membrane. Most of the functions of these peroxisomal cofactor transporters are known from studies in yeast, humans, and plants. Parallels and differences between the transporters in the different organisms are discussed here. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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19 pages, 1272 KiB  
Review
Mitochondrial Pyruvate Carrier Function in Health and Disease across the Lifespan
by Jane L. Buchanan and Eric B. Taylor
Biomolecules 2020, 10(8), 1162; https://doi.org/10.3390/biom10081162 - 08 Aug 2020
Cited by 15 | Viewed by 4586
Abstract
As a nodal mediator of pyruvate metabolism, the mitochondrial pyruvate carrier (MPC) plays a pivotal role in many physiological and pathological processes across the human lifespan, from embryonic development to aging-associated neurodegeneration. Emerging research highlights the importance of the MPC in diverse conditions, [...] Read more.
As a nodal mediator of pyruvate metabolism, the mitochondrial pyruvate carrier (MPC) plays a pivotal role in many physiological and pathological processes across the human lifespan, from embryonic development to aging-associated neurodegeneration. Emerging research highlights the importance of the MPC in diverse conditions, such as immune cell activation, cancer cell stemness, and dopamine production in Parkinson’s disease models. Whether MPC function ameliorates or contributes to disease is highly specific to tissue and cell type. Cell- and tissue-specific differences in MPC content and activity suggest that MPC function is tightly regulated as a mechanism of metabolic, cellular, and organismal control. Accordingly, recent studies on cancer and diabetes have identified protein–protein interactions, post-translational processes, and transcriptional factors that modulate MPC function. This growing body of literature demonstrates that the MPC and other mitochondrial carriers comprise a versatile and dynamic network undergirding the metabolism of health and disease. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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19 pages, 987 KiB  
Review
On the Detection and Functional Significance of the Protein–Protein Interactions of Mitochondrial Transport Proteins
by Youjun Zhang and Alisdair R. Fernie
Biomolecules 2020, 10(8), 1107; https://doi.org/10.3390/biom10081107 - 25 Jul 2020
Cited by 7 | Viewed by 3216
Abstract
Protein–protein assemblies are highly prevalent in all living cells. Considerable evidence has recently accumulated suggesting that particularly transient association/dissociation of proteins represent an important means of regulation of metabolism. This is true not only in the cytosol and organelle matrices, but also at [...] Read more.
Protein–protein assemblies are highly prevalent in all living cells. Considerable evidence has recently accumulated suggesting that particularly transient association/dissociation of proteins represent an important means of regulation of metabolism. This is true not only in the cytosol and organelle matrices, but also at membrane surfaces where, for example, receptor complexes, as well as those of key metabolic pathways, are common. Transporters also frequently come up in lists of interacting proteins, for example, binding proteins that catalyze the production of their substrates or that act as relays within signal transduction cascades. In this review, we provide an update of technologies that are used in the study of such interactions with mitochondrial transport proteins, highlighting the difficulties that arise in their use for membrane proteins and discussing our current understanding of the biological function of such interactions. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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17 pages, 3796 KiB  
Review
AGC2 (Citrin) Deficiency—From Recognition of the Disease till Construction of Therapeutic Procedures
by Takeyori Saheki, Mitsuaki Moriyama, Aki Funahashi and Eishi Kuroda
Biomolecules 2020, 10(8), 1100; https://doi.org/10.3390/biom10081100 - 24 Jul 2020
Cited by 16 | Viewed by 4217
Abstract
Can you imagine a disease in which intake of an excess amount of sugars or carbohydrates causes hyperammonemia? It is hard to imagine the intake causing hyperammonemia. AGC2 or citrin deficiency shows their symptoms following sugar/carbohydrates intake excess and this disease is now [...] Read more.
Can you imagine a disease in which intake of an excess amount of sugars or carbohydrates causes hyperammonemia? It is hard to imagine the intake causing hyperammonemia. AGC2 or citrin deficiency shows their symptoms following sugar/carbohydrates intake excess and this disease is now known as a pan-ethnic disease. AGC2 (aspartate glutamate carrier 2) or citrin is a mitochondrial transporter which transports aspartate (Asp) from mitochondria to cytosol in exchange with glutamate (Glu) and H+. Asp is originally supplied from mitochondria to cytosol where it is necessary for synthesis of proteins, nucleotides, and urea. In cytosol, Asp can be synthesized from oxaloacetate and Glu by cytosolic Asp aminotransferase, but oxaloacetate formation is limited by the amount of NAD+. This means an increase in NADH causes suppression of Asp formation in the cytosol. Metabolism of carbohydrates and other substances which produce cytosolic NADH such as alcohol and glycerol suppress oxaloacetate formation. It is forced under citrin deficiency since citrin is a member of malate/Asp shuttle. In this review, we will describe history of identification of the SLC25A13 gene as the causative gene for adult-onset type II citrullinemia (CTLN2), a type of citrin deficiency, pathophysiology of citrin deficiency together with animal models and possible treatments for citrin deficiency newly developing. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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18 pages, 991 KiB  
Review
The Multifaceted Pyruvate Metabolism: Role of the Mitochondrial Pyruvate Carrier
by Joséphine Zangari, Francesco Petrelli, Benoît Maillot and Jean-Claude Martinou
Biomolecules 2020, 10(7), 1068; https://doi.org/10.3390/biom10071068 - 17 Jul 2020
Cited by 58 | Viewed by 19225
Abstract
Pyruvate, the end product of glycolysis, plays a major role in cell metabolism. Produced in the cytosol, it is oxidized in the mitochondria where it fuels the citric acid cycle and boosts oxidative phosphorylation. Its sole entry point into mitochondria is through the [...] Read more.
