Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
8.3
5.5
Journals
Biomolecules
Special Issues
Advances in Mitochondrial Transport Research
share announcement

Advances in Mitochondrial Transport Research

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

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 19431

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; protein expression; protein reconstitution into liposomes; structure/function relationship
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A Special Issue, “Advances in Mitochondrial Transport Research”, is being prepared for release in Biomolecules.
Mitochondrial transporters are membrane-inserted proteins that catalyze the translocation of solutes across the mitochondrial membrane. They include the mitochondrial carrier family members, the proteins involved in pyruvate transport, ABC transporters, and ion channels and are therefore essential for many biological processes and for cell homeostasis. Identification and functional studies on a number of mitochondrial channels and transporters have been performed over the years using both in vitro and in vivo systems. The structures of these proteins that have been solved have recently paved the way for further investigations. Furthermore, alterations in their function are responsible for several diseases. Original manuscripts, reviews, and communications dealing with any aspect of mitochondrial transport and its related pathophysiology and pharmacology are very welcome. 

Prof. Dr. Ferdinando Palmieri
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • diseases related to mitochondrial transport proteins (MTPs)
  • metabolic roles of MTPs
  • pharmacology of MTPs
  • mitochondrial ABC transporters
  • mitochondrial carriers
  • mitochondrial channels
  • mitochondrial pyruvate transport in pathophysiology
  • mitochondrial transport proteins (MTPs)
  • mitochondrial transporters
  • MTP import
  • MTPs in pathophysiology
  • MTP structure and function
  • regulation of MTP transcription

Published Papers (10 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review

15 pages, 2502 KiB  
Article
Uncoupling Protein 3 Catalyzes the Exchange of C4 Metabolites Similar to UCP2
by Jürgen Kreiter, Tatyana Tyschuk and Elena E. Pohl
Biomolecules 2024, 14(1), 21; https://doi.org/10.3390/biom14010021 - 22 Dec 2023
Cited by 1 | Viewed by 963
Abstract
Uncoupling protein 3 (UCP3) belongs to the mitochondrial carrier protein superfamily SLC25 and is abundant in brown adipose tissue (BAT), the heart, and muscles. The expression of UCP3 in tissues mainly dependent on fatty acid oxidation suggests its involvement in cellular metabolism and [...] Read more.
Uncoupling protein 3 (UCP3) belongs to the mitochondrial carrier protein superfamily SLC25 and is abundant in brown adipose tissue (BAT), the heart, and muscles. The expression of UCP3 in tissues mainly dependent on fatty acid oxidation suggests its involvement in cellular metabolism and has drawn attention to its possible transport function beyond the transport of protons in the presence of fatty acids. Based on the high homology between UCP2 and UCP3, we hypothesized that UCP3 transports C4 metabolites similar to UCP2. To test this, we measured the transport of substrates against phosphate (32Pi) in proteoliposomes reconstituted with recombinant murine UCP3 (mUCP3). We found that mUCP3 mainly transports aspartate and sulfate but also malate, malonate, oxaloacetate, and succinate. The transport rates calculated from the exchange of 32Pi against extraliposomal aspartate and sulfate were 23.9 ± 5.8 and 17.5 ± 5.1 µmol/min/mg, respectively. Using site-directed mutagenesis, we revealed that mutation of R84 resulted in impaired aspartate/phosphate exchange, demonstrating its critical role in substrate transport. The difference in substrate preference between mUCP2 and mUCP3 may be explained by their different tissue expression patterns and biological functions in these tissues. Full article
(This article belongs to the Special Issue Advances in Mitochondrial Transport Research)
►▼ Show Figures

