bims-drumid Biomed News
on Drugs for mitochondrial diseases
Issue of 2024–11–24
twelve papers selected by
Volkmar Weissig, Midwestern University
  1. Targeting mitochondria: restoring the antitumor efficacy of exhausted T cells.
  2. Role of Mitochondrial Iron Uptake in Acetaminophen Hepatotoxicity.
  3. F2,6BP restores mitochondrial genome integrity in Huntington's Disease.
  4. Amyloid Beta-Induced Mitochondrial Dysfunction and Endothelial Permeability in Cerebral Microvascular Endothelial cells: the protective role of Dexmedetomidine.
  5. AMPK: Balancing mitochondrial quality and quantity through opposite regulation of mitophagy pathways.
  6. Targeting mitochondria in Cancer therapy: Machine learning analysis of hyaluronic acid-based drug delivery systems.
  7. Nanotube-mediated mitochondrial transfer: power to the T cells!
  8. Resveratrol: A Natural Compound Targeting the PI3K/Akt/mTOR Pathway in Neurological Diseases.
  9. Passive anti-amyloid β immunotherapy in Alzheimer's disease-opportunities and challenges.
  10. Discovery of Gallic Acid-Based Mitochondriotropic Antioxidant Attenuates LPS-Induced Neuroinflammation.
  11. Textbook oxidative phosphorylation needs to be rewritten.
  12. A mitochondrial redox switch licenses the onset of morphogenesis in animals.
  1. Mol Cancer. 2024 Nov 19. 23(1): 260
    Targeting mitochondria: restoring the antitumor efficacy of exhausted T cells.
    Mei-Qi Yang, Shu-Ling Zhang, Li Sun, Le-Tian Huang, Jing Yu, Jie-Hui Zhang, Yuan Tian, Cheng-Bo Han, Jie-Tao Ma.
      Immune checkpoint blockade therapy has revolutionized cancer treatment, but resistance remains prevalent, often due to dysfunctional tumor-infiltrating lymphocytes. A key contributor to this dysfunction is mitochondrial dysfunction, characterized by defective oxidative phosphorylation, impaired adaptation, and depolarization, which promotes T cell exhaustion and severely compromises antitumor efficacy. This review summarizes recent advances in restoring the function of exhausted T cells through mitochondria-targeted strategies, such as metabolic remodeling, enhanced biogenesis, and regulation of antioxidant and reactive oxygen species, with the aim of reversing the state of T cell exhaustion and improving the response to immunotherapy. A deeper understanding of the role of mitochondria in T cell exhaustion lays the foundation for the development of novel mitochondria-targeted therapies and opens a new chapter in cancer immunotherapy.
    Keywords:  Cancer immunotherapy; Epigenetics; Mitochondria; Mitochondria metabolism; Mitochondrial dynamics; T cell exhaustion
    DOI:  https://doi.org/10.1186/s12943-024-02175-9
  2. Livers. 2024 Sep;4(3): 333-351
    Role of Mitochondrial Iron Uptake in Acetaminophen Hepatotoxicity.
    Jiangting Hu, Anna-Liisa Nieminen, Zhi Zhong, John J Lemasters.
      Overdose of acetaminophen (APAP) produces fulminant hepatic necrosis. The underlying mechanism of APAP hepatotoxicity involves mitochondrial dysfunction, including mitochondrial oxidant stress and the onset of mitochondrial permeability transition (MPT). Reactive oxygen species (ROS) play an important role in APAP-induced hepatotoxicity, and iron is a critical catalyst for ROS formation. This review summarizes the role of mitochondrial ROS formation in APAP hepatotoxicity and further focuses on the role of iron. Normally, hepatocytes take up Fe3+-transferrin bound to transferrin receptors via endocytosis. Concentrated into lysosomes, the controlled release of iron is required for the mitochondrial biosynthesis of heme and non-heme iron-sulfur clusters. After APAP overdose, the toxic metabolite, NAPQI, damages lysosomes, causing excess iron release and the mitochondrial uptake of Fe2+ by the mitochondrial calcium uniporter (MCU). NAPQI also inhibits mitochondrial respiration to promote ROS formation, including H2O2, with which Fe2+ reacts to form highly reactive •OH through the Fenton reaction. •OH, in turn, causes lipid peroxidation, the formation of toxic aldehydes, induction of the MPT, and ultimately, cell death. Fe2+ also facilitates protein nitration. Targeting pathways of mitochondrial iron movement and consequent iron-dependent mitochondrial ROS formation is a promising strategy to intervene against APAP hepatotoxicity in a clinical setting.
