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Mitochondrial Ion Channels and Exchangers in Cellular Pathophysiology
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Mitochondrial Ion Channels and Exchangers in Cellular Pathophysiology

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 (10 February 2023) | Viewed by 10692

Special Issue Editors

Prof. Dr. Konstantin Belosludtsev

E-Mail Website
Guest Editor
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia
Interests: mitochondria; biophysics; diabetes mellitus; myopathy; mitochondrial Ca2+ transport; permeability transition pore; oxidative stress; reactive oxygen species; lipids; membrane proteins; liposomes
Special Issues, Collections and Topics in MDPI journals
Dr. Alexey G. Kruglov

E-Mail Website
Guest Editor
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia
Interests: mitochondria; permeability transition pore; reactive oxygen species; NAD; NADP; dehydrogenase; channel; method

Special Issue Information

Dear Colleagues,

Mitochondria are the major organelles responsible for the orchestration of energy production, metabolism, signaling pathways, and many other processes central to cellular function and dysfunction, including programmed cell death. One of the key roles of mitochondria is the steady-state maintenance of cellular ion homeostasis. Dysregulation and defects in the mitochondrial ion channels, exchangers, and the pore-forming membrane proteins may underlie a number of cellular pathologies. The Special Issue focuses on new insights into the role of mitochondrial ion transport systems: channels, exchangers, and permeability transition in cellular physiology and pathogenesis of various diseases, such as cardiovascular, endocrine, neuromuscular disorders, etc. Contributions will include, but not be limited to, papers dealing with the mitochondrial calcium uniporter complex, permeability transition pore, voltage-dependent anion channels, potassium channels, sodium–calcium exchanger, etc. Articles aimed at the search for novel modulators of ion channels and exchangers of the outer and inner mitochondrial membranes with an eye to possible pharmacological exploitation will be welcomed.

Prof. Dr. Konstantin Belosludtsev
Dr. Alexey G. Kruglov
Guest Editors

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

  • mitochondria
  • ion channels
  • Ca2+ uniporter
  • VDAC
  • permeability transition pore
  • ATP-dependent potassium channel
  • BKCa channel
  • NCLX
  • Letm1

Published Papers (5 papers)

