bims-mionch 2024-04-28 papers

bims-mionch

Biomed News

on Mitochondrial ion channels

Issue of 2024–04–28
fiveteen papers selected by
Gun Kim, Seoul National University

Mitochondrial sites of contact with the nucleus.
Protein insertion into the inner membrane of mitochondria: routes and mechanisms.
Redox Regulation of Mitochondrial Potassium Channels Activity.
Mitochondrial Kinase Signaling for Cardioprotection.
Mitochondrial fractions located in the cytoplasmic and peridroplet areas of white adipocytes have distinct roles.
The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: from molecular mechanisms to therapeutic insights.
Organ-Specific Mitochondrial Alterations Following Ischemia-Reperfusion Injury in Post-Cardiac Arrest Syndrome: A Comprehensive Review.
Mitochondrial Physiology of Cellular Redox Regulations.
Mitochondrial Dysfunction as the Major Basis of Brain Aging.
Molecular mechanisms of mitochondria-mediated ferroptosis: a potential target for antimalarial interventions.
Development and therapeutic implications of small molecular inhibitors that target calcium ion-related channels in tumor treatment.
Voltage Gated Ion Channels: Structure, Pharmacology and Photopharmacology.
Primary mitochondrial diseases: The intertwined pathophysiology of bioenergetic dysregulation, oxidative stress and neuroinflammation.
Important molecular mechanisms in ferroptosis.
Progress in Understanding Oxidative Stress, Aging, and Aging-Related Diseases.

J Cell Biol. 2024 Jun 03. pii: e202305010. [Epub ahead of print]223(6):

Mitochondrial sites of contact with the nucleus.

Michelangelo Campanella, Brindha Kannan.

Membrane contact sites (MCS) between mitochondria and the nucleus have been recently described. Termed nucleus associated mitochondria (NAM), they prime the expression of genes required for cellular resistance to stressors, thus offering a tethering mechanism for homeostatic communication. Here, we discuss the composition of NAM and their physiological and pathological significance.

DOI: https://doi.org/10.1083/jcb.202305010
FEBS Open Bio. 2024 Apr 25.

Protein insertion into the inner membrane of mitochondria: routes and mechanisms.

Büsra Kizmaz, Annika Nutz, Annika Egeler, Johannes M Herrmann.

  The inner membrane of mitochondria contains hundreds of different integral membrane proteins. These proteins transport molecules into and out of the matrix, they carry out multifold catalytic reactions and they promote the biogenesis or degradation of mitochondrial constituents. Most inner membrane proteins are encoded by nuclear genes and synthesized in the cytosol from where they are imported into mitochondria by translocases in the outer and inner membrane. Three different import routes direct proteins into the inner membrane and allow them to acquire their appropriate membrane topology. First, mitochondrial import intermediates can be arrested at the level of the TIM23 inner membrane translocase by a stop-transfer sequence to reach the inner membrane by lateral insertion. Second, proteins can be fully translocated through the TIM23 complex into the matrix from where they insert into the inner membrane in an export-like reaction. Carriers and other polytopic membrane proteins embark on a third insertion pathway: these hydrophobic proteins employ the specialized TIM22 translocase to insert from the intermembrane space (IMS) into the inner membrane. This review article describes these three targeting routes and provides an overview of the machinery that promotes the topogenesis of mitochondrial inner membrane proteins.

Keywords:  TIM22 complex; TIM23 complex; carrier proteins; membrane proteins; mitochondria; protein import

DOI:  https://doi.org/10.1002/2211-5463.13806
Antioxidants (Basel). 2024 Apr 03. pii: 434. [Epub ahead of print]13(4):

Redox Regulation of Mitochondrial Potassium Channels Activity.

Joanna Lewandowska, Barbara Kalenik, Antoni Wrzosek, Adam Szewczyk.

