bims-mihora Biomed News
on Mitohormesis, repair and aging
Issue of 2026–01–04
fourteen papers selected by
Lisa Patel, Istesso
  1. Pterostilbene restores mitochondrial retrograde signaling to activate protective stress responses in Parkinson's disease.
  2. When Mitochondria Falter, the Barrier Fails: Mechanisms of Inner Blood-Retinal Barrier (iBRB) Injury and Opportunities for Mitochondria-Targeted Repair.
  3. The Janus framework of the integrated stress response: from homeostasis to maladaptation.
  4. Linking Cell Architecture to Mitochondrial Signaling in Neurodegeneration: The Role of Intermediate Filaments.
  5. CDC123 is an ATPase that modulates mRNA translation and the Integrated Stress Response by regulating eIF2 complex assembly.
  6. Uptake mechanisms and functions of isolated mitochondria in mesenchymal stromal cells.
  7. Neural stem cells fate under neuroinflammatory conditions and oxidative stress response.
  8. Self-renewal of neuronal mitochondria through asymmetric division.
  9. Targeting innovative therapeutic approaches to the hallmarks of aging to combat Alzheimer's disease.
  10. PGC-1α: key regulator of mitochondrial biogenesis and cellular differentiation in metabolic and regenerative tissues.
  11. Hierarchically Targeting and ROS-Responsive Platform for Diabetic Periodontitis Treatment through Mitochondrial Repair in M1 Macrophages.
  12. Influence of Stress-Induced Senescence on the Secretome of Primary Mesenchymal Stromal Cells.
  13. ER stress sensors at the ER-mitochondrial interface, controlling mitochondrial health in neurodegenerative diseases.
  14. Novel DNJ Derivative Ameliorates Cardiac Hypertrophy by Targeting OPA1 and Restoring Mitochondrial Health.
  1. Front Aging Neurosci. 2025 ;17 1692777
    Pterostilbene restores mitochondrial retrograde signaling to activate protective stress responses in Parkinson's disease.
    Fanshuai Zeng, Wei Li, Liyue Yang, Lu Yao, Xinna Wang.
      Parkinson's disease (PD) is the selective demise of dopaminergic neurons in the substantia nigra. Conventional neuroprotective strategies based on exogenous antioxidants have shown minimal clinical efficacy. Emerging evidence suggests that neuronal loss in PD may stem not only from direct mitochondrial damage but, more critically, from the failure of an intrinsic "early-warning system"-the mitochondrial retrograde signaling (MRS) pathway-impairing the nucleus's ability to launch timely protective responses. This review repositions pterostilbene, a bioavailable dietary polyphenol, from a simple antioxidant to a "signal fidelity enhancer" that supports mitochondria-to-nucleus communication. By stabilizing mitochondrial function and modulating stress-sensing pathways, pterostilbene may restore MRS integrity and promote activation of endogenous defense mechanisms such as the mitochondrial unfolded protein response (UPRmt). The article advocates a paradigm shift in nutritional neuroprotection: from passive supplementation toward reinforcing the neuron's intrinsic capacity for self-maintenance and resilience.
    Keywords:  Parkinson’s disease; cellular resilience; dopaminergic neurons; mitochondrial retrograde signaling; neuroprotection; polyphenols; pterostilbene
    DOI:  https://doi.org/10.3389/fnagi.2025.1692777
  2. Int J Mol Sci. 2025 Dec 12. pii: 11984. [Epub ahead of print]26(24):
    When Mitochondria Falter, the Barrier Fails: Mechanisms of Inner Blood-Retinal Barrier (iBRB) Injury and Opportunities for Mitochondria-Targeted Repair.
    Ziyi Chen, Qianzi Jin, Jiajun Li, Keran Li.