Pyruvate, the end product of glycolysis, plays a major role in cell metabolism. Produced in the cytosol, it is oxidized in the mitochondria where it fuels the citric acid cycle and boosts oxidative phosphorylation. Its sole entry point into mitochondria is through the recently identified mitochondrial pyruvate carrier (MPC). In this review, we report the latest findings on the physiology of the MPC and we discuss how a dysfunctional MPC can lead to diverse pathologies, including neurodegenerative diseases, metabolic disorders, and cancer. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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23 pages, 1114 KiB  
Review
Metabolic Roles of Plant Mitochondrial Carriers
by Alisdair R. Fernie, João Henrique F. Cavalcanti and Adriano Nunes-Nesi
Biomolecules 2020, 10(7), 1013; https://doi.org/10.3390/biom10071013 - 08 Jul 2020
Cited by 11 | Viewed by 3023
Abstract
Mitochondrial carriers (MC) are a large family (MCF) of inner membrane transporters displaying diverse, yet often redundant, substrate specificities, as well as differing spatio-temporal patterns of expression; there are even increasing examples of non-mitochondrial subcellular localization. The number of these six trans-membrane domain [...] Read more.
Mitochondrial carriers (MC) are a large family (MCF) of inner membrane transporters displaying diverse, yet often redundant, substrate specificities, as well as differing spatio-temporal patterns of expression; there are even increasing examples of non-mitochondrial subcellular localization. The number of these six trans-membrane domain proteins in sequenced plant genomes ranges from 39 to 141, rendering the size of plant families larger than that found in Saccharomyces cerevisiae and comparable with Homo sapiens. Indeed, comparison of plant MCs with those from these better characterized species has been highly informative. Here, we review the most recent comprehensive studies of plant MCFs, incorporating the torrent of genomic data emanating from next-generation sequencing techniques. As such we present a more current prediction of the substrate specificities of these carriers as well as review the continuing quest to biochemically characterize this feature of the carriers. Taken together, these data provide an important resource to guide direct genetic studies aimed at addressing the relevance of these vital carrier proteins. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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13 pages, 1624 KiB  
Review
Biogenesis of Mitochondrial Metabolite Carriers
by Patrick Horten, Lilia Colina-Tenorio and Heike Rampelt
Biomolecules 2020, 10(7), 1008; https://doi.org/10.3390/biom10071008 - 07 Jul 2020
Cited by 27 | Viewed by 4823
Abstract
Metabolite carriers of the mitochondrial inner membrane are crucial for cellular physiology since mitochondria contribute essential metabolic reactions and synthesize the majority of the cellular ATP. Like almost all mitochondrial proteins, carriers have to be imported into mitochondria from the cytosol. Carrier precursors [...] Read more.
Metabolite carriers of the mitochondrial inner membrane are crucial for cellular physiology since mitochondria contribute essential metabolic reactions and synthesize the majority of the cellular ATP. Like almost all mitochondrial proteins, carriers have to be imported into mitochondria from the cytosol. Carrier precursors utilize a specialized translocation pathway dedicated to the biogenesis of carriers and related proteins, the carrier translocase of the inner membrane (TIM22) pathway. After recognition and import through the mitochondrial outer membrane via the translocase of the outer membrane (TOM) complex, carrier precursors are ushered through the intermembrane space by hexameric TIM chaperones and ultimately integrated into the inner membrane by the TIM22 carrier translocase. Recent advances have shed light on the mechanisms of TOM translocase and TIM chaperone function, uncovered an unexpected versatility of the machineries, and revealed novel components and functional crosstalk of the human TIM22 translocase. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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25 pages, 1070 KiB  
Review
Physiopathology of the Permeability Transition Pore: Molecular Mechanisms in Human Pathology
by Massimo Bonora, Simone Patergnani, Daniela Ramaccini, Giampaolo Morciano, Gaia Pedriali, Asrat Endrias Kahsay, Esmaa Bouhamida, Carlotta Giorgi, Mariusz R. Wieckowski and Paolo Pinton
Biomolecules 2020, 10(7), 998; https://doi.org/10.3390/biom10070998 - 04 Jul 2020
Cited by 84 | Viewed by 9084
Abstract
Mitochondrial permeability transition (MPT) is the sudden loss in the permeability of the inner mitochondrial membrane (IMM) to low-molecular-weight solutes. Due to osmotic forces, MPT is paralleled by a massive influx of water into the mitochondrial matrix, eventually leading to the structural collapse [...] Read more.
Mitochondrial permeability transition (MPT) is the sudden loss in the permeability of the inner mitochondrial membrane (IMM) to low-molecular-weight solutes. Due to osmotic forces, MPT is paralleled by a massive influx of water into the mitochondrial matrix, eventually leading to the structural collapse of the organelle. Thus, MPT can initiate outer-mitochondrial-membrane permeabilization (MOMP), promoting the activation of the apoptotic caspase cascade and caspase-independent cell-death mechanisms. The induction of MPT is mostly dependent on mitochondrial reactive oxygen species (ROS) and Ca2+, but is also dependent on the metabolic stage of the affected cell and signaling events. Therefore, since its discovery in the late 1970s, the role of MPT in human pathology has been heavily investigated. Here, we summarize the most significant findings corroborating a role for MPT in the etiology of a spectrum of human diseases, including diseases characterized by acute or chronic loss of adult cells and those characterized by neoplastic initiation. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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32 pages, 2970 KiB  
Review
Diseases Caused by Mutations in Mitochondrial Carrier Genes SLC25: A Review
by Ferdinando Palmieri, Pasquale Scarcia and Magnus Monné
Biomolecules 2020, 10(4), 655; https://doi.org/10.3390/biom10040655 - 23 Apr 2020
Cited by 66 | Viewed by 9916
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Mitochondrial Transport Proteins)
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