bims-mihora 2025-11-16 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2025–11–16
35 papers selected by
Lisa Patel, Istesso

UPRmt-regulated mitokines: novel strategies for myocardial injury repair.
Effect of mitochondrial dysfunction on neuropathic pain.
Mechanisms of Mitochondrial Transfer Through TNTs: From Organelle Dynamics to Cellular Crosstalk.
Crosstalk Between Hematopoietic and Mesenchymal Cells in Bone and Tooth Immune Response.
Aging and Corneal Nerve Health: Mechanisms of Degeneration and Emerging Therapies for the Cornea.
Therapeutic potential of natural compounds in the management of chronic diseases: Targeting PINK1-Parkin pathway.
Termination of the integrated stress response.
Regulation of macrophage transcriptional dynamics during acute and chronic wound repair.
Mitochondrial Calcium Channels and MAM Interaction in Calcium Homeostasis Dysregulation in Parkinson's Disease.
Mitochondrial Dysfunction in the Cardiovascular Disease Continuum: Problems of Studying the Progression During the Follow-Up of the Pathologies.
Iron-deplete diet enhances Caenorhabditis elegans lifespan via oxidative stress response pathways.
Rethinking Muscle Aging Through the Lens of Fibro-Adipogenic Progenitors.
Functions of Macrophages in Periodontal Disease Progression and Gingival Tissue Homeostasis.
A retrograde, non-canonical integrated stress response cascade maintains synaptic strength under amino acid deprivation.
Caspase-8 and BID Caught in the Act with Cardiolipin: A New Platform to Provide Mitochondria with Microdomains of Apoptotic Signals.
Urolithin A Alleviates Doxorubicin-Induced Senescence in Mesenchymal Stem Cells.
Preventive Effect of Fisetin on Follicular Granulosa Cells Senescence via Attenuating Oxidative Stress and Upregulating the Wnt/β-Catenin Signaling Pathway.
MYC affects mitochondrial function in IgA nephropathy by promoting the degradation of MFN1 through HRD1.
Mitochondrial dysfunction drives age-related degeneration of the thoracic aorta.
Idebenone alleviates rotenone-induced mitochondrial dysfunction through mitophagy and mitochondrial biogenesis in muscle cells.
Enterococcus faecalis Translocation in Sepsis: Fibrinolysis and Mitochondrial Dysfunction Drive Lung Injury.
Liver regeneration: Literature review.
Redox homeostasis in ferroptosis and aging: a causal role for fard-1 and dhs-25 in Caenorhabditis elegans.
Mammalian Models of Adult Tissue Regeneration.
Distinct Molecular Mechanisms in Oral Mucosal Wound Healing: Translational Insights and Future Directions.
Research on the Application of Mesenchymal Stem Cells for Addressing Mitochondrial Damage in Neurodegenerative Diseases.
Living biomaterials: A promising approach to promoting wound healing.
Ultrasound-responsive piezoelectric hydrogel attenuates oxidative stress-induced nucleus pulposus senescence via AMPK-FOXO1a-mediated mitophagy for intervertebral disc regeneration.
Senescence: An Overlooked VSMC Phenotype and Therapeutic Opportunity?
Unresolved challenges in wound healing: When science meets clinical need.
Nanoparticle-mediated overexpression of RacGAP1 protects against renal ischemia/reperfusion-injury by maintaining mitochondrial homeostasis.
Macrophages: pivotal orchestrators and emerging therapeutic targets in osteoarthritis pathogenesis.
Kynurenine Pathway Dysregulation Impairs Podocyte Morphology and Bioenergetics In Vitro and Leads to Glomerular Dysfunction.
The mechanotransduction-immune axis in organ fibrosis: dual regulatory mechanisms and translational therapeutic perspectives.
Targeting Mitochondrial Dynamics via EV Delivery in Regenerative Cardiology: Mechanistic and Therapeutic Perspectives.

Front Cell Dev Biol. 2025 ;13 1652353

UPRmt-regulated mitokines: novel strategies for myocardial injury repair.

Weinan Gao, Jia Liu, Wenda Zhang, Bin Liu, Luyan Shen.

  Cardiac mitochondria generate ATP, via oxidative phosphorylation (OXPHOS) to sustain continuous and forceful myocardial contraction, thereby meeting systemic metabolic demands. Mitochondrial biogenesis and energy metabolism depend on proteostasis, which can be disrupted by stressors such as hypoxia, leading to impaired cardiac function. As a result, the study of mitochondrial energy metabolism and proteostasis under stress has become a key focus in cardiovascular research. The mitochondrial unfolded protein response (UPRmt) plays a "double-edged sword" role-either protective or detrimental-depending on the type, intensity, and duration of the stressor. This has sparked interest in strategies aimed at enhancing its adaptive signaling while inhibiting maladaptive pathways. Acting as mediators of intercellular communication, mitokines may transmit local mitochondrial stress signals to mitochondria in distant cells and tissues. This review analyzes and summarizes the role of UPRmt in regulating mitochondrial factors and explores the mechanisms through which fibroblast growth factor 21 (FGF21), secreted by the liver and skeletal muscle, influences protein homeostasis in cardiac myocytes. These insights aim to offer new avenues for the development of targeted UPRmt therapies and rehabilitation strategies for heart diseases.