Figure 1

11 pages, 626 KiB  
Article
Phylogenetic Analysis Guides Transporter Protein Deorphanization: A Case Study of the SLC25 Family of Mitochondrial Metabolite Transporters
by Katie L. Byrne, Richard V. Szeligowski and Hongying Shen
Biomolecules 2023, 13(9), 1314; https://doi.org/10.3390/biom13091314 - 28 Aug 2023
Cited by 2 | Viewed by 1707
Abstract
Homology search and phylogenetic analysis have commonly been used to annotate gene function, although they are prone to error. We hypothesize that the power of homology search in functional annotation depends on the coupling of sequence variation to functional diversification, and we herein [...] Read more.
Homology search and phylogenetic analysis have commonly been used to annotate gene function, although they are prone to error. We hypothesize that the power of homology search in functional annotation depends on the coupling of sequence variation to functional diversification, and we herein focus on the SoLute Carrier (SLC25) family of mitochondrial metabolite transporters to survey this coupling in a family-wide manner. The SLC25 family is the largest family of mitochondrial metabolite transporters in eukaryotes that translocate ligands of different chemical properties, ranging from nucleotides, amino acids, carboxylic acids and cofactors, presenting adequate experimentally validated functional diversification in ligand transport. Here, we combine phylogenetic analysis to profile SLC25 transporters across common eukaryotic model organisms, from Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, Danio rerio, to Homo sapiens, and assess their sequence adaptations to the transported ligands within individual subfamilies. Using several recently studied and poorly characterized SLC25 transporters, we discuss the potentials and limitations of phylogenetic analysis in guiding functional characterization. Full article
(This article belongs to the Special Issue Advances in Mitochondrial Transport Research)
►▼ Show Figures

Figure 1

15 pages, 3556 KiB  
Article
Inhibition of the Mitochondrial Carnitine/Acylcarnitine Carrier by Itaconate through Irreversible Binding to Cysteine 136: Possible Pathophysiological Implications
by Nicola Giangregorio, Annamaria Tonazzi, Lara Console, Mariafrancesca Scalise and Cesare Indiveri
Biomolecules 2023, 13(6), 993; https://doi.org/10.3390/biom13060993 - 15 Jun 2023
Cited by 2 | Viewed by 1256
Abstract
Background: The carnitine/acylcarnitine carrier (CAC) represents the route of delivering acyl moieties to the mitochondrial matrix for accomplishing the fatty acid β-oxidation. The CAC has a couple of Cys residues (C136 and C155) most reactive toward ROS and redox signaling compounds such as [...] Read more.
Background: The carnitine/acylcarnitine carrier (CAC) represents the route of delivering acyl moieties to the mitochondrial matrix for accomplishing the fatty acid β-oxidation. The CAC has a couple of Cys residues (C136 and C155) most reactive toward ROS and redox signaling compounds such as GSH, NO, and H2S. Among physiological compounds reacting with Cys, itaconate is produced during inflammation and represents the connection between oxidative metabolism and immune responses. The possible interaction between the CAC and itaconate has been investigated. Methods: the modulatory effects of itaconate on the transport activity of the native and recombinant CAC were tested using the proteoliposome experimental model together with site-directed mutagenesis and computational analysis. Results: Itaconate reacts with the CAC causing irreversible inhibition. Dose–response experiment performed with the native and recombinant protein showed IC50 for itaconate of 11 ± 4.6 mM and 8.4 ± 2.9 mM, respectively. The IC50 decreased to 3.8 ± 1.0 mM by lowering the pH from pH 7.0 to pH 6.5. Inhibition kinetics revealed a non-competitive type of inhibition. C136 is the main target of itaconate, as demonstrated by the increased IC50 of mutants in which this Cys was substituted by Val. The central role of C136 was confirmed by covalent docking. Administration of dimethyl itaconate to HeLa cells inhibited the CAC transport activity, suggesting that itaconate could react with the CAC also in intact cells. Full article
(This article belongs to the Special Issue Advances in Mitochondrial Transport Research)
►▼ Show Figures