      As the central hub of retinal metabolism, mitochondria are vital for sustaining the integrity of the inner blood-retinal barrier (iBRB), which is fundamental to retinal homeostasis. Mitochondrial dysfunction accelerates severe iBRB disruption, a process which is increasingly implicated in a cascade of mitochondrial pathologies including mitochondrial DNA destabilization, oxidative stress, calcium homeostasis disruption, mitochondrial autophagy deficiency, and dysregulated dynamic regulation. This review establishes the iBRB as a crossroads for metabolic, redox, and inflammatory signaling. By analyzing evidence from diabetic retinopathy and retinal vein occlusion models, we clarify how mitochondrial decline translates local energy deficiency into chronic barrier dysfunction. We posit that restoring mitochondrial function is indispensable for vascular resilience and regeneration, a conclusion drawn from integrating molecular, cellular, and translational findings. To advance mitochondrial discoveries into clinical practice, subsequent studies must prioritize achieving spatiotemporally controlled, cell-type-specific interventions with robust in vivo efficacy, thereby successfully translating mitochondrial science into clinical vascular medicine.
    Keywords:  diabetic retinopathy; inner blood-retinal barrier; mitochondrial dysfunction; mitochondrial plasticity; mitochondrial therapy; mitophagy; oxidative stress; retinal vein occlusion
    DOI:  https://doi.org/10.3390/ijms262411984
  3. Life Sci Alliance. 2026 Mar;pii: e202503523. [Epub ahead of print]9(3):
    The Janus framework of the integrated stress response: from homeostasis to maladaptation.
    Dogus M Altintas, Marina Cerqua, Paolo M Comoglio, Cédric Chaveroux.
      Every cell must adapt to environmental changes. When nutrients decrease, oxygen levels fall, or protein synthesis outpaces resources, cells activate stress pathways to restore balance. Among these, the integrated stress response (ISR) stands out for its capability to integrate diverse stress signals into a unified translational output. By temporarily slowing global protein synthesis while maintaining the selective translation of stress-adaptive factors, the ISR saves energy, redirects metabolism, and promotes either recovery or, if challenges surpass repair capacity, cell death. In many chronic diseases-including cancer, metabolic, inflammatory, and fibrotic disorders-ISR activity persists. Is this persistence merely a prolonged defensive phase, or does it represent a rewired, self-sustaining state with its own control mechanisms actively reshaping cell fate and disease? We argue that chronic ISR cannot be defined by time alone, challenging the monolithic view. It signifies a qualitative shift in regulation-from rhythmic homeostasis to entrenched maladaptation. Understanding this Janus framework is essential for elucidating the origins of pathology and for guiding future fundamental and translational research.
    DOI:  https://doi.org/10.26508/lsa.202503523
  4. Int J Mol Sci. 2025 Dec 08. pii: 11852. [Epub ahead of print]26(24):
    Linking Cell Architecture to Mitochondrial Signaling in Neurodegeneration: The Role of Intermediate Filaments.
    Emanuele Marzetti, Rosa Di Lorenzo, Riccardo Calvani, Hélio José Coelho-Júnior, Francesco Landi, Vito Pesce, Anna Picca.
      Mitochondrial dysfunction is a pivotal contributor to neurodegeneration. Neurons heavily rely on mitochondrial oxidative metabolism and therefore need highly efficient quality control mechanisms, including proteostasis, mitochondrial biogenesis, fusion-fission dynamics, and mitophagy, to sustain bioenergetics and synaptic function. With aging, deterioration of mitochondrial quality control pathways leads to impaired oxidative phosphorylation, excessive reactive oxygen species generation, calcium imbalance, and defective clearance of damaged organelles, ultimately compromising neuronal viability. Pathological protein aggregates, such as α-synuclein in Parkinson's disease, β-amyloid and tau in Alzheimer's disease, and misfolded superoxide dismutase 1 and transactive response DNA-binding protein 43 in amyotrophic lateral sclerosis, further aggravate mitochondrial stress, establishing self-perpetuating cycles of neurotoxicity. Such mitochondrial defects underscore mitochondria as a convergent pathogenic hub and a promising therapeutic target for neuroprotection. Intermediate filaments (IFs), traditionally viewed as passive structural elements, have recently gained attention for their roles in cytoplasmic organization, mitochondrial positioning, and energy regulation. Emerging evidence indicates that IF-mitochondria interactions critically influence organelle morphology and function in neurons. This review highlights the multifaceted involvement of mitochondrial dysfunction and IF dynamics in neurodegeneration, emphasizing their potential as targets for novel therapeutic strategies.