Keywords:  cardiac diseases; fibroblast growth factor 21 (FGF21); mitochondrial stress; mitochondrial unfolded protein response (UPRmt); mitokines

DOI:  https://doi.org/10.3389/fcell.2025.1652353
Biomed Pharmacother. 2025 Nov 10. pii: S0753-3322(25)00954-0. [Epub ahead of print]193 118760

Effect of mitochondrial dysfunction on neuropathic pain.

Yunqi Li, Ping Wu, Qingping Wen.

  Neuropathic pain is a chronic pain condition caused by damage to the nervous system. Its pathogenesis is complex, and effective treatments are limited, significantly impairing patients' quality of life. Mitochondria are the energy supply centers of cells and play a crucial role in maintaining neuronal homeostasis. Growing evidence suggests mitochondrial dysfunction is a key contributor to pain initiation and persistence. However, the role of mitochondrial dysfunction in neuropathic pain has been relatively less studied, and its underlying mechanisms remain unclear. This article reviews the latest research progress on the mechanisms by which mitochondrial dysfunction affects neuropathic pain, with a focus on key pathways including mitochondrial morphological alterations, bioenergetic abnormalities (such as reduced adenosine triphosphate production and decreased membrane potential), dynamic impairments (e.g., disrupted axonal transport, mitochondrial fragmentation, and calcium homeostasis imbalance), enhanced oxidative stress, and impaired mitochondrial autophagy. These mechanisms collectively contribute to neuronal dysfunction and abnormal transmission of pain signals. Additionally, this article elaborates on various therapeutic strategies targeting mitochondrial dysfunction, offering novel insights and scientific evidence for the precise treatment of neuropathic pain.

Keywords:  Adenosine triphosphate; Mitochondrial dysfunction; Neuropathic pain; Oxidative stress; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.biopha.2025.118760
Int J Mol Sci. 2025 Oct 30. pii: 10581. [Epub ahead of print]26(21):

Mechanisms of Mitochondrial Transfer Through TNTs: From Organelle Dynamics to Cellular Crosstalk.

Margherita Zamberlan, Martina Semenzato.

  Tunneling nanotubes (TNTs) are dynamic, actin-based intercellular structures that facilitate the transfer of organelles, including mitochondria, between cells. Unlike other protrusive structures such as filopodia and cytonemes, TNTs exhibit structural heterogeneity and functional versatility, enabling both short- and long-range cargo transport. This review explores the mechanisms underlying mitochondrial transfer via TNTs, with a particular focus on cytoskeletal dynamics and the role of key regulatory proteins such as Miro1, GFAP, MICAL2PV, CD38, Connexin 43, M-Sec, thymosin β4, and Talin 2. Miro1 emerges as a central mediator of mitochondrial trafficking, linking organelle motility to cellular stress responses and tissue repair. We delve into the translational implications of TNTs-mediated mitochondrial exchange in regenerative medicine and oncology, highlighting its potential to restore bioenergetics, mitigate oxidative stress, and reprogram cellular states. Despite growing interest, critical gaps remain in understanding the molecular determinants of TNT formation, the quality and fate of transferred mitochondria, and the optimal sources for mitochondrial isolation. Addressing these questions will be essential for harnessing TNTs and mitochondrial transplantation as therapeutic tools.

Keywords:  Miro1; mitochondria; mitochondrial transplantation; tunneling nanotubes

DOI:  https://doi.org/10.3390/ijms262110581
Adv Exp Med Biol. 2026 ;1492 547-565

Crosstalk Between Hematopoietic and Mesenchymal Cells in Bone and Tooth Immune Response.

Larissa Sthefani Sales, Alice Corrêa Silva-Sousa, Guido Artemio Marañón-Vásquez, Francisco Wanderley Garcia de Paula-Silva.

