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Mitochondrial Transport and Energy Metabolism in Health and Diseases

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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 (31 May 2022) | Viewed by 25872

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Special Issue Editor

Prof. Dr. Salvatore Passarella

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Guest Editor

School of Medicine University "Aldo Moro", Piazza Giulio Cesare, 70121 Bari, Italy
Interests: mitochondrial transport; energy metabolism; L-and D-lactate transport and metabolism in animal, plant, yeast, and cancer mitochondria; light-biological systems interactions; programmed cell death

Special Issue Information

Dear Colleagues,

Studies from many laboratories over recent years have uncovered the existence and established the properties of a variety of mitochondrial transporters. The properties of these transporters throw light on a variety of biochemical phenomena that were previously poorly understood. In particular, the role of mitochondrial transport in energy metabolism has been investigated under a variety of physio‐pathological conditions. However, this issue is still not exhaustively elucidated; in particular, some topics merit further attention. They include:

How to study mitochondrial transport: strengths and weaknesses of different experimental approaches;
K⁺, Ca²⁺, and metal ion transport in mitochondria;
Protein movement across the mitochondrial membranes;
How vitamins and vitamin derivatives can enter mitochondria;
How nucleic acids can enter mitochondria;
The transport and metabolism in mitochondria of selected metabolites (e.g., the lactate isomers, citric acid cycle intermediates, amino acids, etc.);
Mitochondrial transport in glucose, fatty acid and amino acid metabolism;
Mitochondrial micro-compartmentation and transport;
Mitochondrial transport in diseases;
Yeast mitochondria as a model in mitochondrial transport studies.

Prof. Dr. Salvatore Passarella
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

mitochondrial transport
energy metabolism
ion mitochondrial transport
vitamin mitochondrial transport
protein mitochondrial transport

Published Papers (6 papers)

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Research

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19 pages, 16474 KiB

Open AccessArticle

Mitochondrial Toxicity Associated with Imatinib and Sorafenib in Isolated Rat Heart Fibers and the Cardiomyoblast H9c2 Cell Line

by Jamal Bouitbir, Miljenko V. Panajatovic and Stephan Krähenbühl

Int. J. Mol. Sci. 2022, 23(4), 2282; https://doi.org/10.3390/ijms23042282 - 18 Feb 2022

Cited by 11 | Viewed by 2988

Abstract

Tyrosine kinase inhibitors (TKIs) are associated with cardiac toxicity, which may be caused by mitochondrial toxicity. The underlying mechanisms are currently unclear and require further investigation. In the present study, we aimed to investigate in more detail the role of the enzyme complexes of the electron transfer system (ETS), mitochondrial oxidative stress, and mechanisms of cell death in cardiac toxicity associated with imatinib and sorafenib. Cardiac myoblast H9c2 cells were exposed to imatinib and sorafenib (1 to 100 µM) for 24 h. Permeabilized rat cardiac fibers were treated with both drugs for 15 min. H9c2 cells exposed to sorafenib for 24 h showed a higher membrane toxicity and ATP depletion in the presence of galactose (favoring mitochondrial metabolism) compared to glucose (favoring glycolysis) but not when exposed to imatinib. Both TKIs resulted in a higher dissipation of the mitochondrial membrane potential in galactose compared to glucose media. Imatinib inhibited Complex I (CI)- and CIII- linked respiration under both conditions. Sorafenib impaired CI-, CII-, and CIII-linked respiration in H9c2 cells cultured with glucose, whereas it inhibited all ETS complexes with galactose. In permeabilized rat cardiac myofibers, acute exposure to imatinib and sorafenib decreased CI- and CIV-linked respiration in the presence of the drugs. Electron microscopy showed enlarged mitochondria with disorganized cristae. In addition, both TKIs caused mitochondrial superoxide accumulation and decreased the cellular GSH pool. Both TKIs induced caspase 3/7 activation, suggesting apoptosis as a mechanism of cell death. Imatinib and sorafenib impaired the function of cardiac mitochondria in isolated rat cardiac fibers and in H9c2 cells at plasma concentrations reached in humans. Both imatinib and sorafenib impaired the function of enzyme complexes of the ETS, which was associated with mitochondrial ROS accumulation and cell death by apoptosis. Full article