    Keywords:  axonal transport; cell architecture; cell quality; cytoskeleton; mitochondrial dynamics; mitochondrial quality; mitophagy; neurofilaments; neuron; reactive oxygen species
    DOI:  https://doi.org/10.3390/ijms262411852
  5. J Biol Chem. 2025 Dec 27. pii: S0021-9258(25)02968-0. [Epub ahead of print] 111116
    CDC123 is an ATPase that modulates mRNA translation and the Integrated Stress Response by regulating eIF2 complex assembly.
    Anthony L Erb, Sara K Young-Baird.
      Hyper- and hypo-activation of the Integrated Stress Response (ISR) results in impaired regulation of global and mRNA-specific translation in multiple disease contexts. During the ISR, specific stress-sensing kinases modulate translation by regulating the activity of the heterotrimeric eukaryotic translation initiation factor eIF2. Here, we identify the chaperone CDC123, which promotes eIF2 biogenesis, as a novel regulator of the ISR. We find that impaired CDC123 activity reduces eIF2 complex assembly, promoting the translational and cellular outcomes of the ISR through a noncanonical mechanism. Pharmacological or genetic strategies are sufficient to rescue the translational defects associated with impaired CDC123 activity. Additionally, we report functional insights into eIF2 heterotrimer formation and provide the first evidence that CDC123-mediated eIF2 complex assembly may be regulated by ATP hydrolysis. These data emphasize the essential contribution of eIF2 biogenesis in mRNA translation regulation, and highlight CDC123 as a possible therapeutic target in the treatment of ISR-related diseases.
    DOI:  https://doi.org/10.1016/j.jbc.2025.111116
  6. Sci Rep. 2025 Dec 29. 15(1): 44799
    Uptake mechanisms and functions of isolated mitochondria in mesenchymal stromal cells.
    Mai Kanai, Miyabi Goto, Shoko Itakura, Makiya Nishikawa, Kosuke Kusamori.
      Mitochondrial transplantation holds great promise as a therapeutic strategy; however, the mechanisms by which recipient cells interact with and internalize isolated mitochondria remain unclear. Therefore, in this study, we isolated functional mitochondria from mesenchymal stromal cells (MSCs) and characterized their biological activities and physicochemical properties. Additionally, effects of isolated mitochondria on MSC functions were evaluated. Treatment with isolated mitochondria promoted cell proliferation, improved cellular viability under stress conditions, and increased the oxygen consumption rate, indicating enhanced bioenergetic capacity. Uptake of isolated mitochondria by MSCs was visualized via fluorescence imaging and quantitatively assessed over time, showing progressive internalization within 24 h. To investigate the mechanism of mitochondrial uptake, endocytosis was chemically inhibited, which revealed that endocytic pathways contributed to the internalization of the isolated mitochondria. These findings suggest that MSCs incorporate isolated mitochondria via active uptake mechanisms and that the internalized mitochondria retain their functional activity. Collectively, our results provide critical evidence of mitochondrial internalization in MSCs and offer insights into the potential applications of mitochondrial therapy for various diseases.
    Keywords:  Biomedicine; Cellular uptake; Endocytosis; Mesenchymal stromal cell; Mitochondrial transplantation
    DOI:  https://doi.org/10.1038/s41598-025-28494-5
  7. Front Cell Neurosci. 2025 ;19 1736865
    Neural stem cells fate under neuroinflammatory conditions and oxidative stress response.