  The immune response within dental tissues encompasses intricate interactions between hematopoietic and mesenchymal cells, which are pivotal for maintaining homeostasis and responding to pathological challenges. Hematopoietic cells, representing a diverse array of immune constituents, play an essential role in orchestrating inflammatory responses and regulating tissue repair mechanisms following injury or infection. These immune cells are instrumental in mediating inflammation, as well as directing the healing processes necessary for restoring tissue integrity. In parallel, mesenchymal cells, which include fibroblasts, odontoblasts, and osteoblasts, are indispensable during the inflammatory response and subsequent resolution of inflammation. The orchestration of these immune responses is governed by complex cellular signaling pathways involving specific cell surface receptors, as well as the secretion of various cytokines and growth factors that facilitate communication between cells. Mesenchymal cells possess not only the capacity to differentiate into multiple dental cell types but also the ability to respond to immunological signals, thus modulating inflammatory responses and actively participating in tissue regeneration and repair. A comprehensive understanding of these mechanisms and cellular interactions provides essential insights into the pathophysiology of inflammatory conditions affecting both connective and mineralized dental tissues. Such knowledge can significantly inform the development of more effective therapeutic strategies aimed at managing these conditions. This chapter delves into the cellular interactions and molecular mediators that are commonly observed in contexts of bacterial contamination of dental tissues and during orthodontic tooth movement, thereby offering a thorough biomolecular perspective on these complex processes.

Keywords:  Bone remodeling; Dental tissue; Hematopoietic cells; Inflammation; Mesenchymal cells

DOI:  https://doi.org/10.1007/978-3-032-03176-1_26
Cells. 2025 Nov 04. pii: 1730. [Epub ahead of print]14(21):

Aging and Corneal Nerve Health: Mechanisms of Degeneration and Emerging Therapies for the Cornea.

Hanieh Niktinat, Melinda Alviar, Marziyeh Kashani, Hamed Massoumi, Ali R Djalilian, Elmira Jalilian.

  Corneal nerves play a crucial role in maintaining ocular surface homeostasis by supporting the functional integrity of corneal epithelial, stromal, and endothelial cells; modulating tear secretion; and facilitating sensory responses essential for overall ocular health. With advancing age, these highly specialized peripheral sensory fibers undergo progressive attrition and morphologic distortion driven by the canonical hallmarks of aging including genomic instability, impaired proteostasis, mitochondrial dysfunction, and chronic low-grade inflammation. The resulting neuro-immune dysregulation reduces trophic support, delays wound healing, and predisposes older adults to dry-eye disease, neurotrophic keratopathy, and postsurgical hypoesthesia. Age-exacerbating cofactors including diabetes, dyslipidemia, neurodegenerative disorders, topical preservatives, chronic contact-lens wear, herpes zoster ophthalmicus, and ocular-surface hypoxia further accelerate sub-basal nerve rarefaction and functional decline. This review provides an overview of age-related physiological alterations in ocular surface nerves, with a particular emphasis on corneal innervation. It also discusses risk factors that speed up these changes. Given the inherently limited regenerative capacity of corneal nerves and their inability to fully restore to baseline conditions following injury or degeneration, it is critical to identify and develop effective strategies aimed at mitigating or delaying physiological nerve degeneration and promoting nerve regeneration. This review also brings up emerging therapeutic strategies, including regenerative medicine, neuroprotective agents, and lifestyle interventions aimed at mitigating age-related corneal nerve degeneration.

Keywords:  aging; confocal microscopy; corneal nerves; extracellular vesicles (EVs); nerve regeneration; neurodegeneration; ocular surface disease; subbasal nerve plexus

DOI:  https://doi.org/10.3390/cells14211730
Pathol Res Pract. 2025 Nov 07. pii: S0344-0338(25)00477-7. [Epub ahead of print]277 156284

Therapeutic potential of natural compounds in the management of chronic diseases: Targeting PINK1-Parkin pathway.

Naglaa F Khedr, Hend M Selim, Gamal A Abourayya.

  Chronic diseases like neurodegenerative disorders, musculoskeletal issues, metabolic diseases, cancer, liver and kidney disorders are increasingly linked to mitochondrial dysfunction. PINK1-Parkin-mediated mitophagy, a vital autophagic process, plays a central role in maintaining cellular homeostasis by selectively eliminating damaged mitochondria, which is crucial for preserving mitochondrial integrity and preventing reactive oxygen species accumulation. Activation of the PINK1-Parkin signaling pathway has emerged as a promising therapeutic strategy to restore mitochondrial function and attenuate disease progression. Recent studies have demonstrated that natural PINK1-Parkin activators offer significant therapeutic potential for treating a wide range of chronic diseases by modulating mitochondrial dynamics, alleviating cellular inflammation, and preventing mitochondrial damage. This review provides an in-depth analysis of the molecular mechanisms underlying PINK1-Parkin signaling, discusses the therapeutic benefits of natural activators, and presents them as a compelling strategy for addressing mitochondrial dysfunction and mitigating the progression of chronic diseases.

Keywords:  Chronic liver diseases; Mitophagy; Musculoskeletal Disorders; Neurodegenerative disorders; PINK1; Parkin

DOI:  https://doi.org/10.1016/j.prp.2025.156284
Science. 2025 Nov 13. eadw5137

Termination of the integrated stress response.

