bims-mionch Biomed News
on Mitochondrial ion channels
Issue of 2024–10–06
seven papers selected by
Gun Kim, Seoul National University
  1. Biogenesis of mitochondrial β-barrel membrane proteins.
  2. New Insights into Mitochondria in Health and Diseases.
  3. Mitochondria: the beating heart of the eukaryotic cell.
  4. Mitochondria, Peroxisomes and Beyond-How Dual Targeting Regulates Organelle Tethering.
  5. Mitochondrial dysfunction, cause or consequence in neurodegenerative diseases?
  6. Targeting mitochondria with small molecules: A promising strategy for combating Parkinson's disease.
  7. Voltage Gated Ion Channels and Sleep.
  1. FEBS Open Bio. 2024 Oct;14(10): 1595-1609
    Biogenesis of mitochondrial β-barrel membrane proteins.
    Iniyan Ganesan, Jon V Busto, Nikolaus Pfanner, Nils Wiedemann.
      β-barrel membrane proteins in the mitochondrial outer membrane are crucial for mediating the metabolite exchange between the cytosol and the mitochondrial intermembrane space. In addition, the β-barrel membrane protein subunit Tom40 of the translocase of the outer membrane (TOM) is essential for the import of the vast majority of mitochondrial proteins encoded in the nucleus. The sorting and assembly machinery (SAM) in the outer membrane is required for the membrane insertion of mitochondrial β-barrel proteins. The core subunit Sam50, which has been conserved from bacteria to humans, is itself a β-barrel protein. The β-strands of β-barrel precursor proteins are assembled at the Sam50 lateral gate forming a Sam50-preprotein hybrid barrel. The assembled precursor β-barrel is finally released into the outer mitochondrial membrane by displacement of the nascent β-barrel, termed the β-barrel switching mechanism. SAM forms supercomplexes with TOM and forms a mitochondrial outer-to-inner membrane contact site with the mitochondrial contact site and cristae organizing system (MICOS) of the inner membrane. SAM shares subunits with the ER-mitochondria encounter structure (ERMES), which forms a membrane contact site between the mitochondrial outer membrane and the endoplasmic reticulum. Therefore, β-barrel membrane protein biogenesis is closely connected to general mitochondrial protein and lipid biogenesis and plays a central role in mitochondrial maintenance.
    Keywords:  Mco6; Mdm10; SAM; Sam35; Sam37; Sam50; mitochondria; outer membrane; sorting and assembly machinery; β‐barrel protein
    DOI:  https://doi.org/10.1002/2211-5463.13905
  2. Int J Mol Sci. 2024 Sep 16. pii: 9975. [Epub ahead of print]25(18):
    New Insights into Mitochondria in Health and Diseases.
    Ya Li, Huhu Zhang, Chunjuan Yu, Xiaolei Dong, Fanghao Yang, Mengjun Wang, Ziyuan Wen, Mohan Su, Bing Li, Lina Yang.
      Mitochondria are a unique type of semi-autonomous organelle within the cell that carry out essential functions crucial for the cell's survival and well-being. They are the location where eukaryotic cells carry out energy metabolism. Aside from producing the majority of ATP through oxidative phosphorylation, which provides essential energy for cellular functions, mitochondria also participate in other metabolic processes within the cell, such as the electron transport chain, citric acid cycle, and β-oxidation of fatty acids. Furthermore, mitochondria regulate the production and elimination of ROS, the synthesis of nucleotides and amino acids, the balance of calcium ions, and the process of cell death. Therefore, it is widely accepted that mitochondrial dysfunction is a factor that causes or contributes to the development and advancement of various diseases. These include common systemic diseases, such as aging, diabetes, Parkinson's disease, and cancer, as well as rare metabolic disorders, like Kearns-Sayre syndrome, Leigh disease, and mitochondrial myopathy. This overview outlines the various mechanisms by which mitochondria are involved in numerous illnesses and cellular physiological activities. Additionally, it provides new discoveries regarding the involvement of mitochondria in both disorders and the maintenance of good health.
    Keywords:  ROS; aging; bioenergetics; mitochondrial; mitochondrial dysfunction; mitochondrial targeted therapy; mtDNA; mutations
    DOI:  https://doi.org/10.3390/ijms25189975
  3. FEBS Open Bio. 2024 Oct;14(10): 1588-1590
    Mitochondria: the beating heart of the eukaryotic cell.
    Johannes M Herrmann.
      Mitochondria are essential organelles of eukaryotic cells. They consist of hundreds of proteins, which are synthesized in the cytosol and imported into mitochondria via different targeting routes. In addition, a small number of proteins are encoded by the organellar genome and synthesized by mitochondrial ribosomes. In this 'In the Limelight' special issue of FEBS Open Bio, five review articles describe these different biogenesis routes of mitochondrial proteins and provide a comprehensive overview of the structures and mechanisms by which mitochondrial proteins are synthesized and transported to their respective location within the organelle. These reviews, written by leading experts, provide a general overview, but also highlight current developments in the field of mitochondrial biogenesis.
    DOI:  https://doi.org/10.1002/2211-5463.13884
  4. Contact (Thousand Oaks). 2024 Jan-Dec;7:7 25152564241264254
    Mitochondria, Peroxisomes and Beyond-How Dual Targeting Regulates Organelle Tethering.
    Johannes Freitag, Thorsten Stehlik, Gert Bange.