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Research

7 pages, 1029 KiB  
Communication
Usnic Acid-Mediated Exchange of Protons for Divalent Metal Cations across Lipid Membranes: Relevance to Mitochondrial Uncoupling
by Tatyana I. Rokitskaya, Alexander M. Arutyunyan, Ljudmila S. Khailova, Alisa D. Kataeva, Alexander M. Firsov, Elena A. Kotova and Yuri N. Antonenko
Int. J. Mol. Sci. 2022, 23(24), 16203; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232416203 - 19 Dec 2022
Viewed by 1323
Abstract
Usnic acid (UA), a unique lichen metabolite, is a protonophoric uncoupler of oxidative phosphorylation, widely known as a weight-loss dietary supplement. In contrast to conventional proton-shuttling mitochondrial uncouplers, UA was found to carry protons across lipid membranes via the induction of an electrogenic [...] Read more.
Usnic acid (UA), a unique lichen metabolite, is a protonophoric uncoupler of oxidative phosphorylation, widely known as a weight-loss dietary supplement. In contrast to conventional proton-shuttling mitochondrial uncouplers, UA was found to carry protons across lipid membranes via the induction of an electrogenic proton exchange for calcium or magnesium cations. Here, we evaluated the ability of various divalent metal cations to stimulate a proton transport through both planar and vesicular bilayer lipid membranes by measuring the transmembrane electrical current and fluorescence-detected pH gradient dissipation in pyranine-loaded liposomes, respectively. Thus, we obtained the following selectivity series of calcium, magnesium, zinc, manganese and copper cations: Zn2+ > Mn2+ > Mg2+ > Ca2+ >> Cu2+. Remarkably, Cu2+ appeared to suppress the UA-mediated proton transport in both lipid membrane systems. The data on the divalent metal cation/proton exchange were supported by circular dichroism spectroscopy of UA in the presence of the corresponding cations. Full article
(This article belongs to the Special Issue Mitochondrial Ion Channels and Exchangers in Cellular Pathophysiology)
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16 pages, 3541 KiB  
Article
The Effect of Uridine on the State of Skeletal Muscles and the Functioning of Mitochondria in Duchenne Dystrophy
by Mikhail V. Dubinin, Vlada S. Starinets, Natalia V. Belosludtseva, Irina B. Mikheeva, Yuliya A. Chelyadnikova, Daria K. Penkina, Alexander A. Vedernikov and Konstantin N. Belosludtsev
Int. J. Mol. Sci. 2022, 23(18), 10660; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810660 - 13 Sep 2022
Cited by 12 | Viewed by 2069
Abstract
Duchenne muscular dystrophy is caused by the loss of functional dystrophin that secondarily causes systemic metabolic impairment in skeletal muscles and cardiomyocytes. The nutraceutical approach is considered as a possible complementary therapy for this pathology. In this work, we have studied the effect [...] Read more.
Duchenne muscular dystrophy is caused by the loss of functional dystrophin that secondarily causes systemic metabolic impairment in skeletal muscles and cardiomyocytes. The nutraceutical approach is considered as a possible complementary therapy for this pathology. In this work, we have studied the effect of pyrimidine nucleoside uridine (30 mg/kg/day for 28 days, i.p.), which plays an important role in cellular metabolism, on the development of DMD in the skeletal muscles of dystrophin deficient mdx mice, as well as its effect on the mitochondrial dysfunction that accompanies this pathology. We found that chronic uridine administration reduced fibrosis in the skeletal muscles of mdx mice, but it had no effect on the intensity of degeneration/regeneration cycles and inflammation, pseudohypetrophy, and muscle strength of the animals. Analysis of TEM micrographs showed that uridine also had no effect on the impaired mitochondrial ultrastructure of mdx mouse skeletal muscle. The administration of uridine was found to lead to an increase in the expression of the Drp1 and Parkin genes, which may indicate an increase in the intensity of organelle fission and the normalization of mitophagy. Uridine had little effect on OXPHOS dysfunction in mdx mouse mitochondria, and moreover, it was suppressed in the mitochondria of wild type animals. At the same time, uridine restored the transport of potassium ions and reduced the production of reactive oxygen species; however, this had no effect on the impaired calcium retention capacity of mdx mouse mitochondria. The obtained results demonstrate that the used dose of uridine only partially prevents mitochondrial dysfunction in skeletal muscles during Duchenne dystrophy, though it mitigates the development of destructive processes in skeletal muscles. Full article
(This article belongs to the Special Issue Mitochondrial Ion Channels and Exchangers in Cellular Pathophysiology)
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8 pages, 1050 KiB  
Communication
Formation of High-Conductive C Subunit Channels upon Interaction with Cyclophilin D
by Giuseppe Federico Amodeo, Natalya Krilyuk and Evgeny V. Pavlov
Int. J. Mol. Sci. 2021, 22(20), 11022; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011022 - 13 Oct 2021
Cited by 5 | Viewed by 1484
Abstract
The c subunit of the ATP synthase is an inner mitochondrial membrane (IMM) protein. Besides its role as the main component of the rotor of the ATP synthase, c subunit from mammalian mitochondria exhibits ion channel activity. In particular, c subunit may be [...] Read more.