    Keywords:  NAPQI; acetaminophen; iron; mitochondria; oxidative stress; •OH
    DOI:  https://doi.org/10.3390/livers4030024
  3. bioRxiv. 2024 Nov 04. pii: 2024.11.04.621834. [Epub ahead of print]
    F2,6BP restores mitochondrial genome integrity in Huntington's Disease.
    Anirban Chakraborty, Santi M Mandal, Mikita Mankevich, Sravan Gopalkrishnashetty Sreenivasmurthy, Muralidhar L Hegde, Balaji Krishnan, Gourisankar Ghosh, Tapas Hazra.
      Several reports have indicated that impaired mitochondrial function contributes to the development and progression of Huntington's disease (HD). Mitochondrial genome damage, particularly DNA strand breaks (SBs), is a potential cause for its compromised functionality. We have recently demonstrated that the activity of polynucleotide kinase 3'-phosphatase (PNKP), a critical DNA end-processing enzyme, is significantly reduced in the nuclear extract of HD patients due to lower level of a metabolite fructose-2,6 bisphosphate (F2,6BP), a biosynthetic product of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3), leading to persistent DNA SBs with 3'-phosphate termini, refractory to subsequent steps for repair completion. PNKP also plays a pivotal role in maintaining mitochondrial genome integrity. In this report, we provide evidence that both PFKFB3 and F2,6BP, an allosteric modulator of glycolysis, are also present in the mitochondria. Notably, the level of F2,6BP, a cofactor of PNKP, is significantly decreased due to the degradation of PFKFB3 in the mitochondrial extract of HD patients' brain. PNKP activity is thus severely decreased in the mitochondrial extract; however, addition of F2,6BP restored PNKP activity. Moreover, supplementation of F2,6BP in HD mouse striatal neuronal cells restored mitochondrial genome integrity and partially restored mitochondrial membrane potential and prevented pathogenic aggregate formation. We observed similar restoration of mitochondrial genome integrity in HD drosophila supplemented with F2,6BP. Our findings, therefore, suggest that F2,6BP or its structural analog hold promise as a therapeutic for restoring both nuclear and mitochondrial genome integrity and thereby of organismal health.
    DOI:  https://doi.org/10.1101/2024.11.04.621834
  4. Brain Res Bull. 2024 Nov 20. pii: S0361-9230(24)00271-5. [Epub ahead of print] 111137
    Amyloid Beta-Induced Mitochondrial Dysfunction and Endothelial Permeability in Cerebral Microvascular Endothelial cells: the protective role of Dexmedetomidine.
    Haifeng Zhao, Mingyue Fan, Jin Zhang, Yi Gao, Liang Chen, Lining Huang.
      Postoperative cognitive dysfunction (POCD) is a common complication in patients who undergo anesthesia in different types of surgeries. Emerging evidence implicates elevated beta-amyloid (Aβ) in the pathogenesis of POCD. Meanwhile, Dexmedetomidine (DEX) has recently shown promise in reducing POCD incidence. This study aimed to elucidate the role of Aβ in inducing endothelial permeability in cerebral microvascular endothelial cells and the underlying mechanisms and testing the effects of DEX. We demonstrated that Aβ1-42, the prevalent Aβ form related to POCD, is cytotoxic to HBMECs, increasing transendothelial permeability and inducing mitochondrial dysfunction, as evidenced by elevated mitochondrial reactive oxygen species (ROS) and decreased ATP production and mitochondrial membrane potential. Furthermore, Aβ1-42 was shown to inhibit Sirt3, exacerbating mitochondrial dysfunction. Conversely, DEX was found to prevent Aβ1-42-induced mitochondrial dysfunction and permeability increases and preserved tight junction proteins in HBMECs.These findings suggest that DEX, as a Sirt3 activator, may offer a pharmacological strategy to mitigate Aβ1-42-related cerebral microvascular endothelial cell dysfunction and preserve cognitive function post-surgery.