Figure 1

13 pages, 3015 KiB  
Article
Generation of a Yeast Cell Model Potentially Useful to Identify the Mammalian Mitochondrial N-Acetylglutamate Transporter
by Ruggiero Gorgoglione, Roberta Seccia, Amer Ahmed, Angelo Vozza, Loredana Capobianco, Alessia Lodi, Federica Marra, Eleonora Paradies, Luigi Palmieri, Vincenzo Coppola, Vincenza Dolce and Giuseppe Fiermonte
Biomolecules 2023, 13(5), 808; https://doi.org/10.3390/biom13050808 - 10 May 2023
Cited by 2 | Viewed by 1698
Abstract
The human mitochondrial carrier family (MCF) consists of 53 members. Approximately one-fifth of them are still orphans of a function. Most mitochondrial transporters have been functionally characterized by reconstituting the bacterially expressed protein into liposomes and transport assays with radiolabeled compounds. The efficacy [...] Read more.
The human mitochondrial carrier family (MCF) consists of 53 members. Approximately one-fifth of them are still orphans of a function. Most mitochondrial transporters have been functionally characterized by reconstituting the bacterially expressed protein into liposomes and transport assays with radiolabeled compounds. The efficacy of this experimental approach is constrained to the commercial availability of the radiolabeled substrate to be used in the transport assays. A striking example is that of N-acetylglutamate (NAG), an essential regulator of the carbamoyl synthetase I activity and the entire urea cycle. Mammals cannot modulate mitochondrial NAG synthesis but can regulate the levels of NAG in the matrix by exporting it to the cytosol, where it is degraded. The mitochondrial NAG transporter is still unknown. Here, we report the generation of a yeast cell model suitable for identifying the putative mammalian mitochondrial NAG transporter. In yeast, the arginine biosynthesis starts in the mitochondria from NAG which is converted to ornithine that, once transported into cytosol, is metabolized to arginine. The deletion of ARG8 makes yeast cells unable to grow in the absence of arginine since they cannot synthetize ornithine but can still produce NAG. To make yeast cells dependent on a mitochondrial NAG exporter, we moved most of the yeast mitochondrial biosynthetic pathway to the cytosol by expressing four E. coli enzymes, argB-E, able to convert cytosolic NAG to ornithine. Although argB-E rescued the arginine auxotrophy of arg8∆ strain very poorly, the expression of the bacterial NAG synthase (argA), which would mimic the function of a putative NAG transporter increasing the cytosolic levels of NAG, fully rescued the growth defect of arg8∆ strain in the absence of arginine, demonstrating the potential suitability of the model generated. Full article
(This article belongs to the Special Issue Advances in Mitochondrial Transport Research)
►▼ Show Figures

Figure 1

15 pages, 3680 KiB  
Article
On the Significance of the ADNT1 Carrier in Arabidopsis thaliana under Waterlogging Conditions
by Roberto Neri-Silva, Rita de Cássia Monteiro-Batista, Paula da Fonseca-Pereira, Mateus Dias Nunes, Ana Luiza Viana-Silva, Tamara Palhares Ribeiro, Jorge L. Pérez-Díaz, David B. Medeiros, Wagner L. Araújo, Alisdair R. Fernie and Adriano Nunes-Nesi
Biomolecules 2023, 13(5), 731; https://doi.org/10.3390/biom13050731 - 24 Apr 2023
Cited by 1 | Viewed by 1577
Abstract
Among the adenylate carriers identified in Arabidopsis thaliana, only the AMP/ATP transporter ADNT1 shows increased expression in roots under waterlogging stress conditions. Here, we investigated the impact of a reduced expression of ADNT1 in A. thaliana plants submitted to waterlogging conditions. For [...] Read more.
Among the adenylate carriers identified in Arabidopsis thaliana, only the AMP/ATP transporter ADNT1 shows increased expression in roots under waterlogging stress conditions. Here, we investigated the impact of a reduced expression of ADNT1 in A. thaliana plants submitted to waterlogging conditions. For this purpose, an adnt1 T-DNA mutant and two ADNT1 antisense lines were evaluated. Following waterlogging, ADNT1 deficiency resulted in a reduced maximum quantum yield of PSII electron transport (significantly for adnt1 and antisense Line 10), indicating a higher impact caused by the stress in the mutants. In addition, ADNT1 deficient lines showed higher levels of AMP in roots under nonstress condition. This result indicates that the downregulation of ADNT1 impacts the levels of adenylates. ADNT1-deficient plants exhibited a differential expression pattern of hypoxia-related genes with an increase in non-fermenting-related-kinase 1 (SnRK1) expression and upregulation of adenylate kinase (ADK) under stress and non-stress conditions. Together, these results indicated that the lower expression of ADNT1 is associated with an early “hypoxic status” due to the perturbation of the adenylate pool caused by reduced AMP import by mitochondria. This perturbation, which is sensed by SnRK1, results in a metabolic reprogramming associated with early induction of the fermentative pathway in ADNT1 deficient plants. Full article
(This article belongs to the Special Issue Advances in Mitochondrial Transport Research)
►▼ Show Figures