  Redox reactions exert a profound influence on numerous cellular functions with mitochondria playing a central role in orchestrating these processes. This pivotal involvement arises from three primary factors: (1) the synthesis of reactive oxygen species (ROS) by mitochondria, (2) the presence of a substantial array of redox enzymes such as respiratory chain, and (3) the responsiveness of mitochondria to the cellular redox state. Within the inner mitochondrial membrane, a group of potassium channels, including ATP-regulated, large conductance calcium-activated, and voltage-regulated channels, is present. These channels play a crucial role in conditions such as cytoprotection, ischemia/reperfusion injury, and inflammation. Notably, the activity of mitochondrial potassium channels is intricately governed by redox reactions. Furthermore, the regulatory influence extends to other proteins, such as kinases, which undergo redox modifications. This review aims to offer a comprehensive exploration of the modulation of mitochondrial potassium channels through diverse redox reactions with a specific focus on the involvement of ROS.

Keywords:  ROS; calcium; ischemia/reperfusion injury; mitochondria; mitochondrial potassium channel; potassium; reactive oxygen species; redox

DOI:  https://doi.org/10.3390/antiox13040434
Int J Mol Sci. 2024 Apr 19. pii: 4491. [Epub ahead of print]25(8):

Mitochondrial Kinase Signaling for Cardioprotection.

Kerstin Boengler, Chantal Eickelmann, Petra Kleinbongard.

  Myocardial ischemia/reperfusion injury is reduced by cardioprotective adaptations such as local or remote ischemic conditioning. The cardioprotective stimuli activate signaling cascades, which converge on mitochondria and maintain the function of the organelles, which is critical for cell survival. The signaling cascades include not only extracellular molecules that activate sarcolemmal receptor-dependent or -independent protein kinases that signal at the plasma membrane or in the cytosol, but also involve kinases, which are located to or within mitochondria, phosphorylate mitochondrial target proteins, and thereby modify, e.g., respiration, the generation of reactive oxygen species, calcium handling, mitochondrial dynamics, mitophagy, or apoptosis. In the present review, we give a personal and opinionated overview of selected protein kinases, localized to/within myocardial mitochondria, and summarize the available data on their role in myocardial ischemia/reperfusion injury and protection from it. We highlight the regulation of mitochondrial function by these mitochondrial protein kinases.

Keywords:  cardioprotection; ischemia; mitochondria; preconditioning; protein kinase; reperfusion

DOI:  https://doi.org/10.3390/ijms25084491
FEBS Lett. 2024 Apr 24.

Mitochondrial fractions located in the cytoplasmic and peridroplet areas of white adipocytes have distinct roles.

Masayuki Fuwa, Kazuo Kajita, Ichiro Mori, Motochika Asano, Toshiko Kajita, Takao Senda, Takeshi Inagaki, Hiroyuki Morita.

  The role of mitochondria in white adipocytes (WAs) has not been fully explored. A recent study revealed that brown adipocytes contain functionally distinct mitochondrial fractions, cytoplasmic mitochondria, and peridroplet mitochondria. However, it is not known whether such a functional division of mitochondria exists in WA. Herein, we observed that mitochondria could be imaged and mitochondrial DNA and protein detected in pellets obtained from the cytoplasmic layer and oil layer of WAs after centrifugation. The mitochondria in each fraction were designated as cytoplasmic mitochondria (CMw) and peridroplet mitochondria (PDMw) in WAs, respectively. CMw had higher β-oxidation activity than PDMw, and PDMw was associated with diacylglycerol acyltransferase 2. Therefore, CMw may be involved in β-oxidation and PDMw in droplet expansion in WAs.

Keywords:  lipid droplet; mitochondria; triglyceride; white adipocyte

DOI:  https://doi.org/10.1002/1873-3468.14877
Cell Mol Biol Lett. 2024 Apr 23. 29(1): 59

The role of mitochondrial dynamics and mitophagy in skeletal muscle atrophy: from molecular mechanisms to therapeutic insights.

Yuhang Lei, Mailin Gan, Yanhao Qiu, Qiuyang Chen, Xingyu Wang, Tianci Liao, Mengying Zhao, Lei Chen, Shunhua Zhang, Ye Zhao, Lili Niu, Yan Wang, Li Zhu, Linyuan Shen.

