bims-mionch Biomed News
on Mitochondrial ion channels
Issue of 2024–04–21
nine papers selected by
Gun Kim, Seoul National University
  1. Role of mitochondria in doxorubicin-mediated cardiotoxicity: from molecular mechanisms to therapeutic strategies.
  2. Endothelial Mitochondria-Associated Membranes (MAMs) Isolation by Percoll Step Gradients.
  3. Mitochondrial calcium signaling in non-neuronal cells: Implications for Alzheimer's disease pathogenesis.
  4. New insights into the structure and dynamics of the TOM complex in mitochondria.
  5. Focusing on mitochondria in the brain: from biology to therapeutics.
  6. Mitocentricity.
  7. Current trends in basic research on Parkinson's disease: from mitochondria, lysosome to α-synuclein.
  8. Inhibition of the mPTP and Lipid Peroxidation Is Additively Protective Against I/R Injury.
  9. Principles of organelle positioning in motile and non-motile cells.
  1. Int J Med Sci. 2024 ;21(5): 809-816
    Role of mitochondria in doxorubicin-mediated cardiotoxicity: from molecular mechanisms to therapeutic strategies.
    Tianen Wang, Guoli Xing, Tong Fu, Yanchun Ma, Qi Wang, Shuxiang Zhang, Xing Chang, Ying Tong.
      This comprehensive review delves into the pivotal role of mitochondria in doxorubicin-induced cardiotoxicity, a significant complication limiting the clinical use of this potent anthracycline chemotherapeutic agent. Doxorubicin, while effective against various malignancies, is associated with dose-dependent cardiotoxicity, potentially leading to irreversible cardiac damage. The review meticulously dissects the molecular mechanisms underpinning this cardiotoxicity, particularly focusing on mitochondrial dysfunction, a central player in this adverse effect. Central to the discussion is the concept of mitochondrial quality control (MQC), including mitochondrial dynamics (fusion/fission balance) and mitophagy. The review presents evidence linking aberrations in these processes to cardiotoxicity in doxorubicin-treated patients. It elucidates how doxorubicin disrupts mitochondrial dynamics, leading to an imbalance between mitochondrial fission and fusion, and impairs mitophagy, culminating in the accumulation of dysfunctional mitochondria and subsequent cardiac cell damage. Furthermore, the review explores emerging therapeutic strategies targeting mitochondrial dysfunction. It highlights the potential of modulating mitochondrial dynamics and enhancing mitophagy to mitigate doxorubicin-induced cardiac damage. These strategies include pharmacological interventions with mitochondrial fission inhibitors, fusion promoters, and agents that modulate mitophagy. The review underscores the promising results from preclinical studies while advocating for more extensive clinical trials to validate these approaches in human patients. In conclusion, this review offers valuable insights into the intricate relationship between mitochondrial dysfunction and doxorubicin-mediated cardiotoxicity. It underscores the need for continued research into targeted mitochondrial therapies as a means to improve the cardiac safety profile of doxorubicin, thereby enhancing the overall treatment outcomes for cancer patients.
    Keywords:  cardiotoxicity; doxorubicin; mitochondria; mitochondrial quality control
    DOI:  https://doi.org/10.7150/ijms.94485
  2. Methods Mol Biol. 2024 ;2782 113-122
    Endothelial Mitochondria-Associated Membranes (MAMs) Isolation by Percoll Step Gradients.
    Margaret Baldini, Cheng Zhang, Jun Yu.
      Mitochondria-associated membranes (MAMs) are regions where the endoplasmic reticulum (ER) interacts with mitochondria and regulate lipid trafficking, calcium signaling, ER stress, and inflammation activation. Isolation of MAMs from endothelial cells is vital for studying insight into the immune regulation of many inflammatory diseases. Endothelial cells (ECs) are critical innate immune cells due to their paracrine function of secreting interleukins, chemokines, cytokines, and growth factors, as well as expressing levels of pattern recognition receptors including toll-like receptors (TLRs). Furthermore, ECs regulate and recruit monocytes by expressing adhesion molecules including vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), P-selectin, and E-selectin, to facilitate monocyte diapedesis in areas of damage and inflammation. This protocol consists of step-by-step instructions on isolating pure MAMs and other subcellular fractions from endothelial cells, which is critical to understanding ER and mitochondria crosstalks in endothelial functions in health and disease.