    Keywords:  Blood–brain barrier (BBB) permeability; Dexmedetomidine (DEX); HBMECs; Postoperative cognitive dysfunction (POCD); Sirt3; amyloid-β (Aβ)
    DOI:  https://doi.org/10.1016/j.brainresbull.2024.111137
  5. Mol Cell. 2024 Nov 21. pii: S1097-2765(24)00880-3. [Epub ahead of print]84(22): 4261-4263
    AMPK: Balancing mitochondrial quality and quantity through opposite regulation of mitophagy pathways.
    Hui Jiang.
      In this issue of Molecular Cell, Longo et al.1 reveal that AMPK, a regulatory kinase activated by metabolic stress, inhibits NIX/BNIP3-dependent mitophagy to preserve mitochondrial quantity and activates PINK1/Parkin-dependent mitophagy to ensure mitochondrial quality.
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.040
  6. Int J Biol Macromol. 2024 Nov 18. pii: S0141-8130(24)08650-1. [Epub ahead of print] 137840
    Targeting mitochondria in Cancer therapy: Machine learning analysis of hyaluronic acid-based drug delivery systems.
    Giorgia Natalia Iaconisi, Amer Ahmed, Graziantonio Lauria, Nunzia Gallo, Giuseppe Fiermonte, Mary K Cowman, Loredana Capobianco, Vincenza Dolce.
       BACKGROUND: Mitochondrial alterations play a crucial role in the development and progression of cancer. Dysfunctional mitochondria contribute to the acquisition of key hallmarks of cancer, including sustained proliferative signaling, evasion of growth suppressors, and resistance to cell death. Consequently, targeting mitochondrial dysfunction has emerged as a promising therapeutic strategy. Hyaluronic acid (HA), a naturally occurring glycosaminoglycan, has garnered significant attention due to its multifaceted roles in cancer biology.
    METHODS: We employed a Systematic Literature Review (SLR) approach to examine a collection of 90 scientific publications using a text mining technique leveraging the Latent Dirichlet Allocation (LDA) algorithm.
    RESULTS: The result of this activity, performed through the MySLR digital platform, allowed us to identify a set of two distinct topics representing the research domain. Specifically, Topic 1 comprised 41 papers, while Topic 2 comprised 49 papers.
    CONCLUSIONS: The computational analysis highlighted that the integration of HA into drug delivery systems represents a promising approach to enhance the effectiveness and safety of cancer therapies. The discussed clinical trials provided compelling evidence of the potential of HA-based treatments in targeting cancer cells while minimizing adverse effects on healthy tissues.
    Keywords:  Apoptosis; Clinical trials; Hyaluronan; Hyaluronic acid; Machine learning; Mitochondria; Tumor; cancer
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.137840
  7. Trends Immunol. 2024 Nov 20. pii: S1471-4906(24)00272-2. [Epub ahead of print]
    Nanotube-mediated mitochondrial transfer: power to the T cells!
    Cosima T Baldari.
      The success of T cell-based immunotherapies is limited by exhaustion, which is associated with mitochondrial dysfunction. Baldwin and colleagues show that bone marrow stromal cells (BMSCs) use nanotubes to transfer mitochondria to T cells, which increases mitochondria mass and fitness and boosts antitumor efficacy. The results pave the way to organelle-based therapies against cancer.
    DOI:  https://doi.org/10.1016/j.it.2024.11.001
  8. Mol Neurobiol. 2024 Nov 23.
    Resveratrol: A Natural Compound Targeting the PI3K/Akt/mTOR Pathway in Neurological Diseases.
