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Compounds Modulating Mitochondrial Ion Channels
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Compounds Modulating Mitochondrial Ion Channels

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Cross-Field Chemistry".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 18787

Special Issue Editors

Prof. Dr. Adam Szewczyk

E-Mail Website
Guest Editor
Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland
Interests: bioenergetics; membrane proteins; ion channels; intracellular ion channels; mitochondria; mitochondrial ion channels; potassium channels; membrane transport; channel pharmacology
Dr. Bogusz Kulawiak

E-Mail Website
Guest Editor
Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland
Interests: mitochondria; potassium channels; mitochondrial membrane transport proteins; bioenergetics; respiratory chain; mitochondrial cytoprotection

Special Issue Information

Dear Colleagues,

This Special Issue will provide a critical overview of compounds modulating mitochondrial channels. In this Special Issue, the pharmacological properties of mitochondrial channels and their modulation by channel inhibitors and channel activators will be described. Recently, in mitochondrial membranes, a variety of channel proteins have been described. On top of the well-characterized porin channel in the outer mitochondrial membrane, a plethora of channel proteins were identified in the inner mitochondrial membranes. These include both anion-selective channels and cation-selective channels. The latter group is represented by calcium channels and potassium channels such as ATP, voltage-regulated, or calcium-activated potassium channels. The recent understanding of the molecular identity of mitochondrial permeability transition pore also leads to a new pharmacology of this protein. The main part of this Special Issue will describe the basic characteristics of each channel type mentioned above and its interaction with various molecules. Available channel modulators will be critically evaluated and rated by suitability for research and medical usage. Information on the potential side effects of these substances will be reported. Mitochondrial channel modulators will also be described in the physiological context of cytoprotection or cancer cell death. Thus, this Special Issue can be very useful for beginners in the field of mitochondrial channels.

Prof. Dr. Adam Szewczyk
Dr. Bogusz Kulawiak
Guest Editors

Manuscript Submission Information

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Keywords

  • Mitochondria
  • Channels
  • Transport
  • Porin
  • Permeability transition pore
  • Calcium
  • Potassium
  • Chloride
  • Cytoprotection
  • Cancer
  • Ros
  • Potassium channel openers

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Published Papers (5 papers)

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Research

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18 pages, 5524 KiB  
Article
Identification of the Large-Conductance Ca2+-Regulated Potassium Channel in Mitochondria of Human Bronchial Epithelial Cells
by Aleksandra Sek, Rafal P. Kampa, Bogusz Kulawiak, Adam Szewczyk and Piotr Bednarczyk
Molecules 2021, 26(11), 3233; https://doi.org/10.3390/molecules26113233 - 27 May 2021
Cited by 16 | Viewed by 3181
Abstract
Mitochondria play a key role in energy metabolism within the cell. Potassium channels such as ATP-sensitive, voltage-gated or large-conductance Ca2+-regulated channels have been described in the inner mitochondrial membrane. Several hypotheses have been proposed to describe the important roles of mitochondrial [...] Read more.
Mitochondria play a key role in energy metabolism within the cell. Potassium channels such as ATP-sensitive, voltage-gated or large-conductance Ca2+-regulated channels have been described in the inner mitochondrial membrane. Several hypotheses have been proposed to describe the important roles of mitochondrial potassium channels in cell survival and death pathways. In the current study, we identified two populations of mitochondrial large-conductance Ca2+-regulated potassium (mitoBKCa) channels in human bronchial epithelial (HBE) cells. The biophysical properties of the channels were characterized using the patch-clamp technique. We observed the activity of the channel with a mean conductance close to 285 pS in symmetric 150/150 mM KCl solution. Channel activity was increased upon application of the potassium channel opener NS11021 in the micromolar concentration range. The channel activity was completely inhibited by 1 µM paxilline and 300 nM iberiotoxin, selective inhibitors of the BKCa channels. Based on calcium and iberiotoxin modulation, we suggest that the C-terminus of the protein is localized to the mitochondrial matrix. Additionally, using RT-PCR, we confirmed the presence of α pore-forming (Slo1) and auxiliary β3-β4 subunits of BKCa channel in HBE cells. Western blot analysis of cellular fractions confirmed the mitochondrial localization of α pore-forming and predominately β3 subunits. Additionally, the regulation of oxygen consumption and membrane potential of human bronchial epithelial mitochondria in the presence of the potassium channel opener NS11021 and inhibitor paxilline were also studied. In summary, for the first time, the electrophysiological and functional properties of the mitoBKCa channel in a bronchial epithelial cell line were described. Full article
(This article belongs to the Special Issue Compounds Modulating Mitochondrial Ion Channels)
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Review