(This article belongs to the Special Issue Mitochondrial Transport and Energy Metabolism in Health and Diseases)

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17 pages, 4120 KiB

Open AccessArticle

Teriflunomide Preserves Neuronal Activity and Protects Mitochondria in Brain Slices Exposed to Oxidative Stress

by Bimala Malla, Agustin Liotta, Helena Bros, Rebecca Ulshöfer, Friedemann Paul, Anja E. Hauser, Raluca Niesner and Carmen Infante-Duarte

Int. J. Mol. Sci. 2022, 23(3), 1538; https://doi.org/10.3390/ijms23031538 - 28 Jan 2022

Cited by 9 | Viewed by 2840

Abstract

Teriflunomide (TFN) limits relapses in relapsing–remitting multiple sclerosis (RRMS) by reducing lymphocytic proliferation through the inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) and the subsequent modulation of de novo pyrimidine synthesis. Alterations of mitochondrial function as a consequence of oxidative stress have been reported during neuroinflammation. Previously, we showed that TFN prevents alterations of mitochondrial motility caused by oxidative stress in peripheral axons. Here, we aimed to validate TFN effects on mitochondria and neuronal activity in hippocampal brain slices, in which cellular distribution and synaptic circuits are largely preserved. TFN effects on metabolism and neuronal activity were investigated by assessing oxygen partial pressure and local field potential in acute slices. Additionally, we imaged mitochondria in brain slices from the transgenic Thy1-CFP/COX8A)S2Lich/J (mitoCFP) mice using two-photon microscopy. Although TFN could not prevent oxidative stress-related depletion of ATP, it preserved oxygen consumption and neuronal activity in CNS tissue during oxidative stress. Furthermore, TFN prevented mitochondrial shortening and fragmentation of puncta-shaped and network mitochondria during oxidative stress. Regarding motility, TFN accentuated the decrease in mitochondrial displacement and increase in speed observed during oxidative stress. Importantly, these effects were not associated with neuronal viability and did not lead to axonal damage. In conclusion, during conditions of oxidative stress, TFN preserves the functionality of neurons and prevents morphological and motility alterations of mitochondria. Full article

(This article belongs to the Special Issue Mitochondrial Transport and Energy Metabolism in Health and Diseases)

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Review

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22 pages, 5226 KiB

Open AccessReview

Mitochondrial Processing Peptidases—Structure, Function and the Role in Human Diseases

by Nina Kunová, Henrieta Havalová, Gabriela Ondrovičová, Barbora Stojkovičová, Jacob A. Bauer, Vladena Bauerová-Hlinková, Vladimir Pevala and Eva Kutejová

Int. J. Mol. Sci. 2022, 23(3), 1297; https://doi.org/10.3390/ijms23031297 - 24 Jan 2022

Cited by 12 | Viewed by 4487

Abstract

Mitochondrial proteins are encoded by both nuclear and mitochondrial DNA. While some of the essential subunits of the oxidative phosphorylation (OXPHOS) complexes responsible for cellular ATP production are synthesized directly in the mitochondria, most mitochondrial proteins are first translated in the cytosol and then imported into the organelle using a sophisticated transport system. These proteins are directed mainly by targeting presequences at their N-termini. These presequences need to be cleaved to allow the proper folding and assembly of the pre-proteins into functional protein complexes. In the mitochondria, the presequences are removed by several processing peptidases, including the mitochondrial processing peptidase (MPP), the inner membrane processing peptidase (IMP), the inter-membrane processing peptidase (MIP), and the mitochondrial rhomboid protease (Pcp1/PARL). Their proper functioning is essential for mitochondrial homeostasis as the disruption of any of them is lethal in yeast and severely impacts the lifespan and survival in humans. In this review, we focus on characterizing the structure, function, and substrate specificities of mitochondrial processing peptidases, as well as the connection of their malfunctions to severe human diseases. Full article

(This article belongs to the Special Issue Mitochondrial Transport and Energy Metabolism in Health and Diseases)

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35 pages, 4377 KiB

Open AccessReview

Mitochondrial Transport in Glycolysis and Gluconeogenesis: Achievements and Perspectives

by Salvatore Passarella, Avital Schurr and Piero Portincasa

Int. J. Mol. Sci. 2021, 22(23), 12620; https://doi.org/10.3390/ijms222312620 - 23 Nov 2021