    Filippo Torrisi, Simona Denaro, Jenny Ragonese, Simona D'Aprile, Agata Zappalà, Rosalba Parenti.
      Neural stem cells (NSCs) are defined by their self-renewal capacity and multipotent differentiation potential, making them essential for nervous system development and for the maintenance of adult brain homeostasis. Although confined to the subventricular zone and the subgranular zone of the hippocampus in adulthood, NSCs preserve a functional capacity for neurogenesis and tissue regeneration. This regenerative potential becomes particularly important in neuropathological conditions, where tissue damage is often accompanied by neuroinflammation and oxidative stress. Within this hostile microenvironment, NSCs have to cope with inflammatory mediators and reactive oxygen species that can affect their survival, proliferation, and cellular differentiation. NSCs also are actively modulated by diverse molecular pathways in response to stress conditions promoting stemness or stem cell exhaustion. Therefore, understanding the crosstalk between neuroinflammatory and oxidative stress in NSCs fate is crucial for elucidating the mechanisms of neurogenesis and homeostasis recovery and for designing therapeutic strategies.
    Keywords:  NRF2; cytokines; differentiation; metabolic rewiring; redox homeostasis
    DOI:  https://doi.org/10.3389/fncel.2025.1736865
  8. bioRxiv. 2025 Dec 18. pii: 2025.12.17.694973. [Epub ahead of print]
    Self-renewal of neuronal mitochondria through asymmetric division.
    Tejashree Pradip Waingankar, Camryn Zurita, Angelica E Lang, Cliff Vuong, Ahmad Shami, Diana Bautista, Catherine Drerup, Samantha C Lewis.
      Mitochondrial ATP production is essential for life. Mitochondrial function depends on the spatio-temporal coordination of nuclear and mitochondrial genome expression, yet how this coordination occurs in highly polarized cells such as neurons remains poorly understood. Using high-resolution imaging in mouse peripheral sensory neurons and zebrafish larvae, we identified a sub-population of mitochondria enriched in mtDNA that are positioned at the collateral branch points of long sensory neurites, both in vitro and in vivo . While the mitochondria in neurites are generally depleted of mtDNA, those at axon branch points preferentially engage in mtDNA replication and transcription, accumulate nuclear-encoded mitochondrial mRNA, and are spatially linked to nascent cytosolic peptide synthesis. The mtDNA-positive mitochondrial pool exhibits asymmetric genome partitioning at division, shedding highly motile daughters that lack mtDNA. Asymmetric division rejuvenates the membrane potential of the mtDNA-rich, biogenesis-dedicated mitochondria. We also found that, in peripheral sensory neurons, axonal mitochondria rarely fuse or share matrix contents, explaining how differentiated daughters maintain their distinct composition and fate after fission. Thus, division-coupled mitochondrial self-renewal is yoked to neurite topology in sensory neurons, patterning mitochondrial diversity and homeostasis from micron to meter scales.
    DOI:  https://doi.org/10.64898/2025.12.17.694973
  9. Neural Regen Res. 2025 Dec 30.
    Targeting innovative therapeutic approaches to the hallmarks of aging to combat Alzheimer's disease.
    Michal Izrael, Orli Miriam Frenkel.
      Aging is the leading risk factor for neurodegenerative diseases, including Alzheimer's disease. Mounting evidence implicates twelve interconnected hallmarks of aging, such as genomic instability, mitochondrial dysfunction, cellular senescence, and altered intercellular communication, as core contributors to cognitive decline. In this review, we will first delineate the hallmarks of aging and their mechanistic roles according to their functions in the aging brain and Alzheimer's disease. These hallmarks can be grouped into four major functional clusters: (i) Genomic and epigenomic instability, (ii) proteostasis and organelle dysfunction, (iii) cellular fate and regenerative decline, and (iv) cellular senescence. Then, we provide an overview of innovative therapeutic approaches aimed at modifying these hallmarks, focusing on the emerging paradigm of supplementation of rejuvenation factors that are derived from young plasma, stem cell secretomes, or their derivatives (e.g., extracellular vesicles). Finally, we discuss key aging-related biological factors that can influence Alzheimer's disease progression and evaluate their potential as therapeutic targets.