    Keywords:  Endoplasmic reticulum; Endothelial cells; Immunity; Inflammation; Mitochondria; Mitochondria-associated membranes; Subcellular fractions
    DOI:  https://doi.org/10.1007/978-1-0716-3754-8_8
  3. Biochim Biophys Acta Mol Basis Dis. 2024 Apr 15. pii: S0925-4439(24)00158-3. [Epub ahead of print]1870(5): 167169
    Mitochondrial calcium signaling in non-neuronal cells: Implications for Alzheimer's disease pathogenesis.
    Darpan Raghav, Shatakshi Shukla, Pooja Jadiya.
      Mitochondrial dysregulation is pivotal in Alzheimer's disease (AD) pathogenesis. Calcium governs vital mitochondrial processes impacting energy conversion, oxidative stress, and cell death signaling. Disruptions in mitochondrial calcium (mCa2+) handling induce calcium overload and trigger the opening of mitochondrial permeability transition pore, ensuing energy deprivation and resulting in AD-related neuronal cell death. However, the role of mCa2+ in non-neuronal cells (microglia, astrocytes, oligodendrocytes, endothelial cells, and pericytes) remains elusive. This review provides a comprehensive exploration of mitochondrial heterogeneity and calcium signaling, offering insights into specific differences among various brain cell types in AD.
    Keywords:  Alzheimer's disease; Brain cells; Calcium; Heterogeneity; Mitochondria
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167169
  4. Biochem Soc Trans. 2024 Apr 17. pii: BST20231236. [Epub ahead of print]
    New insights into the structure and dynamics of the TOM complex in mitochondria.
    Stephan Nussberger, Robin Ghosh, Shuo Wang.
      To date, there is no general physical model of the mechanism by which unfolded polypeptide chains with different properties are imported into the mitochondria. At the molecular level, it is still unclear how transit polypeptides approach, are captured by the protein translocation machinery in the outer mitochondrial membrane, and how they subsequently cross the entropic barrier of a protein translocation pore to enter the intermembrane space. This deficiency has been due to the lack of detailed structural and dynamic information about the membrane pores. In this review, we focus on the recently determined sub-nanometer cryo-EM structures and our current knowledge of the dynamics of the mitochondrial two-pore outer membrane protein translocation machinery (TOM core complex), which provide a starting point for addressing the above questions. Of particular interest are recent discoveries showing that the TOM core complex can act as a mechanosensor, where the pores close as a result of interaction with membrane-proximal structures. We highlight unusual and new correlations between the structural elements of the TOM complexes and their dynamic behavior in the membrane environment.
    Keywords:  Tom complex; electron cryo-microscopy; mechanosensitivity; mitochondria; protein translocation; single-molecule microscopy
    DOI:  https://doi.org/10.1042/BST20231236
  5. Transl Neurodegener. 2024 Apr 17. 13(1): 23
    Focusing on mitochondria in the brain: from biology to therapeutics.
    Nanshan Song, Shuyuan Mei, Xiangxu Wang, Gang Hu, Ming Lu.
      Mitochondria have multiple functions such as supplying energy, regulating the redox status, and producing proteins encoded by an independent genome. They are closely related to the physiology and pathology of many organs and tissues, among which the brain is particularly prominent. The brain demands 20% of the resting metabolic rate and holds highly active mitochondrial activities. Considerable research shows that mitochondria are closely related to brain function, while mitochondrial defects induce or exacerbate pathology in the brain. In this review, we provide comprehensive research advances of mitochondrial biology involved in brain functions, as well as the mitochondria-dependent cellular events in brain physiology and pathology. Furthermore, various perspectives are explored to better identify the mitochondrial roles in neurological diseases and the neurophenotypes of mitochondrial diseases. Finally, mitochondrial therapies are discussed. Mitochondrial-targeting therapeutics are showing great potentials in the treatment of brain diseases.