Figure 1

14 pages, 3055 KiB  
Article
Ablation of GPR56 Causes β-Cell Dysfunction by ATP Loss through Mistargeting of Mitochondrial VDAC1 to the Plasma Membrane
by Israa Mohammad Al-Amily, Marie Sjögren, Pontus Duner, Mohammad Tariq, Claes B. Wollheim and Albert Salehi
Biomolecules 2023, 13(3), 557; https://doi.org/10.3390/biom13030557 - 18 Mar 2023
Viewed by 2063
Abstract
The activation of G Protein-Coupled Receptor 56 (GPR56), also referred to as Adhesion G-Protein-Coupled Ceceptor G1 (ADGRG1), by Collagen Type III (Coll III) prompts cell growth, proliferation, and survival, among other attributes. We investigated the signaling cascades mediating this functional effect in relation [...] Read more.
The activation of G Protein-Coupled Receptor 56 (GPR56), also referred to as Adhesion G-Protein-Coupled Ceceptor G1 (ADGRG1), by Collagen Type III (Coll III) prompts cell growth, proliferation, and survival, among other attributes. We investigated the signaling cascades mediating this functional effect in relation to the mitochondrial outer membrane voltage-dependent anion Channel-1 (VDAC1) expression in pancreatic β-cells. GPR56KD attenuated the Coll III-induced suppression of P70S6K, JNK, AKT, NFκB, STAT3, and STAT5 phosphorylation/activity in INS-1 cells cultured at 20 mM glucose (glucotoxicity) for 72 h. GPR56-KD also increased Chrebp, Txnip, and Vdac1 while decreasing Vdac2 mRNA expression. In GPR56-KD islet β-cells, Vdac1 was co-localized with SNAP-25, demonstrating its plasma membrane translocation. This resulted in ATP loss, reduced cAMP production and impaired glucose-stimulated insulin secretion (GSIS) in INS-1 and human EndoC βH1 cells. The latter defects were reversed by an acute inhibition of VDAC1 with an antibody or the VDAC1 inhibitor VBIT-4. We demonstrate that Coll III potentiates GSIS by increasing cAMP and preserving β-cell functionality under glucotoxic conditions in a GPR56-dependent manner by attenuating the inflammatory response. These results emphasize GPR56 and VDAC1 as drug targets in conditions with impaired β-cell function. Full article
(This article belongs to the Special Issue Advances in Mitochondrial Transport Research)
►▼ Show Figures