      Eukaryotic cells feature distinct membrane-enclosed organelles such as mitochondria and peroxisomes, each playing vital roles in cellular function and organization. These organelles are linked at membrane contact sites, facilitating interorganellar molecule and ion exchange. Most contact-forming proteins identified to date are membrane proteins or membrane-associated proteins, which can form very stable contacts. Recent findings suggest additional mechanistically distinct tethering events that arise from dual protein targeting. Proteins bearing targeting signals for multiple organelles, such as an N-terminal signal for mitochondria and a C-terminal signal for peroxisomes, function as tethers, fostering contacts by engaging targeting factors at both organelles. A number of dually targeted membrane proteins can contribute to contact site formation and transit from one organelle to the other as well. These interactions may enable the fine-tuning of organelle proximity, hence, adapting connections to meet varying physiological demands.
    Keywords:  dual targeting; mitochondrion; peroxisome; protein trafficking; targeting signal; tether
    DOI:  https://doi.org/10.1177/25152564241264254
  5. Bioessays. 2024 Oct 04. e2400023
    Mitochondrial dysfunction, cause or consequence in neurodegenerative diseases?
    Zoë P Van Acker, Thomas Leroy, Wim Annaert.
      Neurodegenerative diseases encompass a spectrum of conditions characterized by the gradual deterioration of neurons in the central and peripheral nervous system. While their origins are multifaceted, emerging data underscore the pivotal role of impaired mitochondrial functions and endolysosomal homeostasis to the onset and progression of pathology. This article explores whether mitochondrial dysfunctions act as causal factors or are intricately linked to the decline in endolysosomal function. As research delves deeper into the genetics of neurodegenerative diseases, an increasing number of risk loci and genes associated with the regulation of endolysosomal and autophagy functions are being identified, arguing for a downstream impact on mitochondrial health. Our hypothesis centers on the notion that disturbances in endolysosomal processes may propagate to other organelles, including mitochondria, through disrupted inter-organellar communication. We discuss these views in the context of major neurodegenerative diseases including Alzheimer's and Parkinson's diseases, and their relevance to potential therapeutic avenues.
    Keywords:  lysosomal homeostasis; mitochondrial homeostasis; neurodegenerative diseases
    DOI:  https://doi.org/10.1002/bies.202400023
  6. Mitochondrion. 2024 Sep 30. pii: S1567-7249(24)00129-6. [Epub ahead of print] 101971
    Targeting mitochondria with small molecules: A promising strategy for combating Parkinson's disease.
    Chinmay Pal.
      Parkinson's disease (PD), a neurodegenerative disorder, is one of the most significant challenges confronting modern societies, affecting millions of patients globally each year. The pathophysiology of PD is significantly influenced by mitochondrial dysfunction, as evident by the contribution of altered mitochondrial dynamics, bioenergetics, and increased oxidative stress to neuronal death. This review examines the potential use of small molecules that target mitochondria as a therapeutic approach for treating PD. Progress in mitochondrial biology has revealed various mitochondrial targets that can be modulated to restore function and mitigate neurodegeneration. Small molecules that promote mitochondrial biogenesis, enhance mitochondrial dynamics, decrease oxidative stress, and prevent the opening of the mitochondrial permeability transition pore (mPTP) have shown promise in preclinical models. Additionally, targeting mitochondrial quality control mechanisms, such as mitophagy, provides another therapeutic approach. This review explores recent research on small molecules targeting mitochondria, examines their mechanisms of action, and assesses their potential efficacy and safety profiles. By highlighting the most promising candidates and addressing the challenges and future directions in this field, this review aims to offer a comprehensive overview of current and future prospects for mitochondrial-targeted therapies in PD. Ultimately, treating mitochondrial dysfunction holds significant promise for developing disease-modifying PD medications, giving patients hope for better outcomes and improved quality of life.
    Keywords:  Mitochondrial dysfunction; Oxidative Stress; Parkinson’s disease; Reactive oxygen species; Small molecule
    DOI:  https://doi.org/10.1016/j.mito.2024.101971
  7. J Membr Biol. 2024 Oct 01.
    Voltage Gated Ion Channels and Sleep.
    Yan Zhang, Jiawen Wu, Yuxian Zheng, Yangkun Xu, Ziqi Yu, Yong Ping.
      Ion channels are integral components of the nervous system, playing a pivotal role in shaping membrane potential, neuronal excitability, synaptic transmission and plasticity. Dysfunction in these channels, such as improper expression or localization, can lead to irregular neuronal excitability and synaptic communication, which may manifest as various behavioral abnormalities, including disrupted rest-activity cycles. Research has highlighted the significant impact of voltage gated ion channels on sleep parameters, influencing sleep latency, duration and waveforms. Furthermore, these ion channels have been implicated in the vulnerability to, and the pathogenesis of, several neurological and psychiatric disorders, including epilepsy, autism, schizophrenia, and Alzheimer's disease (AD). In this comprehensive review, we aim to provide a summary of the regulatory role of three predominant types of voltage-gated ion channels-calcium (Ca2+), sodium (Na+), and potassium (K+)-in sleep across species, from flies to mammals. We will also discuss the association of sleep disorders with various human diseases that may arise from the dysfunction of these ion channels, thereby underscoring the potential therapeutic benefits of targeting specific ion channel subtypes for sleep disturbance treatment.
    Keywords:  Ion channels; Neurological disorders; Sleep; Sleep disorders; Thalamocortical circuits
    DOI:  https://doi.org/10.1007/s00232-024-00325-0
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