Cited by 18 | Viewed by 3843

Abstract

Some metabolic pathways involve two different cell components, for instance, cytosol and mitochondria, with metabolites traffic occurring from cytosol to mitochondria and vice versa, as seen in both glycolysis and gluconeogenesis. However, the knowledge on the role of mitochondrial transport within these two glucose metabolic pathways remains poorly understood, due to controversial information available in published literature. In what follows, we discuss achievements, knowledge gaps, and perspectives on the role of mitochondrial transport in glycolysis and gluconeogenesis. We firstly describe the experimental approaches for quick and easy investigation of mitochondrial transport, with respect to cell metabolic diversity. In addition, we depict the mitochondrial shuttles by which NADH formed in glycolysis is oxidized, the mitochondrial transport of phosphoenolpyruvate in the light of the occurrence of the mitochondrial pyruvate kinase, and the mitochondrial transport and metabolism of L-lactate due to the L-lactate translocators and to the mitochondrial L-lactate dehydrogenase located in the inner mitochondrial compartment. Full article

(This article belongs to the Special Issue Mitochondrial Transport and Energy Metabolism in Health and Diseases)

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17 pages, 971 KiB

Open AccessReview

Mitochondrial Metal Ion Transport in Cell Metabolism and Disease

by Xuan Wang, Peng An, Zhenglong Gu, Yongting Luo and Junjie Luo

Int. J. Mol. Sci. 2021, 22(14), 7525; https://doi.org/10.3390/ijms22147525 - 14 Jul 2021

Cited by 29 | Viewed by 4485

Abstract

Mitochondria are vital to life and provide biological energy for other organelles and cell physiological processes. On the mitochondrial double layer membrane, there are a variety of channels and transporters to transport different metal ions, such as Ca²⁺, K⁺, Na⁺, Mg²⁺, Zn²⁺ and Fe²⁺/Fe³⁺. Emerging evidence in recent years has shown that the metal ion transport is essential for mitochondrial function and cellular metabolism, including oxidative phosphorylation (OXPHOS), ATP production, mitochondrial integrity, mitochondrial volume, enzyme activity, signal transduction, proliferation and apoptosis. The homeostasis of mitochondrial metal ions plays an important role in maintaining mitochondria and cell functions and regulating multiple diseases. In particular, channels and transporters for transporting mitochondrial metal ions are very critical, which can be used as potential targets to treat neurodegeneration, cardiovascular diseases, cancer, diabetes and other metabolic diseases. This review summarizes the current research on several types of mitochondrial metal ion channels/transporters and their functions in cell metabolism and diseases, providing strong evidence and therapeutic strategies for further insights into related diseases. Full article

(This article belongs to the Special Issue Mitochondrial Transport and Energy Metabolism in Health and Diseases)

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46 pages, 3815 KiB

Open AccessReview

Nonalcoholic Fatty Liver Disease (NAFLD). Mitochondria as Players and Targets of Therapies?

by Agostino Di Ciaula, Salvatore Passarella, Harshitha Shanmugam, Marica Noviello, Leonilde Bonfrate, David Q.-H. Wang and Piero Portincasa

Int. J. Mol. Sci. 2021, 22(10), 5375; https://doi.org/10.3390/ijms22105375 - 20 May 2021

Cited by 64 | Viewed by 5955

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and represents the hepatic expression of several metabolic abnormalities of high epidemiologic relevance. Fat accumulation in the hepatocytes results in cellular fragility and risk of progression toward necroinflammation, i.e., nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Several pathways contribute to fat accumulation and damage in the liver and can also involve the mitochondria, whose functional integrity is essential to maintain liver bioenergetics. In NAFLD/NASH, both structural and functional mitochondrial abnormalities occur and can involve mitochondrial electron transport chain, decreased mitochondrial β-oxidation of free fatty acids, excessive generation of reactive oxygen species, and lipid peroxidation. NASH is a major target of therapy, but there is no established single or combined treatment so far. Notably, translational and clinical studies point to mitochondria as future therapeutic targets in NAFLD since the prevention of mitochondrial damage could improve liver bioenergetics. Full article

(This article belongs to the Special Issue Mitochondrial Transport and Energy Metabolism in Health and Diseases)

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