  Skeletal muscle is the largest metabolic organ of the human body. Maintaining the best quality control and functional integrity of mitochondria is essential for the health of skeletal muscle. However, mitochondrial dysfunction characterized by mitochondrial dynamic imbalance and mitophagy disruption can lead to varying degrees of muscle atrophy, but the underlying mechanism of action is still unclear. Although mitochondrial dynamics and mitophagy are two different mitochondrial quality control mechanisms, a large amount of evidence has indicated that they are interrelated and mutually regulated. The former maintains the balance of the mitochondrial network, eliminates damaged or aged mitochondria, and enables cells to survive normally. The latter degrades damaged or aged mitochondria through the lysosomal pathway, ensuring cellular functional health and metabolic homeostasis. Skeletal muscle atrophy is considered an urgent global health issue. Understanding and gaining knowledge about muscle atrophy caused by mitochondrial dysfunction, particularly focusing on mitochondrial dynamics and mitochondrial autophagy, can greatly contribute to the prevention and treatment of muscle atrophy. In this review, we critically summarize the recent research progress on mitochondrial dynamics and mitophagy in skeletal muscle atrophy, and expound on the intrinsic molecular mechanism of skeletal muscle atrophy caused by mitochondrial dynamics and mitophagy. Importantly, we emphasize the potential of targeting mitochondrial dynamics and mitophagy as therapeutic strategies for the prevention and treatment of muscle atrophy, including pharmacological treatment and exercise therapy, and summarize effective methods for the treatment of skeletal muscle atrophy.

Keywords:  Intermodulation; Mitochondrial dynamics; Mitophagy; Molecular mechanism; Prevention and treatment; Skeletal muscle atrophy

DOI:  https://doi.org/10.1186/s11658-024-00572-y
Life (Basel). 2024 Apr 05. pii: 477. [Epub ahead of print]14(4):

Organ-Specific Mitochondrial Alterations Following Ischemia-Reperfusion Injury in Post-Cardiac Arrest Syndrome: A Comprehensive Review.

Eriko Nakamura, Tomoaki Aoki, Yusuke Endo, Jacob Kazmi, Jun Hagiwara, Cyrus E Kuschner, Tai Yin, Junhwan Kim, Lance B Becker, Kei Hayashida.

   BACKGROUND: Mitochondrial dysfunction, which is triggered by systemic ischemia-reperfusion (IR) injury and affects various organs, is a key factor in the development of post-cardiac arrest syndrome (PCAS). Current research on PCAS primarily addresses generalized mitochondrial responses, resulting in a knowledge gap regarding organ-specific mitochondrial dynamics. This review focuses on the organ-specific mitochondrial responses to IR injury, particularly examining the brain, heart, and kidneys, to highlight potential therapeutic strategies targeting mitochondrial dysfunction to enhance outcomes post-IR injury.
METHODS AND RESULTS: We conducted a narrative review examining recent advancements in mitochondrial research related to IR injury. Mitochondrial responses to IR injury exhibit considerable variation across different organ systems, influenced by unique mitochondrial structures, bioenergetics, and antioxidative capacities. Each organ demonstrates distinct mitochondrial behaviors that have evolved to fulfill specific metabolic and functional needs. For example, cerebral mitochondria display dynamic responses that can be both protective and detrimental to neuronal activity and function during ischemic events. Cardiac mitochondria show vulnerability to IR-induced oxidative stress, while renal mitochondria exhibit a unique pattern of fission and fusion, closely linked to their susceptibility to acute kidney injury. This organ-specific heterogeneity in mitochondrial responses requires the development of tailored interventions. Progress in mitochondrial medicine, especially in the realms of genomics and metabolomics, is paving the way for innovative strategies to combat mitochondrial dysfunction. Emerging techniques such as mitochondrial transplantation hold the potential to revolutionize the management of IR injury in resuscitation science.
CONCLUSIONS: The investigation into organ-specific mitochondrial responses to IR injury is pivotal in the realm of resuscitation research, particularly within the context of PCAS. This nuanced understanding holds the promise of revolutionizing PCAS management, addressing the unique mitochondrial dysfunctions observed in critical organs affected by IR injury.

