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Transport Mechanisms of Mitochondrial Membrane Proteins

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (15 April 2024) | Viewed by 13185

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Special Issue Editors

Prof. Dr. Ferdinando Palmieri

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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

Dr. Magnus Monné

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Guest Editor

Department of Sciences, University of Basilicata, 85100 Potenza, Italy
Interests: mitochondrial carriers; transporters; membrane proteins; transporter-substrate interactions; transport mechanism; protein structure

Special Issue Information

Dear Colleagues,

A Special Issue on “Transport Mechanisms of Mitochondrial Membrane Proteins” is being prepared for the International Journal of Molecular Sciences.

The two mitochondrial membranes contain a large number of membrane proteins involved in various transport functions, for example the outer membrane VDAC, the inner membrane mitochondrial carriers (SLC25 superfamily members), ATP binding cassette transporters and respiratory chain electron transfer complexes. Whereas the outer membrane proteins provide a more general selective permeability filter for diffusion, the inner membrane proteins are highly selective for their transported substrates such as nucleotides, ions, protons, electrons, metabolites, amino acids and cofactors. Biochemical characterization of the mitochondrial membrane proteins has established substrate specificity, kinetic parameters and modes of transport (antiport, uniport or symport). Transport mechanisms of various mitochondrial membrane proteins have been proposed based on transport kinetics, inhibitor studies, modes of transport, mutagenesis and, in particular, structural analyses and dynamics.

Original manuscripts and reviews examining different aspects of the transport mechanisms of the mitochondrial membrane proteins are welcome.

Prof. Dr. Ferdinando Palmieri
Dr. Magnus Monné
Guest Editors

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Keywords

mitochondrial carriers
transport mechanism
transport cycle
mitochondrial ADP/ATP carrier
kinetics of transport
antiport transport
uniport transport
symport transport
structures of transporters
regulation of transport
structure-function relationships of transporters
inhibitors of transporters
molecular dynamics simulations of transporters
site-directed mutagenesis
transport assays

Published Papers (6 papers)

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Research

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18 pages, 4295 KiB

Open AccessArticle

FA Sliding as the Mechanism for the ANT1-Mediated Fatty Acid Anion Transport in Lipid Bilayers

by Jürgen Kreiter, Sanja Škulj, Zlatko Brkljača, Sarah Bardakji, Mario Vazdar and Elena E. Pohl

Int. J. Mol. Sci. 2023, 24(18), 13701; https://doi.org/10.3390/ijms241813701 - 05 Sep 2023

Cited by 2 | Viewed by 1294

Abstract

Mitochondrial adenine nucleotide translocase (ANT) exchanges ADP for ATP to maintain energy production in the cell. Its protonophoric function in the presence of long-chain fatty acids (FA) is also recognized. Our previous results imply that proton/FA transport can be best described with the FA cycling model, in which protonated FA transports the proton to the mitochondrial matrix. The mechanism by which ANT1 transports FA anions back to the intermembrane space remains unclear. Using a combined approach involving measurements of the current through the planar lipid bilayers reconstituted with ANT1, site-directed mutagenesis and molecular dynamics simulations, we show that the FA anion is first attracted by positively charged arginines or lysines on the matrix side of ANT1 before moving along the positively charged protein–lipid interface and binding to R79, where it is protonated. We show that R79 is also critical for the competitive binding of ANT1 substrates (ADP and ATP) and inhibitors (carboxyatractyloside and bongkrekic acid). The binding sites are well conserved in mitochondrial SLC25 members, suggesting a general mechanism for transporting FA anions across the inner mitochondrial membrane. Full article

(This article belongs to the Special Issue Transport Mechanisms of Mitochondrial Membrane Proteins)

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12 pages, 2202 KiB

Open AccessArticle

Role of UCP2 in the Energy Metabolism of the Cancer Cell Line A549

by Jessica Segalés, Carlos Sánchez-Martín, Aleida Pujol-Morcillo, Marta Martín-Ruiz, Patricia de los Santos, Daniel Lobato-Alonso, Eduardo Oliver and Eduardo Rial

Int. J. Mol. Sci. 2023, 24(9), 8123; https://doi.org/10.3390/ijms24098123 - 01 May 2023

