bims-drumid Biomed News
on Drugs for mitochondrial diseases
Issue of 2024–12–29
six papers selected by
Volkmar Weissig, Midwestern University
  1. Nuclear respiratory factor-1 (NRF1) induction drives mitochondrial biogenesis and attenuates amyloid beta-induced mitochondrial dysfunction and neurotoxicity.
  2. The Mitochondria-Targeted Micelle Inhibits Alzheimer's Disease Progression by Alleviating Neuronal Mitochondrial Dysfunction and Neuroinflammation.
  3. Mitochondrial-targeted therapies in traumatic brain injury: From bench to bedside.
  4. Mitochondria-targeting materials and therapies for regenerative engineering.
  5. Breaking Through Physiological Barriers: Nanorobotic Strategies for Active Drug Delivery.
  6. Mitochondria-targeted antioxidant MitoQ improves the quality of low temperature-preserved yak semen via alleviating oxidative stress.
  1. Neurotherapeutics. 2024 Dec 26. pii: S1878-7479(24)00200-9. [Epub ahead of print] e00513
    Nuclear respiratory factor-1 (NRF1) induction drives mitochondrial biogenesis and attenuates amyloid beta-induced mitochondrial dysfunction and neurotoxicity.
    Matteo Massaro, Gherardo Baudo, Hyunho Lee, Haoran Liu, Elvin Blanco.
      Mitochondrial dysfunction is an important driver of neurodegeneration and synaptic abnormalities in Alzheimer's disease (AD). Amyloid beta (Aβ) in mitochondria leads to increased reactive oxygen species (ROS) production, resulting in a vicious cycle of oxidative stress in coordination with a defective electron transport chain (ETC), decreasing ATP production. AD neurons exhibit impaired mitochondrial dynamics, evidenced by fusion and fission imbalances, increased fragmentation, and deficient mitochondrial biogenesis, contributing to fewer mitochondria in brains of AD patients. Nuclear respiratory factor-1 (NRF1) is a regulator of mitochondrial biogenesis through its activation of mitochondrial transcription factor A (TFAM). Our hypothesis posited that NRF1 induction in neuronal cells exposed to amyloid β1-42 (Aβ1-42) would increase de novo mitochondrial synthesis and improve mitochondrial function, restoring neuronal survival. Following NRF1 messenger RNA (mRNA) transfection of Aβ1-42-treated SH-SY5Y cells, a marked increase in mitochondrial mass was observed. Metabolic programming toward enhanced oxidative phosphorylation resulted in increased ATP production. Oxidative stress in the form of mitochondrial ROS accumulation was reduced and mitochondrial membrane potential preserved. Mitochondrial homeostasis was maintained, evidenced by balanced fusion and fission processes. Ultimately, improvement of mitochondrial function was associated with significant decreases in Aβ1-42-induced neuronal death and neurite disruption. Our findings highlight the potential of NRF1 upregulation to counteract Aβ1-42-associated mitochondrial dysfunction and neurodegenerative cell processes, opening avenues for innovative therapeutic approaches aimed at safeguarding mitochondrial health in AD neurons.
    Keywords:  Alzheimer's disease; Amyloid beta; Mitochondrial biogenesis; Mitochondrial dysfunction; Nuclear respiratory factor-1 (NRF1)
    DOI:  https://doi.org/10.1016/j.neurot.2024.e00513
  2. Small. 2024 Dec 23. e2408581
    The Mitochondria-Targeted Micelle Inhibits Alzheimer's Disease Progression by Alleviating Neuronal Mitochondrial Dysfunction and Neuroinflammation.
    Wenqiang Qian, Daozhou Liu, Jie Liu, Miao Liu, Qifeng Ji, Bangle Zhang, Zhifu Yang, Ying Cheng, Siyuan Zhou.