    Keywords:  Alzheimer's disease; aging hallmarks; cellular senescence; genomic instability; neurodegeneration; proteostasis dysfunction; regenerative decline; rejuvenation factors; secretome
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00966
  10. Cell Biosci. 2025 Dec 27.
    PGC-1α: key regulator of mitochondrial biogenesis and cellular differentiation in metabolic and regenerative tissues.
    Lijuan Cao, Yanan Li, Artem Smirnov, Ramouna Voshtani, Tingting Wang, Changshun Shao, Eleonora Candi, Gerry Melino, Yufang Shi, Jiankai Fang.
      Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a crucial coactivator that regulates mitochondrial biogenesis and function across diverse tissues, including the brain, heart, skeletal muscle, bone marrow, and liver. The diversity of PGC-1α isoforms in distinct tissues allows this co-transcription factor to exert wide-ranging biological effects, including regulating mitochondrial functions, oxidative stress, and endoplasmic reticulum homeostasis. Here, we focus on the key roles of PGC-1α in cell differentiation. Initially identified in brown adipose tissue in response to cold exposure, PGC-1α regulates cell differentiation by modulating gene expression networks involved in mitochondrial biogenesis. PGC-1α influences cell fate in several cell types, including adipocytes, skeletal muscle cells, and bone marrow-derived cells. A deeper understanding of PGC-1α provides valuable insights into developmental biology, tissue formation, and potential therapeutic targets for regenerative medicine and disease treatment. This review explores recent progress in understanding the roles of PGC-1α in cell differentiation, offering an integrated perspective on its significance in tissue and organism development.
    Keywords:  Cell differentiation; Metabolic reprogramming; PGC-1α; Tissue regeneration
    DOI:  https://doi.org/10.1186/s13578-025-01519-2
  11. ACS Appl Mater Interfaces. 2025 Dec 28.
    Hierarchically Targeting and ROS-Responsive Platform for Diabetic Periodontitis Treatment through Mitochondrial Repair in M1 Macrophages.
    Wenjia Xie, Yuxuan Wang, Jicenyuan Wu, Xu Wang, Jiaxin Wu, Bin Cheng, Hao Feng, Xinxu Huang, Xinting Cheng, Junyu Chen, Qianbing Wan, Jian Wang, Xibo Pei.
      Diabetic periodontitis is characterized by persistent and aggravated inflammation, largely driven by a reactive oxygen species (ROS) vicious loop in M1 macrophages driven by mitochondrial dysfunction. To disrupt this pathogenic cascade, we developed hierarchically targeted polymeric nanoparticles (MPPT NPs) by conjugating the tuftsin peptide for selective uptake by M1 macrophages and loading mitoquinone mesylate (MitoQ) to restore mitochondrial function after mitochondrial localization. For local retention and responsive drug release, MPPT NPs were incorporated into a ROS-responsive hydrogel (MTP hydrogel) constructed by cross-linking poly(vinyl alcohol) (PVA) with a ROS-cleavable linker (N1-(4-boronobenzyl)-N3-(4-boronophenyl)-N1,N1,N3,N3-tetramethylpropane-1,3-diaminium (TSPBA)). This constructed platform not only enabled the on-demand release of MPPT NPs but also provided additional ROS-scavenging ability. In vitro studies demonstrated that MTTP NPs effectively repaired oxidatively damaged mitochondria and suppressed NLRP3 inflammasome priming and activation. MTP hydrogel platform reduced pro-inflammatory cytokine release and rescued inflammation-induced osteogenic impairment. In a diabetic periodontitis rat model, local administration of the MTP hydrogel significantly attenuated periodontal tissue destruction and promoted alveolar bone regeneration, achieving BV/TV 1.5 times that of previous reports. Collectively, this hierarchically targeted and ROS-responsive platform disrupts the ROS vicious loop in M1 macrophages by repairing damaged mitochondria, offering a promising therapeutic strategy for the management of diabetic periodontitis.