Cited by 1 | Viewed by 1834

Abstract

The uncoupling protein UCP2 is a mitochondrial carrier for which transport activity remains controversial. The physiological contexts in which UCP2 is expressed have led to the assumption that, like UCP1, it uncouples oxidative phosphorylation and thereby reduces the generation of reactive oxygen species. Other reports have involved UCP2 in the Warburg effect, and results showing that UCP2 catalyzes the export of matrix C4 metabolites to facilitate glutamine utilization suggest that the carrier could be involved in the metabolic adaptations required for cell proliferation. We have examined the role of UCP2 in the energy metabolism of the lung adenocarcinoma cell line A549 and show that UCP2 silencing decreased the basal rate of respiration, although this inhibition was not compensated by an increase in glycolysis. Silencing did not lead to either changes in proton leakage, as determined by the rate of respiration in the absence of ATP synthesis, or changes in the rate of formation of reactive oxygen species. The decrease in energy metabolism did not alter the cellular energy charge. The decreased cell proliferation observed in UCP2-silenced cells would explain the reduced cellular ATP demand. We conclude that UCP2 does not operate as an uncoupling protein, whereas our results are consistent with its activity as a C4-metabolite carrier involved in the metabolic adaptations of proliferating cells. Full article

(This article belongs to the Special Issue Transport Mechanisms of Mitochondrial Membrane Proteins)

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22 pages, 5404 KiB

Open AccessArticle

In Silico Analysis of the Structural Dynamics and Substrate Recognition Determinants of the Human Mitochondrial Carnitine/Acylcarnitine SLC25A20 Transporter

by Andrea Pasquadibisceglie, Virginia Quadrotta and Fabio Polticelli

Int. J. Mol. Sci. 2023, 24(4), 3946; https://doi.org/10.3390/ijms24043946 - 15 Feb 2023

Cited by 1 | Viewed by 1795

Abstract

The Carnitine-Acylcarnitine Carrier is a member of the mitochondrial Solute Carrier Family 25 (SLC25), known as SLC25A20, involved in the electroneutral exchange of acylcarnitine and carnitine across the inner mitochondrial membrane. It acts as a master regulator of fatty acids β-oxidation and is known to be involved in neonatal pathologies and cancer. The transport mechanism, also known as “alternating access”, involves a conformational transition in which the binding site is accessible from one side of the membrane or the other. In this study, through a combination of state-of-the-art modelling techniques, molecular dynamics, and molecular docking, the structural dynamics of SLC25A20 and the early substrates recognition step have been analyzed. The results obtained demonstrated a significant asymmetry in the conformational changes leading to the transition from the c- to the m-state, confirming previous observations on other homologous transporters. Moreover, analysis of the MD simulations’ trajectories of the apo-protein in the two conformational states allowed for a better understanding of the role of SLC25A20 Asp231His and Ala281Val pathogenic mutations, which are at the basis of Carnitine-Acylcarnitine Translocase Deficiency. Finally, molecular docking coupled to molecular dynamics simulations lend support to the multi-step substrates recognition and translocation mechanism already hypothesized for the ADP/ATP carrier. Full article

(This article belongs to the Special Issue Transport Mechanisms of Mitochondrial Membrane Proteins)

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16 pages, 4942 KiB

Open AccessArticle

by Qiuzi Yi, Shihao Yao, Boyuan Ma and Xiaohui Cang

Int. J. Mol. Sci. 2022, 23(18), 10877; https://doi.org/10.3390/ijms231810877 - 17 Sep 2022