    Biswajit Kumar Utpal, Fatima Zohra Mokhfi, Mehrukh Zehravi, Sherouk Hussein Sweilam, Jeetendra Kumar Gupta, Shaik Kareemulla, Ronald Darwin C, A Anka Rao, Voleti Vijaya Kumar, Pavankumar Krosuri, Dharani Prasad, Sharukh L Khan, Sajib Chandra Roy, Safia Obaidur Rab, Mohammed Ali Alshehri, Talha Bin Emran.
      Neurological diseases (NDs), including neurodegenerative disorders and acute injuries, are a significant global health concern. The PI3K/Akt/mTOR pathway, a crucial signaling cascade, is responsible for the survival of cells, proliferation, and metabolism. Dysregulation of this pathway has been linked to neurological conditions, indicating its potential as a vital target for therapeutic approaches. Resveratrol (RSV), a natural compound found in berries, peanuts, and red grapes, has antioxidant, anti-cancer, and anti-inflammatory effects. Its ability to modulate the PI3K/Akt/mTOR pathway has been interesting in NDs. Studies have shown that RSV can activate the PI3K/Akt pathway, promoting cell survival and inhibiting apoptosis of neuronal cells. Its impact on mTOR, a downstream effector of Akt, further contributes to its neuroprotective effects. RSV's ability to restore autophagic flux presents a promising avenue for therapeutic intervention. Its anti-inflammatory properties suppress inflammatory responses by inhibiting key signaling molecules within the pathway. Additionally, RSV's role in enhancing mitochondrial function contributes to its neuroprotective profile. This study highlights RSV's potential as a multifaceted therapeutic agent in NDs, specifically by PI3K/Akt/mTOR pathway modulation. Additional investigation is required to optimize its therapeutic capacity in diverse neurological conditions.
    Keywords:  Clinical studies; Neurological diseases; PI3K/Akt/mTOR pathway; Resveratrol
    DOI:  https://doi.org/10.1007/s12035-024-04608-4
  9. Lancet. 2024 Nov 13. pii: S0140-6736(24)01883-X. [Epub ahead of print]
    Passive anti-amyloid β immunotherapy in Alzheimer's disease-opportunities and challenges.
    Michael T Heneka, David Morgan, Frank Jessen.
      With the advent of the first disease-modifying, anti-amyloid β-directed passive immunotherapy for Alzheimer's disease, questions arise who, when, and how to treat. This paper describes shortly the pathogenic basis of and preclinical data, which have, more than two decades ago, initiated the development of this vaccination therapy. We discuss clinical trial results of aducanumab, lecanemab, and donanemab. We also review appropriate use recommendations of these novel treatments on patient selection and safety monitoring. Furthermore, estimations of numbers of patient who will qualify for treatment regarding inclusion and exclusion criteria and estimations on readiness of health-care systems for identifying the right patients and for providing the treatment are reported. In our view, we are experiencing a fundamental shift from syndrome-based Alzheimer's dementia care to early, biomarker-guided treatment of Alzheimer's disease. This shift requires substantial adjustments of infrastructure and resources, but also holds promise of eventually achieving substantial slowing of disease progression and delaying dementia.
    DOI:  https://doi.org/10.1016/S0140-6736(24)01883-X
  10. Free Radic Biol Med. 2024 Nov 18. pii: S0891-5849(24)01054-2. [Epub ahead of print]
    Discovery of Gallic Acid-Based Mitochondriotropic Antioxidant Attenuates LPS-Induced Neuroinflammation.
    Shubham Garg, Aniket Jana, Sanju Gupta, Mohammad Umar Arshi, Prabir Kumar Gharai, Juhee Khan, Rajsekhar Roy, Surajit Ghosh.