      Mitochondrial dysfunction plays an important role in neuroinflammation and cognitive impairment in Alzheimer's disease (AD). Herein, this work designs a mitochondria-targeted micelle CsA-TK-SS-31 (CTS) to block the progression of AD by simultaneously alleviating mitochondrial dysfunction in microglia and neurons. The mitochondria-targeted peptide SS-31 drives cyclosporin A (CsA) to penetrate the blood-brain barrier (BBB) and delivers CsA to mitochondria of microglia and neurons in the brains of 5 × FAD mice. Under the high level of reactive oxygen species (ROS) environment in damaged mitochondria of microglia and neurons, the linker (thioketal, TK) between CsA and SS-31 is broken and CsA and SS-31 are released while consuming ROS in the microenvironment. The released CsA and SS-31 synergistically restore the mitochondrial membrane potential and the balance between the fission and fusion of mitochondria, which subsequently protect neurons from apoptosis and reduce the activation of microglia in the brains of 5 × FAD mice. Ultimately, the neuroinflammation and cognitive impairment of 5 × FAD mice are ameliorated. This research provides a synergistic treatment strategy for AD through alleviating mitochondrial dysfunction to reduce neuroinflammation and restore the function of neurons simultaneously.
    Keywords:  alzheimer's disease; amyloid β; microglia; mitochondrial dysfunction; neuroinflammation
    DOI:  https://doi.org/10.1002/smll.202408581
  3. Neurotherapeutics. 2024 Dec 24. pii: S1878-7479(24)00202-2. [Epub ahead of print] e00515
    Mitochondrial-targeted therapies in traumatic brain injury: From bench to bedside.
    Sidra Tabassum, Silin Wu, Chang-Hun Lee, Bosco Seong Kyu Yang, Aaron M Gusdon, Huimahn A Choi, Xuefang S Ren.
      Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide, with limited effective therapeutic options currently available. Recent research has highlighted the pivotal role of mitochondrial dysfunction in the pathophysiology of TBI, making mitochondria an attractive target for therapeutic intervention. This review comprehensively examines advancements in mitochondrial-targeted therapies for TBI, bridging the gap from basic research to clinical applications. We discuss the underlying mechanisms of mitochondrial damage in TBI, including oxidative stress, impaired bioenergetics, mitochondrial dynamics, and apoptotic pathways. Furthermore, we highlight the complex interplay between mitochondrial dysfunction, inflammation, and blood-brain barrier (BBB) integrity, elucidating how these interactions exacerbate injury and impede recovery. We also evaluate various preclinical studies exploring pharmacological agents, gene therapy, and novel drug delivery systems designed to protect and restore mitochondrial function. Clinical trials and their outcomes are assessed to evaluate the translational potential of mitochondrial-targeted therapies in TBI. By integrating findings from bench to bedside, this review emphasizes promising therapeutic avenues and addresses remaining challenges. It also provides guidance for future research to pave the way for innovative treatments that improve patient outcomes in TBI.
    Keywords:  Mitochondrial dysfunction; Novel drug delivery system; Therapeutic interventions; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.neurot.2024.e00515
  4. Biomaterials. 2024 Dec 15. pii: S0142-9612(24)00559-3. [Epub ahead of print]316 123023
    Mitochondria-targeting materials and therapies for regenerative engineering.
    Hongying Fu, Jingrong Cheng, Le Hu, Boon Chin Heng, Xuehui Zhang, Xuliang Deng, Yang Liu.
      The hemostatic, inflammatory, proliferative, and remodeling phases of healing require precise spatiotemporal coordination and orchestration of numerous biological processes. As the primary energy generators in the cell, mitochondria play multifunctional roles in regulating metabolism, stress reactions, immunity, and cell density during the process of tissue regeneration. Mitochondrial dynamics involves numerous crucial processes, fusion, fission, autophagy, and translocation, which are all necessary for preserving mitochondrial function, distributing energy throughout cells, and facilitating cellular signaling. Tissue regeneration is specifically associated with mitochondrial dynamics due to perturbations of Ca2+, H2O2 and ROS levels, which can result in mitochondrial malfunction. Increasing evidence from multiple models suggests that clinical interventions or medicinal drugs targeting mitochondrial dynamics could be a promising approach. This review highlights significant advances in the understanding of mitochondrial dynamics in tissue regeneration, with specific attention on mitochondria-targeting biomaterials that accelerate multiple tissues' regeneration by regulating mitochondrial metabolism. The innovations in nanomaterials and nanosystems enhance mitochondrial-targeting therapies are critically examined with the prospects of modulating mitochondrial dynamics for new therapies in regenerative engineering.