Keywords:  acute kidney injury; cardiac arrest; cardiac injury; ischemia; ischemic stroke; mitochondria; reperfusion injury

DOI:  https://doi.org/10.3390/life14040477
Physiol Res. 2024 Apr 22.

Mitochondrial Physiology of Cellular Redox Regulations.

P Ježek, A Dlasková, H Engstová, J Špačková, J Tauber, P Průchová, E Kloppel, O Mozheitova, M Jabůrek.

Mitochondria (mt) represent the vital hub of the molecular physiology of the cell, being decision-makers in cell life/death and information signaling, including major redox regulations and redox signaling. Now we review recent advances in understanding mitochondrial redox homeostasis, including superoxide sources and H2O2 consumers, i.e., antioxidant mechanisms, as well as exemplar situations of physiological redox signaling, including the intramitochondrial one and mt-to-cytosol redox signals, which may be classified as acute and long-term signals. This review exemplifies the acute redox signals in hypoxic cell adaptation and upon insulin secretion in pancreatic beta-cells. We also show how metabolic changes under these circumstances are linked to mitochondrial cristae narrowing at higher intensity of ATP synthesis. Also, we will discuss major redox buffers, namely the peroxiredoxin system, which may also promote redox signaling. We will point out that pathological thresholds exist, specific for each cell type, above which the superoxide sources exceed regular antioxidant capacity and the concomitant harmful processes of oxidative stress subsequently initiate etiology of numerous diseases. The redox signaling may be impaired when sunk in such excessive pro-oxidative state.
Biomolecules. 2024 Mar 26. pii: 402. [Epub ahead of print]14(4):

Mitochondrial Dysfunction as the Major Basis of Brain Aging.

Stephen C Bondy.

  The changes in the properties of three biological events that occur with cerebral aging are discussed. These adverse changes already begin to develop early in mid-life and gradually become more pronounced with senescence. Essentially, they are reflections of the progressive decline in effectiveness of key processes, resulting in the deviation of essential biochemical trajectories to ineffective and ultimately harmful variants of these programs. The emphasis of this review is the major role played by the mitochondria in the transition of these three important processes toward more deleterious variants as brain aging proceeds. The immune system: the shift away from an efficient immune response to a more unfocused, continuing inflammatory condition. Such a state is both ineffective and harmful. Reactive oxygen species are important intracellular signaling systems. Additionally, microglial phagocytic activity utilizing short lived reactive oxygen species contribute to the removal of aberrant or dead cells and bacteria. These processes are transformed into an excessive, untargeted, and persistent generation of pro-oxidant free radicals (oxidative stress). The normal efficient neural transmission is modified to a state of undirected, chronic low-level excitatory activity. Each of these changes is characterized by the occurrence of continuous activity that is inefficient and diffused. The signal/noise ratio of several critical biological events is thus reduced as beneficial responses are gradually replaced by their impaired and deleterious variants.

Keywords:  aging; brain; excitotoxicity; inflammation; mitochondria; oxidative stress

DOI:  https://doi.org/10.3390/biom14040402
Front Cell Dev Biol. 2024 ;12 1374735

Molecular mechanisms of mitochondria-mediated ferroptosis: a potential target for antimalarial interventions.

Adegbolagun Grace Adegboro, Israel Sunmola Afolabi.

  Ferroptosis is an iron-dependent form of regulated cell death characterized by glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) inactivation, and the build-up of lipotoxic reactive species. Ferroptosis-targeted induction is a promising therapeutic approach for addressing antimalarial drug resistance. In addition to being the primary source of intracellular energy supply and reactive oxygen species (ROS) generation, mitochondria actively participate in diverse forms of regulated cell death, including ferroptosis. Altered mitochondrial morphology and functionality are attributed to ferroptosis. Diverse mitochondria-related proteins and metabolic activities have been implicated in fine-tuning the action of ferroptosis inducers. Herein, we review recent progress in this evolving field, elucidating the numerous mechanisms by which mitochondria regulate ferroptosis and giving an insight into the role of the organelle in ferroptosis. Additionally, we present an overview of how mitochondria contribute to ferroptosis in malaria. Furthermore, we attempt to shed light on an inclusive perspective on how targeting malaria parasites' mitochondrion and attacking redox homeostasis is anticipated to induce ferroptosis-mediated antiparasitic effects.