Figure 1

23 pages, 5725 KiB  
Article
The Multicellular Effects of VDAC1 N-Terminal-Derived Peptide
by Uttpal Anand, Anna Shteinfer-Kuzmine, Gal Sela, Manikandan Santhanam, Benjamin Gottschalk, Rajaa Boujemaa-Paterski, Ohad Medalia, Wolfgang F. Graier and Varda Shoshan-Barmatz
Biomolecules 2022, 12(10), 1387; https://doi.org/10.3390/biom12101387 - 28 Sep 2022
Cited by 5 | Viewed by 2234
Abstract
The mitochondrial voltage-dependent anion channel-1 (VDAC1) protein functions in a variety of mitochondria-linked physiological and pathological processes, including metabolism and cell signaling, as well as in mitochondria-mediated apoptosis. VDAC1 interacts with about 150 proteins to regulate the integration of mitochondrial functions with other [...] Read more.
The mitochondrial voltage-dependent anion channel-1 (VDAC1) protein functions in a variety of mitochondria-linked physiological and pathological processes, including metabolism and cell signaling, as well as in mitochondria-mediated apoptosis. VDAC1 interacts with about 150 proteins to regulate the integration of mitochondrial functions with other cellular activities. Recently, we developed VDAC1-based peptides that have multiple effects on cancer cells and tumors including apoptosis induction. Here, we designed several cell-penetrating VDAC1 N-terminal-derived peptides with the goal of identifying the shortest peptide with improved cellular stability and activity. We identified the D-Δ(1-18)N-Ter-Antp comprising the VDAC1 N-terminal region (19–26 amino acids) fused to the Antp, a cell-penetrating peptide. We demonstrated that this peptide induced apoptosis, autophagy, senescence, cell volume enlargement, and the refusion of divided daughter cells into a single cell, it was responsible for reorganization of actin and tubulin filaments, and increased cell adhesion. In addition, the peptide induced alterations in the expression of proteins associated with cell metabolism, signaling, and division, such as enhancing the expression of nuclear factor kappa B and decreasing the expression of the nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha. These cellular effects may result from the peptide interfering with VDAC1 interaction with its interacting proteins, thereby blocking multiple mitochondrial/VDAC1 pathways associated with cell functions. The results of this study further support the role of VDAC1 as a mitochondrial gatekeeper protein in controlling a variety of cell functions via interaction with associated proteins. Full article
(This article belongs to the Special Issue Advances in Mitochondrial Transport Research)
►▼ Show Figures

Figure 1

Review

Jump to: Research

29 pages, 2414 KiB  
Review
Solute Transport through Mitochondrial Porins In Vitro and In Vivo
by Roland Benz
Biomolecules 2024, 14(3), 303; https://doi.org/10.3390/biom14030303 - 04 Mar 2024
Viewed by 985
Abstract
Mitochondria are most likely descendants of strictly aerobic prokaryotes from the class Alphaproteobacteria. The mitochondrial matrix is surrounded by two membranes according to its relationship with Gram-negative bacteria. Similar to the bacterial outer membrane, the mitochondrial outer membrane acts as a molecular [...] Read more.
Mitochondria are most likely descendants of strictly aerobic prokaryotes from the class Alphaproteobacteria. The mitochondrial matrix is surrounded by two membranes according to its relationship with Gram-negative bacteria. Similar to the bacterial outer membrane, the mitochondrial outer membrane acts as a molecular sieve because it also contains diffusion pores. However, it is more actively involved in mitochondrial metabolism because it plays a functional role, whereas the bacterial outer membrane has only passive sieving properties. Mitochondrial porins, also known as eukaryotic porins or voltage-dependent anion-selective channels (VDACs) control the permeability properties of the mitochondrial outer membrane. They contrast with most bacterial porins because they are voltage-dependent. They switch at relatively small transmembrane potentials of 20 to 30 mV in closed states that exhibit different permeability properties than the open state. Whereas the open state is preferentially permeable to anionic metabolites of mitochondrial metabolism, the closed states prefer cationic solutes, in particular, calcium ions. Mitochondrial porins are encoded in the nucleus, synthesized at cytoplasmatic ribosomes, and post-translationally imported through special transport systems into mitochondria. Nineteen beta strands form the beta-barrel cylinders of mitochondrial and related porins. The pores contain in addition an α-helical structure at the N-terminal end of the protein that serves as a gate for the voltage-dependence. Similarly, they bind peripheral proteins that are involved in mitochondrial function and compartment formation. This means that mitochondrial porins are localized in a strategic position to control mitochondrial metabolism. The special features of the role of mitochondrial porins in apoptosis and cancer will also be discussed in this article. Full article
(This article belongs to the Special Issue Advances in Mitochondrial Transport Research)
►▼ Show Figures