    Keywords:  diabetic periodontitis; inflammasome regulation; macrophage; mitochondrial dysfunction; nanoparticle hydrogel; reactive oxygen species
    DOI:  https://doi.org/10.1021/acsami.5c20136
  12. Biomolecules. 2025 Dec 13. pii: 1734. [Epub ahead of print]15(12):
    Influence of Stress-Induced Senescence on the Secretome of Primary Mesenchymal Stromal Cells.
    Daria Kashirina, Diana Matveeva, Mariia Ezdakova, Alexander Brzhozovskiy, Alexey Kononikhin, Ludmila Pastushkova, Irina Larina, Evgeny Nikolaev, Ludmila Buravkova, Andrey Ratushnyy.
      Mesenchymal stromal cells (MSCs) are promising therapeutic agents, largely due to their capacity for self-renewal, differentiation, and immunomodulation. Importantly, these beneficial effects are frequently mediated by the MSC secretome, which contains factors with anti-inflammatory, anti-apoptotic, and pro-regenerative properties. However, cellular senescence can impair these critical functions. To identify senescence-associated changes in the MSC secretome that may regulate aging and intercellular communication, we performed a mass spectrometry-based proteomic analysis of the conditioned medium from MSCs undergoing stress-induced senescence. Our analysis confirmed the upregulation of established aging markers, such as IL-6, PAI-1, and IGFBP7. Furthermore, we identified a significant increase in lesser-known senescence-associated secretory phenotype (SASP) components, including INHBA-a known inhibitor of proliferation-and DKK3, which blocks stromal cell pluripotency. Pathway analysis revealed that stress-induced senescence broadly affected proteins involved in glycolysis, immune response, hemostasis, and the regulation of cell death and the cell cycle. These alterations are likely to negatively impact the MSC microenvironment. Interestingly, the cellular response to senescence was dualistic. Alongside detrimental SASP factors, we observed an increase in protective proteins such as annexins (ANXA1, ANXA2), antioxidants (TXN, PRDX1, PRDX6), and the heat shock protein HSPB1, which collectively defend neighboring cells from inflammation and oxidative stress. These findings underscore the complex etiology of cellular senescence and the paradoxical nature of the SASP. The obtained data also emphasize the necessity of comprehensive proteomic profiling of the MSC secretome across different aging models to harness the full therapeutic potential of MSCs and their secretomes for regenerative medicine.
    Keywords:  SASP; mass spectrometry; mesenchymal stromal cells; proteomics; secretome; stress-induced senescence
    DOI:  https://doi.org/10.3390/biom15121734
  13. Front Neurosci. 2025 ;19 1665272
    ER stress sensors at the ER-mitochondrial interface, controlling mitochondrial health in neurodegenerative diseases.
    Chaitanya Kunja, Vaishali Kumar, Pradeep Kodam, Chamundeshwari Devi Gopu, Shuvadeep Maity.
      The endoplasmic reticulum (ER) and mitochondria are essential organelles that interact closely at specialized sites known as ER-mitochondria-associated membranes (MAMs). MAM is enriched with proteins from both the ER and mitochondria. ER stress sensors-inositol-requiring enzyme 1 (IRE1) and protein kinase RNA-like ER kinase (PERK) - are traditionally recognized for their roles in the unfolded protein response (UPR), which mitigates proteotoxic stress. However, recent studies reveal their non-canonical functions at MAMs, where they regulate calcium signaling, mitochondrial dynamics, and apoptosis through interactions with MAM-resident proteins. Disruption of these pathways is implicated in various diseases, particularly neurodegenerative disorders. This review highlights the emerging roles of IRE1 and PERK in preserving mitochondrial function and their relevance to neurodegeneration. It also examines pharmacological strategies targeting these proteins, which influence both UPR signaling and ER-mitochondrial communication, offering a comprehensive perspective on their roles in health and disease.