Keywords:  antimalarial drug resistance; antiparasitic; ferroptosis; iron; mitochondria; reactive species

DOI:  https://doi.org/10.3389/fcell.2024.1374735
Drug Discov Today. 2024 Apr 24. pii: S1359-6446(24)00120-X. [Epub ahead of print] 103995

Development and therapeutic implications of small molecular inhibitors that target calcium ion-related channels in tumor treatment.

Linxi Zhang, Changyu Ren, Jiao Liu, Shuai Huang, Chengyong Wu, Jifa Zhang.

  Calcium ion dysregulation exerts profound effects on various physiological activities such as tumor proliferation, migration, and drug resistance. Calcium ion-related channels play a regulatory role in maintaining calcium ion homeostasis, with most channels being highly expressed in tumor cells. Additionally, these channels serve as potential drug targets for the development of antitumor medications. In this review, we first discuss the current research status of these pathways, examining how they modulate various tumor functions such as epithelial-mesenchymal transition (EMT), metabolism, and drug resistance. Simultaneously, we summarize the recent progress in the study of novel small-molecule drugs over the past 5 years and their current status.

Keywords:  calcium ion-related channels; cancer; drug discovery; small-molecular inhibitor

DOI:  https://doi.org/10.1016/j.drudis.2024.103995
Chemphyschem. 2024 Apr 22. e202400162

Voltage Gated Ion Channels: Structure, Pharmacology and Photopharmacology.

Vito F Palmisano, Nuria Anguita-Ortiz, Shirin Faraji, Juan Jose Nogueira.

  Voltage-gated ion channels are transmembrane proteins responsible for the generation and propagation of action potentials in excitable cells. In the past few years, crystal structures of ion channels have become accessible and, when combined with mutagenesis data, have aided in the discovery of drugs that can modulate ion conduction. However, many traditional drugs lack selectivity and come with adverse side effects. The emergence of photopharmacology has provided an orthogonal way of controlling the activity of compounds, enabling the regulation of ion conduction with light. In this review, we explore the central pore region of voltage-gated sodium and potassium channels, providing insights from both structural and pharmacological perspectives. We discuss the different binding modes of synthetic compounds that can physically occlude the pore and, therefore, block the ion conduction. Moreover, we examine recent advances in the photopharmacology of voltage-gated ion channels, introducing molecular approaches aimed at controlling their activity by using photosensitive drugs.

Keywords:  Ion Conduction Block; Local Anesthetics; Photopharmacology; Photoswitches; Voltage Gated Ion Channels

DOI:  https://doi.org/10.1002/cphc.202400162
Eur J Clin Invest. 2024 Apr 21. e14217

Primary mitochondrial diseases: The intertwined pathophysiology of bioenergetic dysregulation, oxidative stress and neuroinflammation.

Kevin Aguilar, Patrycja Jakubek, Antonio Zorzano, Mariusz R Wieckowski.