Figure 1

17 pages, 1532 KiB  
Review
The Mitochondrial Calcium Uniporter (MCU): Molecular Identity and Role in Human Diseases
by Donato D’Angelo and Rosario Rizzuto
Biomolecules 2023, 13(9), 1304; https://doi.org/10.3390/biom13091304 - 25 Aug 2023
Cited by 2 | Viewed by 2437
Abstract
Calcium (Ca2+) ions act as a second messenger, regulating several cell functions. Mitochondria are critical organelles for the regulation of intracellular Ca2+. Mitochondrial calcium (mtCa2+) uptake is ensured by the presence in the inner mitochondrial membrane (IMM) [...] Read more.
Calcium (Ca2+) ions act as a second messenger, regulating several cell functions. Mitochondria are critical organelles for the regulation of intracellular Ca2+. Mitochondrial calcium (mtCa2+) uptake is ensured by the presence in the inner mitochondrial membrane (IMM) of the mitochondrial calcium uniporter (MCU) complex, a macromolecular structure composed of pore-forming and regulatory subunits. MtCa2+ uptake plays a crucial role in the regulation of oxidative metabolism and cell death. A lot of evidence demonstrates that the dysregulation of mtCa2+ homeostasis can have serious pathological outcomes. In this review, we briefly discuss the molecular structure and the function of the MCU complex and then we focus our attention on human diseases in which a dysfunction in mtCa2+ has been shown. Full article
(This article belongs to the Special Issue Advances in Mitochondrial Transport Research)
►▼ Show Figures

Figure 1

16 pages, 1293 KiB  
Review
The Hepatic Mitochondrial Pyruvate Carrier as a Regulator of Systemic Metabolism and a Therapeutic Target for Treating Metabolic Disease
by Kyle S. McCommis and Brian N. Finck
Biomolecules 2023, 13(2), 261; https://doi.org/10.3390/biom13020261 - 31 Jan 2023
Cited by 6 | Viewed by 3527
Abstract
Pyruvate sits at an important metabolic crossroads of intermediary metabolism. As a product of glycolysis in the cytosol, it must be transported into the mitochondrial matrix for the energy stored in this nutrient to be fully harnessed to generate ATP or to become [...] Read more.
Pyruvate sits at an important metabolic crossroads of intermediary metabolism. As a product of glycolysis in the cytosol, it must be transported into the mitochondrial matrix for the energy stored in this nutrient to be fully harnessed to generate ATP or to become the building block of new biomolecules. Given the requirement for mitochondrial import, it is not surprising that the mitochondrial pyruvate carrier (MPC) has emerged as a target for therapeutic intervention in a variety of diseases characterized by altered mitochondrial and intermediary metabolism. In this review, we focus on the role of the MPC and related metabolic pathways in the liver in regulating hepatic and systemic energy metabolism and summarize the current state of targeting this pathway to treat diseases of the liver. Available evidence suggests that inhibiting the MPC in hepatocytes and other cells of the liver produces a variety of beneficial effects for treating type 2 diabetes and nonalcoholic steatohepatitis. We also highlight areas where our understanding is incomplete regarding the pleiotropic effects of MPC inhibition. Full article
(This article belongs to the Special Issue Advances in Mitochondrial Transport Research)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-10
Back to TopTop