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34 pages, 1214 KiB  
Review
Alternative Targets for Modulators of Mitochondrial Potassium Channels
by Antoni Wrzosek, Shur Gałecka, Monika Żochowska, Anna Olszewska and Bogusz Kulawiak
Molecules 2022, 27(1), 299; https://doi.org/10.3390/molecules27010299 - 4 Jan 2022
Cited by 10 | Viewed by 3884
Abstract
Mitochondrial potassium channels control potassium influx into the mitochondrial matrix and thus regulate mitochondrial membrane potential, volume, respiration, and synthesis of reactive oxygen species (ROS). It has been found that pharmacological activation of mitochondrial potassium channels during ischemia/reperfusion (I/R) injury activates cytoprotective mechanisms [...] Read more.
Mitochondrial potassium channels control potassium influx into the mitochondrial matrix and thus regulate mitochondrial membrane potential, volume, respiration, and synthesis of reactive oxygen species (ROS). It has been found that pharmacological activation of mitochondrial potassium channels during ischemia/reperfusion (I/R) injury activates cytoprotective mechanisms resulting in increased cell survival. In cancer cells, the inhibition of these channels leads to increased cell death. Therefore, mitochondrial potassium channels are intriguing targets for the development of new pharmacological strategies. In most cases, however, the substances that modulate the mitochondrial potassium channels have a few alternative targets in the cell. This may result in unexpected or unwanted effects induced by these compounds. In our review, we briefly present the various classes of mitochondrial potassium (mitoK) channels and describe the chemical compounds that modulate their activity. We also describe examples of the multidirectional activity of the activators and inhibitors of mitochondrial potassium channels. Full article
(This article belongs to the Special Issue Compounds Modulating Mitochondrial Ion Channels)
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22 pages, 1083 KiB  
Review
Modulation and Pharmacology of the Mitochondrial Permeability Transition: A Journey from F-ATP Synthase to ANT
by Andrea Carrer, Claudio Laquatra, Ludovica Tommasin and Michela Carraro
Molecules 2021, 26(21), 6463; https://doi.org/10.3390/molecules26216463 - 26 Oct 2021
Cited by 8 | Viewed by 3181
Abstract
The permeability transition (PT) is an increased permeation of the inner mitochondrial membrane due to the opening of the PT pore (PTP), a Ca2+-activated high conductance channel involved in Ca2+ homeostasis and cell death. Alterations of the PTP have been [...] Read more.
The permeability transition (PT) is an increased permeation of the inner mitochondrial membrane due to the opening of the PT pore (PTP), a Ca2+-activated high conductance channel involved in Ca2+ homeostasis and cell death. Alterations of the PTP have been associated with many pathological conditions and its targeting represents an incessant challenge in the field. Although the modulation of the PTP has been extensively explored, the lack of a clear picture of its molecular nature increases the degree of complexity for any target-based approach. Recent advances suggest the existence of at least two mitochondrial permeability pathways mediated by the F-ATP synthase and the ANT, although the exact molecular mechanism leading to channel formation remains elusive for both. A full comprehension of this to-pore conversion will help to assist in drug design and to develop pharmacological treatments for a fine-tuned PT regulation. Here, we will focus on regulatory mechanisms that impinge on the PTP and discuss the relevant literature of PTP targeting compounds with particular attention to F-ATP synthase and ANT. Full article
(This article belongs to the Special Issue Compounds Modulating Mitochondrial Ion Channels)
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17 pages, 749 KiB  
Review
The Diversity of the Mitochondrial Outer Membrane Protein Import Channels: Emerging Targets for Modulation
by Monika Mazur, Hanna Kmita and Małgorzata Wojtkowska
Molecules 2021, 26(13), 4087; https://doi.org/10.3390/molecules26134087 - 4 Jul 2021
Cited by 7 | Viewed by 3988
Abstract
The functioning of mitochondria and their biogenesis are largely based on the proper function of the mitochondrial outer membrane channels, which selectively recognise and import proteins but also transport a wide range of other molecules, including metabolites, inorganic ions and nucleic acids. To [...] Read more.
The functioning of mitochondria and their biogenesis are largely based on the proper function of the mitochondrial outer membrane channels, which selectively recognise and import proteins but also transport a wide range of other molecules, including metabolites, inorganic ions and nucleic acids. To date, nine channels have been identified in the mitochondrial outer membrane of which at least half represent the mitochondrial protein import apparatus. When compared to the mitochondrial inner membrane, the presented channels are mostly constitutively open and consequently may participate in transport of different molecules and contribute to relevant changes in the outer membrane permeability based on the channel conductance. In this review, we focus on the channel structure, properties and transported molecules as well as aspects important to their modulation. This information could be used for future studies of the cellular processes mediated by these channels, mitochondrial functioning and therapies for mitochondria-linked diseases. Full article
(This article belongs to the Special Issue Compounds Modulating Mitochondrial Ion Channels)
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11 pages, 578 KiB  
Review
Mitochondrial K+ Transport: Modulation and Functional Consequences
by Osvaldo Pereira, Jr. and Alicia J. Kowaltowski
Molecules 2021, 26(10), 2935; https://doi.org/10.3390/molecules26102935 - 14 May 2021
Cited by 18 | Viewed by 3615
Abstract
The existence of a K+ cycle in mitochondria has been predicted since the development of the chemiosmotic theory and has been shown to be crucial for several cellular phenomena, including regulation of mitochondrial volume and redox state. One of the pathways known [...] Read more.
The existence of a K+ cycle in mitochondria has been predicted since the development of the chemiosmotic theory and has been shown to be crucial for several cellular phenomena, including regulation of mitochondrial volume and redox state. One of the pathways known to participate in K+ cycling is the ATP-sensitive K+ channel, MitoKATP. This channel was vastly studied for promoting protection against ischemia reperfusion when pharmacologically activated, although its molecular identity remained unknown for decades. The recent molecular characterization of MitoKATP has opened new possibilities for modulation of this channel as a mechanism to control cellular processes. Here, we discuss different strategies to control MitoKATP activity and consider how these could be used as tools to regulate metabolism and cellular events. Full article
(This article belongs to the Special Issue Compounds Modulating Mitochondrial Ion Channels)
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