The c subunit of the ATP synthase is an inner mitochondrial membrane (IMM) protein. Besides its role as the main component of the rotor of the ATP synthase, c subunit from mammalian mitochondria exhibits ion channel activity. In particular, c subunit may be involved in one of the pathways leading to the formation of the permeability transition pore (PTP) during mitochondrial permeability transition (PT), a phenomenon consisting of the permeabilization of the IMM due to high levels of calcium. Our previous study on the synthetic c subunit showed that high concentrations of calcium induce misfolding into cross-β oligomers that form low-conductance channels in model lipid bilayers of about 400 pS. Here, we studied the effect of cyclophilin D (CypD), a mitochondrial chaperone and major regulator of PTP, on the electrophysiological activity of the c subunit to evaluate its role in the functional properties of c subunit. Our study shows that in presence of CypD, c subunit exhibits a larger conductance, up to 4 nS, that could be related to its potential role in mitochondrial toxicity. Further, our results suggest that CypD is necessary for the formation of c subunit induced PTP but may not be an integral part of the pore. Full article
(This article belongs to the Special Issue Mitochondrial Ion Channels and Exchangers in Cellular Pathophysiology)
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13 pages, 22743 KiB  
Article
Identification of Phosphorylated Calpain 3 in Rat Brain Mitochondria under mPTP Opening
by Yulia Baburuna, Linda Sotnikova and Olga Krestinina
Int. J. Mol. Sci. 2021, 22(19), 10613; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910613 - 30 Sep 2021
Cited by 2 | Viewed by 1542
Abstract
The protein phosphorylation of the membrane-bound mitochondrial proteins has become of interest from the point of view of its regulatory role of the function of the respiratory chain, opening of the mitochondrial permeability transition pore (mPTP), and initiation of apoptosis. Earlier, we noticed [...] Read more.
The protein phosphorylation of the membrane-bound mitochondrial proteins has become of interest from the point of view of its regulatory role of the function of the respiratory chain, opening of the mitochondrial permeability transition pore (mPTP), and initiation of apoptosis. Earlier, we noticed that upon phosphorylation of proteins in some proteins, the degree of their phosphorylation increases with the opening of mPTP. Two isoforms of myelin basic protein and cyclic nucleotide phosphodiesterase were identified in rat brain non-synaptic mitochondria and it was concluded that they are involved in mPTP regulation. In the present study, using the mass spectrometry method, the phosphorylated protein was identified as Calpain 3 in rat brain non-synaptic mitochondria. In the present study, the phosphoprotein Calpain-3 (p94) (CAPN3) was identified in the rat brain mitochondria as a phosphorylated truncated form of p60–62 kDa by two-dimensional electrophoresis and mass spectrometry. We showed that the calpain inhibitor, calpeptin, was able to suppress the Ca2+ efflux from mitochondria, preventing the opening of mPTP. It was found that phosphorylated truncated CALP3 with a molecular weight of 60–62 contains p-Tyr, which indicates the possible involvement of protein tyrosine phosphatase in this process. Full article
(This article belongs to the Special Issue Mitochondrial Ion Channels and Exchangers in Cellular Pathophysiology)
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15 pages, 3669 KiB  
Article
Alisporivir Treatment Alleviates Mitochondrial Dysfunction in the Skeletal Muscles of C57BL/6NCrl Mice with High-Fat Diet/Streptozotocin-Induced Diabetes Mellitus
by Konstantin N. Belosludtsev, Vlada S. Starinets, Eugeny Yu. Talanov, Irina B. Mikheeva, Mikhail V. Dubinin and Natalia V. Belosludtseva
Int. J. Mol. Sci. 2021, 22(17), 9524; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179524 - 02 Sep 2021
Cited by 11 | Viewed by 3063
Abstract
Diabetes mellitus is a systemic metabolic disorder associated with mitochondrial dysfunction, with mitochondrial permeability transition (MPT) pore opening being recognized as one of its pathogenic mechanisms. Alisporivir has been recently identified as a non-immunosuppressive analogue of the MPT pore blocker cyclosporin A and [...] Read more.
Diabetes mellitus is a systemic metabolic disorder associated with mitochondrial dysfunction, with mitochondrial permeability transition (MPT) pore opening being recognized as one of its pathogenic mechanisms. Alisporivir has been recently identified as a non-immunosuppressive analogue of the MPT pore blocker cyclosporin A and has broad therapeutic potential. The purpose of the present work was to study the effect of alisporivir (2.5 mg/kg/day i.p.) on the ultrastructure and functions of the skeletal muscle mitochondria of mice with diabetes mellitus induced by a high-fat diet combined with streptozotocin injections. The glucose tolerance tests indicated that alisporivir increased the rate of glucose utilization in diabetic mice. An electron microscopy analysis showed that alisporivir prevented diabetes-induced changes in the ultrastructure and content of the mitochondria in myocytes. In diabetes, the ADP-stimulated respiration, respiratory control, and ADP/O ratios and the level of ATP synthase in the mitochondria decreased, whereas alisporivir treatment restored these indicators. Alisporivir eliminated diabetes-induced increases in mitochondrial lipid peroxidation products. Diabetic mice showed decreased mRNA levels of Atp5f1a, Ant1, and Ppif and increased levels of Ant2 in the skeletal muscles. The skeletal muscle mitochondria of diabetic animals were sensitized to the MPT pore opening. Alisporivir normalized the expression level of Ant2 and mitochondrial susceptibility to the MPT pore opening. In parallel, the levels of Mfn2 and Drp1 also returned to control values, suggesting a normalization of mitochondrial dynamics. These findings suggest that the targeting of the MPT pore opening by alisporivir is a therapeutic approach to prevent the development of mitochondrial dysfunction and associated oxidative stress in the skeletal muscles in diabetes. Full article
(This article belongs to the Special Issue Mitochondrial Ion Channels and Exchangers in Cellular Pathophysiology)
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