    Keywords:  Brain; Mitochondria; Mitochondrial transfer; Neurological disorders
    DOI:  https://doi.org/10.1186/s40035-024-00409-w
  6. Biochemistry (Mosc). 2024 Feb;89(2): 223-240
    Mitocentricity.
    Dmitry B Zorov, Polina A Abramicheva, Nadezda V Andrianova, Valentina A Babenko, Ljubava D Zorova, Savva D Zorov, Irina B Pevzner, Vasily A Popkov, Dmitry S Semenovich, Elmira I Yakupova, Denis N Silachev, Egor Y Plotnikov, Gennady T Sukhikh.
      Worldwide, interest in mitochondria is constantly growing, as evidenced by scientific statistics, and studies of the functioning of these organelles are becoming more prevalent than studies of other cellular structures. In this analytical review, mitochondria are conditionally placed in a certain cellular center, which is responsible for both energy production and other non-energetic functions, without which the existence of not only the eukaryotic cell itself, but also the entire organism is impossible. Taking into account the high multifunctionality of mitochondria, such a fundamentally new scheme of cell functioning organization, including mitochondrial management of processes that determine cell survival and death, may be justified. Considering that this issue is dedicated to the memory of V. P. Skulachev, who can be called mitocentric, due to the history of his scientific activity almost entirely aimed at studying mitochondria, this work examines those aspects of mitochondrial functioning that were directly or indirectly the focus of attention of this outstanding scientist. We list all possible known mitochondrial functions, including membrane potential generation, synthesis of Fe-S clusters, steroid hormones, heme, fatty acids, and CO2. Special attention is paid to the participation of mitochondria in the formation and transport of water, as a powerful biochemical cellular and mitochondrial regulator. The history of research on reactive oxygen species that generate mitochondria is subject to significant analysis. In the section "Mitochondria in the center of death", special emphasis is placed on the analysis of what role and how mitochondria can play and determine the program of death of an organism (phenoptosis) and the contribution made to these studies by V. P. Skulachev.
    Keywords:  CO2; cell; death; fatty acids; heme; membrane potential; mitochondria; organism; phenoptosis; reactive oxygen species; steroids; swelling; uncoupling; water
    DOI:  https://doi.org/10.1134/S0006297924020044
  7. J Neural Transm (Vienna). 2024 Apr 13.
    Current trends in basic research on Parkinson's disease: from mitochondria, lysosome to α-synuclein.
    Hideaki Matsui, Ryosuke Takahashi.
      Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra and other brain regions. A key pathological feature of PD is the abnormal accumulation of α-synuclein protein within affected neurons, manifesting as Lewy bodies and Lewy neurites. Despite extensive research efforts spanning several decades, the underlying mechanisms of PD and disease-modifying therapies remain elusive. This review provides an overview of current trends in basic research on PD. Initially, it discusses the involvement of mitochondrial dysfunction in the pathogenesis of PD, followed by insights into the role of lysosomal dysfunction and disruptions in the vesicular transport system. Additionally, it delves into the pathological and physiological roles of α-synuclein, a crucial protein associated with PD pathophysiology. Overall, the purpose of this review is to comprehend the current state of elucidating the intricate mechanisms underlying PD and to outline future directions in understanding this disease.
    Keywords:  Lysosome; Mitochondria; Parkinson’s disease; Vesicular transport; α-synuclein
    DOI:  https://doi.org/10.1007/s00702-024-02774-2
  8. Circ Res. 2024 Apr 15.
    Inhibition of the mPTP and Lipid Peroxidation Is Additively Protective Against I/R Injury.
