bims-drumid Biomed News
on Drugs for mitochondrial diseases
Issue of 2024–12–08
seven papers selected by
Volkmar Weissig, Midwestern University
  1. Inside-out submitochondrial particles affect the mitochondrial permeability transition pore opening under conditions of mitochondrial dysfunction.
  2. Pioneering Advances and Innovative Applications of Mesoporous Carriers for Mitochondria-Targeted Therapeutics.
  3. Mitochondrial Transplantation in Brain Disorders: Achievements, Methods, and Challenges.
  4. Mitochondrial-targeted liposome-based drug delivery - Therapeutic potential and challenges.
  5. Extracellular Vesicles in Idiopathic Pulmonary Fibrosis: Pathogenesis, Biomarkers and Innovative Therapeutic Strategies.
  6. Extracellular vesicles for delivering therapeutic agents in ischemia/reperfusion injury.
  7. A Novel Method for Mitochondrial Membrane Potential Detection in Heart Tissue Following Ischemia-reperfusion in Mice.
  1. Biochim Biophys Acta Bioenerg. 2024 Nov 29. pii: S0005-2728(24)00498-5. [Epub ahead of print]1866(1): 149528
    Inside-out submitochondrial particles affect the mitochondrial permeability transition pore opening under conditions of mitochondrial dysfunction.
    Cristina Algieri, Antonia Cugliari, Patrycja Anna Glogowski, Silvia Granata, Micaela Fabbri, Fabiana Trombetti, Maria Laura Bacci, Salvatore Nesci.
      The inside-out submitochondrial particles (IO-SMPs) showed a strong protective effect against mitochondrial permeability transition pore (mPTP) opening in mitochondria isolated from swine hearts 3 h after explantation. The latter condition was used to emulate situation of mitochondrial damage. We identified that the protective effect of IO-SMPs cannot be attributed to a functional modulation of the enzymatic complexes involved in mPTP formation. Indeed, oxidative phosphorylation and F1FO-ATPase activity were not affected. Conversely, mPTP desensitization might be caused by structural modification. IO-SMP incorporation into the mitochondria can modulate the membrane-bound enzyme complexes' functionality, inducing F1FO-ATPase to be unable to carry out the conformational changes useful for mPTP opening. Thus, the data are a valid starting point for IO-SMP application in the treatment of impaired cardiovascular conditions supported by mPTP opening.
    Keywords:  F(1)F(O)-ATPase; Inside-out submitochondrial particles; Mitochondrial dysfunction; Mitochondrial permeability transition pore
    DOI:  https://doi.org/10.1016/j.bbabio.2024.149528
  2. Br J Biomed Sci. 2024 ;81 13707
    Pioneering Advances and Innovative Applications of Mesoporous Carriers for Mitochondria-Targeted Therapeutics.
    Mohamad Anas Al Tahan, Sana Al Tahan.
      Mitochondria, known as the cell's powerhouse, play a critical role in energy production, cellular maintenance, and stemness regulation in non-cancerous cells. Despite their importance, using drug delivery systems to target the mitochondria presents significant challenges due to several barriers, including cellular uptake limitations, enzymatic degradation, and the mitochondrial membranes themselves. Additionally, barriers in the organs to be targetted, along with extracellular barriers formed by physiological processes such as the reticuloendothelial system, contribute to the rapid elimination of nanoparticles designed for mitochondrial-based drug delivery. Overcoming these challenges has led to the development of various strategies, such as molecular targeting using cell-penetrating peptides, genomic editing, and nanoparticle-based systems, including porous carriers, liposomes, micelles, and Mito-Porters. Porous carriers stand out as particularly promising candidates as drug delivery systems for targeting the mitochondria due to their large pore size, surface area, and ease of functionalisation. Depending on the pore size, they can be classified as micro-, meso-, or macroporous and are either ordered or non-ordered based on both size and pore uniformity. Several methods are employed to target the mitochondria using porous carriers, such as surface modifications with polyethylene glycol (PEG), incorporation of targeting ligands like triphenylphosphonium, and capping the pores with gold nanoparticles or chitosan to enable controlled and triggered drug delivery. Photodynamic therapy is another approach, where drug-loaded porous carriers generate reactive oxygen species (ROS) to enhance mitochondrial targeting. Further advancements have been made in the form of functionalised porous silica and carbon nanoparticles, which have demonstrated potential for effective drug delivery to mitochondria. This review highlights the various approaches that utilise porous carriers, specifically focusing on silica-based systems, as efficient vehicles for targeting mitochondria, paving the way for improved drug delivery strategies in mitochondrial therapies.