   OBJECTIVES AND SCOPE: Primary mitochondrial diseases (PMDs) are rare genetic disorders resulting from mutations in genes crucial for effective oxidative phosphorylation (OXPHOS) that can affect mitochondrial function. In this review, we examine the bioenergetic alterations and oxidative stress observed in cellular models of primary mitochondrial diseases (PMDs), shedding light on the intricate complexity between mitochondrial dysfunction and cellular pathology. We explore the diverse cellular models utilized to study PMDs, including patient-derived fibroblasts, induced pluripotent stem cells (iPSCs) and cybrids. Moreover, we also emphasize the connection between oxidative stress and neuroinflammation.
INSIGHTS: The central nervous system (CNS) is particularly vulnerable to mitochondrial dysfunction due to its dependence on aerobic metabolism and the correct functioning of OXPHOS. Similar to other neurodegenerative diseases affecting the CNS, individuals with PMDs exhibit several neuroinflammatory hallmarks alongside neurodegeneration, a pattern also extensively observed in mouse models of mitochondrial diseases. Based on histopathological analysis of postmortem human brain tissue and findings in mouse models of PMDs, we posit that neuroinflammation is not merely a consequence of neurodegeneration but a potential pathogenic mechanism for disease progression that deserves further investigation. This recognition may pave the way for novel therapeutic strategies for this group of devastating diseases that currently lack effective treatments.
SUMMARY: In summary, this review provides a comprehensive overview of bioenergetic alterations and redox imbalance in cellular models of PMDs while underscoring the significance of neuroinflammation as a potential driver in disease progression.

Keywords:  ETC; OXPHOS; bioenergetics; metabolism; mitochondria; mtDNA; nDNA; neuroinflammation; oxidative stress

DOI:  https://doi.org/10.1111/eci.14217
Mol Cell Biochem. 2024 Apr 26.

Important molecular mechanisms in ferroptosis.

Lunmeng Lai, Menglei Tan, Mingming Hu, Xiyue Yue, Lulu Tao, Yanru Zhai, Yunsen Li.

  Ferroptosis is a type of cell death that is caused by the oxidation of lipids and is dependent on the presence of iron. It was first characterized by Brent R. Stockwell in 2012, and since then, research in the field of ferroptosis has rapidly expanded. The process of ferroptosis-induced cell death is genetically, biochemically, and morphologically distinct from other forms of cellular death, such as apoptosis, necroptosis, and non-programmed cell death. Extensive research has been devoted to comprehending the intricate process of ferroptosis and the various factors that contribute to it. While the majority of these studies have focused on examining the effects of lipid metabolism and mitochondria on ferroptosis, recent findings have highlighted the significant involvement of signaling pathways and associated proteins, including Nrf2, P53, and YAP/TAZ, in this process. This review provides a concise summary of the crucial signaling pathways associated with ferroptosis based on relevant studies. It also elaborates on the drugs that have been employed in recent years to treat ferroptosis-related diseases by targeting the relevant signaling pathways. The established and potential therapeutic targets for ferroptosis-related diseases, such as cancer and ischemic heart disease, are systematically addressed.

Keywords:  Cell signaling pathway; Ferroptosis; Nuclear factor-erythroid 2-related factor 2; P53

DOI:  https://doi.org/10.1007/s11010-024-05009-w
Antioxidants (Basel). 2024 Mar 25. pii: 394. [Epub ahead of print]13(4):

Progress in Understanding Oxidative Stress, Aging, and Aging-Related Diseases.

Jianying Yang, Juyue Luo, Xutong Tian, Yaping Zhao, Yumeng Li, Xin Wu.

  Under normal physiological conditions, reactive oxygen species (ROS) are produced through redox reactions as byproducts of respiratory and metabolic activities. However, due to various endogenous and exogenous factors, the body may produce excessive ROS, which leads to oxidative stress (OS). Numerous studies have shown that OS causes a variety of pathological changes in cells, including mitochondrial dysfunction, DNA damage, telomere shortening, lipid peroxidation, and protein oxidative modification, all of which can trigger apoptosis and senescence. OS also induces a variety of aging-related diseases, such as retinal disease, neurodegenerative disease, osteoarthritis, cardiovascular diseases, cancer, ovarian disease, and prostate disease. In this review, we aim to introduce the multiple internal and external triggers that mediate ROS levels in rodents and humans as well as the relationship between OS, aging, and aging-related diseases. Finally, we present a statistical analysis of effective antioxidant measures currently being developed and applied in the field of aging research.

Keywords:  aging; aging-related diseases; antioxidants; reactive oxygen species

DOI:  https://doi.org/10.3390/antiox13040394