    Keywords:  Mitochondria-targeting materials; Mitochondrial dynamics; Mitochondrial transfer; Regenerative engineering
    DOI:  https://doi.org/10.1016/j.biomaterials.2024.123023
  5. Bioconjug Chem. 2024 Dec 27.
    Breaking Through Physiological Barriers: Nanorobotic Strategies for Active Drug Delivery.
    Meng Mao, Yingjie Wu, Qiang He.
      Self-propelled micro/nanomotors (MNMs) represent a groundbreaking advancement in precision drug delivery, offering potential solutions to persistent challenges such as systemic toxicity, limited bioavailability, and nonspecific distribution. By transforming various energy sources into mechanical motion, MNMs are able to autonomously navigate through complex physiological environments, facilitating targeted delivery of therapeutic agents to previously inaccessible regions. However, to achieve efficient in vivo drug delivery, biomedical MNMs must demonstrate their ability to overcome crucial physiological barriers encompassing mucosal surfaces, blood flow dynamics, vascular endothelium, and cellular membrane. This review provides a comprehensive overview of the latest strategies developed to address these obstacles while also analyzing the broader challenges and opportunities associated with clinical translation. Our objective is to establish a solid foundation for future research in medical MNMs by focusing on enhancing drug delivery efficiency and advancing precision medicine, ultimately paving the way for practical theragnostic applications and wider clinical adoption.
    DOI:  https://doi.org/10.1021/acs.bioconjchem.4c00480
  6. Anim Reprod Sci. 2024 Dec 19. pii: S0378-4320(24)00280-X. [Epub ahead of print]273 107680
    Mitochondria-targeted antioxidant MitoQ improves the quality of low temperature-preserved yak semen via alleviating oxidative stress.
    Yanjin Zhu, Jun Yu, Qinhui Yang, Yumian Xie, Xupeng Li, Zhuo Chen, Yan Xiong, Wei Fu, Honghong He, Shi Yin, Daoliang Lan, Jian Li, Xianrong Xiong.
      Low-temperature preservation of yak semen during transportation and conservation is crucial to accelerate yak breeding. The effects of low-temperature cooling on yak semen quality, however, are poorly understood. This study aimed to determine the dose-dependent effect of mitochondria-targeted antioxidant "MitoQ" on the motility, oxidative status, and mitochondrial function of yak semen during low-temperature preservation. Semen samples were collected from six adult healthy Maiwa yaks and preserved at 4 ℃ in semen extender containing 0, 50, 100, 200, and 400 nM MitoQ, respectively. Firstly, the motility, membrane integrity, acrosome integrity, and abnormity index of yak spermatozoa were evaluated to determine the optimal MitoQ concentration. Next, the effect of MitoQ at the optimal concentration on spermatozoa antioxidant capacity, including reactive oxygen species (ROS) and malondialdehyde (MDA) contents, total antioxidant capacity (T-AOC), and superoxide dismutase content (SOD) levels, as well as mitochondrial membrane potential were analyzed. Up to 96 h of low-temperature storage, 200 nM MitoQ showed the most optimal effect on motility, membrane integrity, and acrosome integrity (P < 0.05) but not on sperm morphology (P > 0.05). Also, 200 nM MitoQ markedly reduced yak spermatozoa ROS and MDA contents for up to 48 h of low-temperature storage (P < 0.05). Finally, 200 nM MitoQ significantly improved T-AOC, SOD, and mitochondrial membrane potential for up to 24, 48, and 72 h of low-temperature storage, respectively (P < 0.05). In summary, semen extender supplementation with 200 nM MitoQ is beneficial for low-temperature yak semen preservation via improving the oxidative status.
    Keywords:  Cold-store; MitoQ; Oxidative stress; Semen; Yak
    DOI:  https://doi.org/10.1016/j.anireprosci.2024.107680
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