    Keywords:  TPP+; mesoporous silica; mitochondria; porous carriers; targeting
    DOI:  https://doi.org/10.3389/bjbs.2024.13707
  3. Neurosci Biobehav Rev. 2024 Dec 03. pii: S0149-7634(24)00440-8. [Epub ahead of print] 105971
    Mitochondrial Transplantation in Brain Disorders: Achievements, Methods, and Challenges.
    Aurélien Riou, Aline Broeglin, Amandine Grimm.
      Mitochondrial transplantation is a new treatment strategy aimed at repairing cellular damage by introducing healthy mitochondria into injured cells. The approach shows promise in protecting brain function in various neurological disorders such as traumatic brain injury/ischemia, neurodegenerative diseases, cognitive disorders, and cancer. These conditions are often characterized by mitochondrial dysfunction, leading to impaired energy production and neuronal death. The review highlights promising preclinical studies where mitochondrial transplantation has been shown to restore mitochondrial function, reduce inflammation, and improve cognitive and motor functions in several animal models. It also addresses significant challenges that must be overcome before this therapy can be clinically applied. Current efforts to overcome these challenges, including advancements in isolation techniques, cryopreservation methods, finding an appropriate mitochondria source, and potential delivery routes, are discussed. Considering the rising incidence of neurological disorders and the limited effectiveness of current treatments, this review offers a comprehensive overview of the current state of mitochondrial transplantation research and critically assesses the remaining obstacles. It provides valuable insights that could steer future studies and potentially lead to more effective treatments for various brain disorders.
    Keywords:  Cognitive disorders; ischemia; mitochondrial transplantation; neurodegenerative diseases; traumatic brain injury
    DOI:  https://doi.org/10.1016/j.neubiorev.2024.105971
  4. J Drug Target. 2024 Dec 02. 1-22
    Mitochondrial-targeted liposome-based drug delivery - Therapeutic potential and challenges.
    Lissette Sanchez-Aranguren, Mohamad Anas Al Tahan, Muhammad Uppal, Parag Juvale, Mandeep Kaur Marwah.
      Liposomes, as nanocarriers for therapeutics, are a prominent focus in translational medicine. Given their biocompatibility, liposomes are suitable drug delivery systems rendering highly efficient therapeutic outcomes with minimal off-site toxicity. In different scenarios of human disease, it is essential not only to maintain therapeutic drug levels but also to target them to the appropriate intracellular compartment. Mitochondria regulate cellular signalling, calcium balance, and energy production, playing a crucial role in various human diseases. The notion of focusing on mitochondria for targeted drug delivery was proposed several decades ago, yet the practical application of this idea and its translation to clinical use is still in development. Mitochondrial-targeted liposomes offer an alternative to standard drug delivery systems, potentially reducing off-target interactions, side effects, and drug dosage or frequency. . To advance this field, it is imperative to integrate various disciplines such as efficient chemical design, pharmacology, pharmaceutics, and cell biology. This review summarises scientific advances in the design, development and characterisation of novel liposome-based drug delivery systems targeting the mitochondria while revisiting their translational potential.
    Keywords:  liposomes; mitochondria; mitochondrial dysfunction; nanocarriers; targeted drug delivery
    DOI:  https://doi.org/10.1080/1061186X.2024.2437440
  5. Int J Nanomedicine. 2024 ;19 12593-12614
    Extracellular Vesicles in Idiopathic Pulmonary Fibrosis: Pathogenesis, Biomarkers and Innovative Therapeutic Strategies.
    Yibao Yang, Mengen Lv, Qing Xu, Xiaojuan Wang, Zhujun Fang.
      Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible interstitial lung disease caused by aberrant deposition of extracellular matrix in the lungs with significant morbidity and mortality. The therapeutic choices for IPF remain limited. Extracellular vesicles (EVs), as messengers for intercellular communication, are cell-secreted lipid bilayer nanoscale particles found in body fluids, and regulate the epithelial phenotype and profibrotic signaling pathways by transporting bioactive cargo to recipients in the pathogenesis of IPF. Furthermore, an increasing number of studies suggests that EVs derived from stem cells can be employed as a cell-free therapeutic approach for IPF, given their intrinsic tissue-homing capabilities and regeneration characteristics. This review highlights new sights of EVs in the pathogenesis of IPF, their potential as diagnostic and prognostic biomarkers, and prospects as novel drug delivery systems and next-generation therapeutics against IPF. Notably, bringing engineering strategies to EVs holds great promise for enhancing the therapeutic effect of anti-pulmonary fibrosis and promoting clinical transformation.
    Keywords:  diagnosis; extracellular vesicles; idiopathic pulmonary fibrosis; pathogenesis; therapy
    DOI:  https://doi.org/10.2147/IJN.S491335
  6. Asian J Pharm Sci. 2024 Dec;19(6): 100965
    Extracellular vesicles for delivering therapeutic agents in ischemia/reperfusion injury.
    Weihang Zhou, Xinchi Jiang, Jianqing Gao.
      Ischemia/reperfusion (I/R) injury is marked by the restriction and subsequent restoration of blood supply to an organ. This process can exacerbate the initial tissue damage, leading to further disorders, disability, and even death. Extracellular vesicles (EVs) are crucial in cell communication by releasing cargo that regulates the physiological state of recipient cells. The development of EVs presents a novel avenue for delivering therapeutic agents in I/R therapy. The therapeutic potential of EVs derived from stem cells, endothelial cells, and plasma in I/R injury has been actively investigated. Therefore, this review aims to provide an overview of the pathological process of I/R injury and the biophysical properties of EVs. We noted that EVs serve as nontoxic, flexible, and multifunctional carriers for delivering therapeutic agents capable of intervening in I/R injury progression. The therapeutic efficacy of EVs can be enhanced through various engineering strategies. Improving the tropism of EVs via surface modification and modulating their contents via preconditioning are widely investigated in preclinical studies. Finally, we summarize the challenges in the production and delivery of EV-based therapy in I/R injury and discuss how it can advance. This review will encourage further exploration in developing efficient EV-based delivery systems for I/R treatment.
    Keywords:  Drug delivery; Extracellular vesicle engineering; Extracellular vesicles; Ischemia/reperfusion injury; Nanocarrier
    DOI:  https://doi.org/10.1016/j.ajps.2024.100965
  7. Curr Med Sci. 2024 Dec 04.
    A Novel Method for Mitochondrial Membrane Potential Detection in Heart Tissue Following Ischemia-reperfusion in Mice.
    Chao Yin, Chen-Xing Huang, Le Pan, Ke-Jia Jin, Ying Wang, Meng-Ying Cao, Hong Lin, Pan Gao, Na Li, Hui Gong, Yun-Zeng Zou.
       OBJECTIVE: Myocardial ischemia-reperfusion (I/R) injury is associated with a significant reduction in the mitochondrial membrane potential (MMP, ΔΨm). Fluorescence-based assays are effective for labelling active mitochondria in living cells; their application in heart tissue, however, represents a challenge because of a low yield of viable cardiomyocytes after cardiac perfusion. This study aimed to examine a novel method for detecting the changes in the MMP of mouse heart tissue following I/R injury.
    METHODS: The I/R model was established, which was characterized by distinct ischemic area and apoptosis in heart tissue. The MMP was detected via a confocal microscope after the ascending aorta was clamped and the mitochondrial probe solution (containing Mito-Tracker Deep Red FM) was perfused from the apex via a peristaltic pump.
    RESULTS: This method enabled the distribution of the probe solution throughout the cardiac tissue via the coronary circulation. Fluorescence detection revealed that the MMP was profoundly reduced in both ischemic area and border area following I/R when compared with that in the sham group. There was no obvious difference in the MMP of the remote area between the I/R group and the sham group.
    CONCLUSION: This study presents a novel method for detecting the MMP in heart tissue, and this method will facilitate the evaluation of changes in the MMP in different regions following I/R.
    Keywords:  heart tissue; ischaemia-reperfusion; mitochondrial function; mitochondrial membrane potential
    DOI:  https://doi.org/10.1007/s11596-024-2956-1
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