Cited by 1 | Viewed by 1272

Abstract

The ADP/ATP carrier (AAC) plays a central role in oxidative metabolism by exchanging ATP and ADP across the inner mitochondrial membrane. Previous experiments have shown the involvement of the matrix loops of AAC in its function, yet potential mechanisms remain largely elusive. One obstacle is the limited information on the structural dynamics of the matrix loops. In the current work, unbiased all-atom molecular dynamics (MD) simulations were carried out on c-state wild-type AAC and mutants. Our results reveal that: (1) two ends of a matrix loop are tethered through interactions between the residue of triplet 38 (Q38, D143 and Q240) located at the C-end of the odd-numbered helix and residues of the [YF]xG motif located before the N-end of the short matrix helix in the same domain; (2) the initial progression direction of a matrix loop is determined by interactions between the negatively charged residue of the [DE]G motif located at the C-end of the short matrix helix and the capping arginine (R30, R139 and R236) in the previous domain; (3) the two chemically similar residues D and E in the highly conserved [DE]G motif are actually quite different; (4) the N-end of the M3 loop is clamped by the [DE]G motif and the capping arginine of domain 2 from the two sides, which strengthens interactions between domain 2 and domain 3; and (5) a highly asymmetric stable core exists within domains 2 and 3 at the m-gate level. Moreover, our results help explain almost all extremely conserved residues within the matrix loops of the ADP/ATP carriers from a structural point of view. Taken together, the current work highlights asymmetry in the three matrix loops and implies a close relationship between asymmetry and ADP/ATP transport. Full article

(This article belongs to the Special Issue Transport Mechanisms of Mitochondrial Membrane Proteins)

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17 pages, 3799 KiB

Open AccessArticle

Evidence for Non-Essential Salt Bridges in the M-Gates of Mitochondrial Carrier Proteins

by Daniela Valeria Miniero, Magnus Monné, Maria Antonietta Di Noia, Luigi Palmieri and Ferdinando Palmieri

Int. J. Mol. Sci. 2022, 23(9), 5060; https://doi.org/10.3390/ijms23095060 - 02 May 2022

Cited by 5 | Viewed by 1698

Abstract

Mitochondrial carriers, which transport metabolites, nucleotides, and cofactors across the mitochondrial inner membrane, have six transmembrane α-helices enclosing a translocation pore with a central substrate binding site whose access is controlled by a cytoplasmic and a matrix gate (M-gate). The salt bridges formed by the three PX[DE]XX[RK] motifs located on the odd-numbered transmembrane α-helices greatly contribute to closing the M-gate. We have measured the transport rates of cysteine mutants of the charged residue positions in the PX[DE]XX[RK] motifs of the bovine oxoglutarate carrier, the yeast GTP/GDP carrier, and the yeast NAD⁺ transporter, which all lack one of these charged residues. Most single substitutions, including those of the non-charged and unpaired charged residues, completely inactivated transport. Double mutations of charged pairs showed that all three carriers contain salt bridges non-essential for activity. Two double substitutions of these non-essential charge pairs exhibited higher transport rates than their corresponding single mutants, whereas swapping the charged residues in these positions did not increase activity. The results demonstrate that some of the residues in the charged residue positions of the PX[DE]XX[KR] motifs are important for reasons other than forming salt bridges, probably for playing specific roles related to the substrate interaction-mediated conformational changes leading to the M-gate opening/closing. Full article

(This article belongs to the Special Issue Transport Mechanisms of Mitochondrial Membrane Proteins)

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Review

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18 pages, 1765 KiB

Open AccessReview

Roles of Noncoding RNAs in Regulation of Mitochondrial Electron Transport Chain and Oxidative Phosphorylation

by Ami Kobayashi, Toshihiko Takeiwa, Kazuhiro Ikeda and Satoshi Inoue

Int. J. Mol. Sci. 2023, 24(11), 9414; https://doi.org/10.3390/ijms24119414 - 28 May 2023

Cited by 2 | Viewed by 4020

Abstract

The mitochondrial electron transport chain (ETC) plays an essential role in energy production by inducing oxidative phosphorylation (OXPHOS) to drive numerous biochemical processes in eukaryotic cells. Disorders of ETC and OXPHOS systems are associated with mitochondria- and metabolism-related diseases, including cancers; thus, a comprehensive understanding of the regulatory mechanisms of ETC and OXPHOS systems is required. Recent studies have indicated that noncoding RNAs (ncRNAs) play key roles in mitochondrial functions; in particular, some ncRNAs have been shown to modulate ETC and OXPHOS systems. In this review, we introduce the emerging roles of ncRNAs, including microRNAs (miRNAs), transfer-RNA-derived fragments (tRFs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), in the mitochondrial ETC and OXPHOS regulation. Full article

(This article belongs to the Special Issue Transport Mechanisms of Mitochondrial Membrane Proteins)

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