    Keywords:  ER stress sensors; ER-mitochondrial interactions; IRE1; UPR signaling; mitochondrial health; neurodegenerative diseases; pERK
    DOI:  https://doi.org/10.3389/fnins.2025.1665272
  14. Circ Res. 2025 Dec 29.
    Novel DNJ Derivative Ameliorates Cardiac Hypertrophy by Targeting OPA1 and Restoring Mitochondrial Health.
    Xue Ding, Yangwei Jiang, Xiaochen Wang, Chujun Li, Zhengyi Kong, Lei Fu, Zhaoying Lei, Huajian Cai, Yufei Dong, Chengyu Shi, Xinwan Su, Tilo Kunath, Ziyi Wang, Damiano Buratto, Aifu Lin, Jianzhong Shao, Dong Zhang, Zhong Liu, Ping Liang, Ruhong Zhou, Qingfeng Yan.
       BACKGROUND: Pathological cardiac hypertrophy, an abnormal enlargement of cardiomyocytes and interstitial fibrosis in response to sustained injury or pressure overload, may lead to heart failure or even sudden death. Affected patients often also exhibit myocardial mitochondrial dysfunction and associated structural damage. Discovering more potent mitochondrial-targeting compounds may therefore hold great benefit, both for elucidating the mechanisms of cardiac hypertrophy and for treating affected patients.
    METHODS: A series of novel 1-deoxynojirimycin (DNJ) derivatives was designed based on the unique binding mode of DNJ with OPA1 (optic atrophy 1). Two-step phenotypic screening was then performed using patient-specific cytoplasmic hybrid cells and iPSC-derived cardiomyocytes to identify promising candidates. Molecular dynamics simulations, combined with proteomic, biochemical, and physiological assays, were used to assess potential therapeutic mechanisms for mitochondrial disorders. OPA1 mutant cell lines were established to test candidate compound target specificity. Pathological cardiac hypertrophy models were established in mice and rats through angiotensin II induction and abdominal aortic constriction, enabling comprehensive evaluation of the candidates' preventive and therapeutic efficacy.
    RESULTS: DNJ occupies a cavity formed by the GTPase domain of the OPA1 dimer, acting as an additional linker at the dimeric OPA1 interface. Here, we have designed and identified a novel DNJ derivative, DNJ5a. Compared with DNJ, DNJ5a exhibits enhanced in silico and in vitro binding specificity, providing additional anchor sites for direct OPA1 interaction. This interaction facilitates the stabilization of the OPA1 dimeric form to repair mitochondrial cristae damage and maintain inner membrane integrity. Comprehensive improvements in mitochondrial bioenergetics, Ca2+ homeostasis, mitophagy, and multidimensional functional responses are seen to result. In 2 rodent animal cardiac hypertrophy models, DNJ5a administration showed excellent preventive and therapeutic efficacy towards promoting mitochondrial health and cardiac function in vivo.
    CONCLUSIONS: Unlike conventional mitochondrial drugs, which act to alleviate symptoms, DNJ5a can specifically target OPA1-GTPase and comprehensively improve mitochondrial health to ameliorate cardiac hypertrophy. These findings underscore mitochondrial abnormality as a primary contributor to pathological cardiac remodeling and present OPA1 as a strong potential drug target. The underlying mechanism of this novel agonist DNJ5a may pave the way towards developing many other promising mitochondrial-targeted therapeutics.
    Keywords:  1-deoxynojirimycin; cardiomegaly; mitochondria; mitophagy; optic atrophy, autosomal dominant
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327407
This page is being maintained by Thomas Krichel. It was last updated on 2026‒01‒07 at 12:14.