      Mitochondria are complex organelle that plays a pivotal role in energy metabolism, regulation of stress responses, and also serve as a major hub for biosynthetic processes. In addition to their well-established function in cellular energetics, it also serves as the primary site for the origin of intracellular reactive oxygen species (ROS), which function as signaling molecules and can lead to oxidative stress when generated in excess. Moreover, mitochondrial dysfunction is one of the leading cause of neuroinflammation. In this regard, we have rationally designed a triazine derived mitochondriotropic antioxidants (Mito-TBA), based on gallic acid and triphenylphosphonium (TPP) cation to specifically target mitochondria to mitigate neuroinflammation. In vitro Mito-TBA-3 inhibits mitoautophagy, offers neuroprotection by inhibiting the LPS induced TLR-4 activation and activating the Nrf-2/ ARE pathway in PC-12 derived neurons. In vivo Mito-TBA-3 rescue memory deficit, reversed depression like behavior, inhibited neuroinflammation, and decreased proinflammatory cytokines in LPS induced neuroinflammation rat model. Overall, based on biophysical, in vitro and in vivo analysis, Mito-TBA-3 offers valuable insights as a potent therapeutic lead molecule to combat neurodegeneration even outperforming a well-known non-steroidal anti-inflammatory drug (Aspirin), it also has the potential to use as a promising therapeutic candidate for other mitochondrial oxidative stress related disorders.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.11.020
  11. Trends Biochem Sci. 2024 Nov 21. pii: S0968-0004(24)00254-8. [Epub ahead of print]
    Textbook oxidative phosphorylation needs to be rewritten.
    Alicia J Kowaltowski, Fernando Abdulkader.
      Oxidative phosphorylation (OxPhos) is the energy-transfer process that generates most of our ATP, fueled by proton and electrical gradients across the inner mitochondrial membrane. A new surprising finding by Hernansanz-Agustín et al. demonstrates that between one-third and half of this gradient is attributable to Na+, transported in exchange for protons within complex I.
    Keywords:  complex I; ion transport; mitochondria; oxidative phosphorylation; sodium–proton exchange
    DOI:  https://doi.org/10.1016/j.tibs.2024.11.002
  12. bioRxiv. 2024 Oct 29. pii: 2024.10.28.620733. [Epub ahead of print]
    A mitochondrial redox switch licenses the onset of morphogenesis in animals.
    Updip Kahlon, Francesco Dalla Ricca, Saraswathi J Pillai, Marine Olivetta, Kevin M Tharp, Li-En Jao, Omaya Dudin, Kent McDonald, Mustafa G Aydogan.
      Embryos undergo pre-gastrulation cleavage cycles to generate a critical cell mass before transitioning to morphogenesis. The molecular underpinnings of this transition have traditionally centered on zygotic chromatin remodeling and genome activation1,2, as their repression can prevent downstream processes of differentiation and organogenesis. Despite precedents that oxygen depletion can similarly suspend development in early embryos3-6, hinting at a pivotal role for oxygen metabolism in this transition, whether there is a bona fide chemical switch that licenses the onset of morphogenesis remains unknown. Here we discover that a mitochondrial oxidant acts as a metabolic switch to license the onset of animal morphogenesis. Concomitant with the instatement of mitochondrial membrane potential, we found a burst-like accumulation of mitochondrial superoxide (O2 -) during fly blastoderm formation. In vivo chemistry experiments revealed that an electron leak from site IIIQo at ETC Complex III is responsible for O2 - production. Importantly, depleting mitochondrial O2 - fully mimics anoxic conditions and, like anoxia, induces suspended animation prior to morphogenesis, but not after. Specifically, H2O2, and not ONOO-, NO, or HO•, can single-handedly account for this mtROS-based response. We demonstrate that depleting mitochondrial O2 - similarly prevents the onset of morphogenetic events in vertebrate embryos and ichthyosporea, close relatives of animals. We postulate that such redox-based metabolic licensing of morphogenesis is an ancient trait of holozoans that couples the availability of oxygen to development, conserved from early-diverging animal relatives to vertebrates.
    DOI:  https://doi.org/10.1101/2024.10.28.620733
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