    Arielys Mendoza, Pooja Patel, Dexter Robichaux, Daniel Ramirez, Jason Karch.
       BACKGROUND: During myocardial ischemia/reperfusion (I/R) injury, high levels of matrix Ca2+ and reactive oxygen species (ROS) induce the opening of the mitochondrial permeability transition pore (mPTP), which causes mitochondrial dysfunction and ultimately necrotic death. However, the mechanisms of how these triggers individually or cooperatively open the pore have yet to be determined.
    METHODS: Here, we use a combination of isolated mitochondrial assays and in vivo I/R surgery in mice. We challenged isolated liver and heart mitochondria with Ca2+, ROS, and Fe2+ to induce mitochondrial swelling. Using inhibitors of the mPTP (cyclosporine A or ADP) lipid peroxidation (Fer-1 [ferrostatin-1], mitoquinone), we determined how the triggers elicit mitochondrial damage. Additionally, we used the combination of inhibitors during I/R injury in mice to determine if dual inhibition of these pathways is additivity protective.
    RESULTS: In the absence of Ca2+, we determined that ROS fails to trigger mPTP opening. Instead, high levels of ROS induce mitochondrial dysfunction and rupture independently of the mPTP through lipid peroxidation. As expected, Ca2+ in the absence of ROS induces mPTP-dependent mitochondrial swelling. Subtoxic levels of ROS and Ca2+ synergize to induce mPTP opening. Furthermore, this synergistic form of Ca2+- and ROS-induced mPTP opening persists in the absence of CypD (cyclophilin D), suggesting the existence of a CypD-independent mechanism for ROS sensitization of the mPTP. These ex vivo findings suggest that mitochondrial dysfunction may be achieved by multiple means during I/R injury. We determined that dual inhibition of the mPTP and lipid peroxidation is significantly more protective against I/R injury than individually targeting either pathway alone.
    CONCLUSIONS: In the present study, we have investigated the relationship between Ca2+ and ROS, and how they individually or synergistically induce mitochondrial swelling. Our findings suggest that Ca2+ mediates mitochondrial damage through the opening of the mPTP, although ROS mediates its damaging effects through lipid peroxidation. However, subtoxic levels both Ca2+ and ROS can induce mPTP-mediated mitochondrial damage. Targeting both of these triggers to preserve mitochondria viability unveils a highly effective therapeutic approach for mitigating I/R injury.
    Keywords:  apoptosis; cell death; heart attack; mice; mitochondria
    DOI:  https://doi.org/10.1161/CIRCRESAHA.123.323882
  9. EMBO Rep. 2024 Apr 16.
    Principles of organelle positioning in motile and non-motile cells.
    Janina Kroll, Jörg Renkawitz.
      Cells are equipped with asymmetrically localised and functionally specialised components, including cytoskeletal structures and organelles. Positioning these components to specific intracellular locations in an asymmetric manner is critical for their functionality and affects processes like immune responses, tissue maintenance, muscle functionality, and neurobiology. Here, we provide an overview of strategies to actively move, position, and anchor organelles to specific locations. By conceptualizing the cytoskeletal forces and the organelle-to-cytoskeleton connectivity, we present a framework of active positioning of both membrane-enclosed and membrane-less organelles. Using this framework, we discuss how different principles of force generation and organelle anchorage are utilised by different cells, such as mesenchymal and amoeboid cells, and how the microenvironment influences the plasticity of organelle positioning. Given that motile cells face the challenge of coordinating the positioning of their content with cellular motion, we particularly focus on principles of organelle positioning during migration. In this context, we discuss novel findings on organelle positioning by anchorage-independent mechanisms and their advantages and disadvantages in motile as well as stationary cells.
    Keywords:  Cytoplasmic Streaming; Cytoskeletal Forces; Motile and Branched Cells; Organelle Positioning; Organelle-Cytoskeleton Interface
    DOI:  https://doi.org/10.1038/s44319-024-00135-4
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