Claudia De Miguel, Sigurdur R Thorkelsson, Agnieszka Fatalska, George Hodgson, Chao Wang, Anne Bertolotti.

Stress responses enable cells to detect, adapt to, and survive challenges. The benefit of these signaling pathways depends on their reversibility. The integrated stress response (ISR) is elicited by phosphorylation of translation initiation factor eIF2, which traps and inhibits rate-limiting translation factor eIF2B thereby attenuating translation initiation. Termination of this pathway thus requires relieving eIF2B from P-eIF2 inhibition. Here, we found that eIF2 phosphatase subunits PPP1R15A and PPP1R15B (R15B) bound P-eIF2 in complex with eIF2B. Biochemical investigations guided by cryo-EM structures of native eIF2-eIF2B and P-eIF2-eIF2B complexes bound to R15B demonstrated that R15B enabled dephosphorylation of otherwise dephosphorylation-incompetent P-eIF2 on eIF2B. This sheds light on ISR termination, revealing that R15B rescues eIF2B from P-eIF2 inhibition, thereby safeguarding translation and cell fitness.

DOI: https://doi.org/10.1126/science.adw5137
Inflamm Res. 2025 Nov 14. 74(1): 164

Regulation of macrophage transcriptional dynamics during acute and chronic wound repair.

Sk Rameej Raja, Mobbassar Hassan Sk, Syed Wajeed, Rigzin Yangdol, Ayushi Yadav, Himanshi Jindal, Arib Fatima, Arif Siddiquie, Laxmi Pulakat, Ramachandran Subramanian, Mirza S Baig.

  Wound healing is a complex and tightly controlled physiological process that involves various cell types, among which macrophages play a critical role in tissue repair and regeneration. Transcription regulators influence gene expression in macrophages at several phases of wound healing, such as hemostasis, inflammation, proliferation, and remodeling. This article explores the transcription factors that regulate the activity of macrophages during wound healing and help in ECM remodeling. Understanding how these transcription regulators coordinate macrophage actions in response to cellular and molecular stimuli is essential for determining the process behind acute and chronic healing. This review highlights the therapeutic interventions through modulating transcriptional activity to improve wound healing and resolve fibrosis in chronic wounds. Furthermore, this review also explores the roles of transcription factors in macrophages, suggesting valuable insights into innovative strategies to improve tissue regeneration in chronic or pathological conditions.

Keywords:  Extracellular matrix; Fibroblast; Inflammation; Pathological conditions; Transcription regulators; Wound healing

DOI:  https://doi.org/10.1007/s00011-025-02133-1
Neurochem Res. 2025 Nov 15. 50(6): 361

Mitochondrial Calcium Channels and MAM Interaction in Calcium Homeostasis Dysregulation in Parkinson's Disease.

Bingjie Han, Jie Bai.

  Parkinson's disease (PD), the second most common neurodegenerative disorder worldwide, currently lacks effective treatment options due to its complex pathogenesis. Growing evidence in recent years demonstrates that intracellular Calcium (Ca²⁺) homeostasis disruption plays a critical role in PD development and progression. Ca²⁺ imbalance not only causes Ca²⁺-dependent synaptic dysfunction and impaired neuronal plasticity but also leads to progressive neuronal loss, collectively forming the core pathological characteristics of PD neurodegeneration. Notably, mitochondrial Ca²⁺ imbalance has been identified as a key pathogenic factor in PD. As vital intracellular Ca²⁺ regulators, dysfunctional mitochondria can induce abnormal opening of the mitochondrial permeability transition pore (mPTP), triggering apoptotic cascades. Furthermore, mitochondrial Ca²⁺ overload disrupts oxidative phosphorylation, resulting in excessive reactive oxygen species production that exacerbates neuronal damage. Recent studies reveal the essential role of mitochondria-endoplasmic reticulum interactions in maintaining Ca²⁺ homeostasis, with these organelles forming structurally and functionally integrated connections through mitochondrial ER-associated membrane (MAM) to cooperatively regulate Ca²⁺ ion dynamics. This review describes the molecular mechanisms of mitochondrial Ca²⁺ imbalance in PD pathogenesis and summarizes the potential of mitochondrial channels and MAM-associated proteins as PD therapeutic targets. By thoroughly analyzing these targets mechanisms, we aim to provide a theoretical foundation for developing novel PD treatment strategies based on Ca²⁺ homeostasis regulation. These findings not only expand our understanding of PD pathogenesis but also point toward developing targeted neuroprotective therapies.

Keywords:  Calcium homeostasis; Mitochondria; Mitochondrial endoplasmic reticulum-associated membrane; Parkinson’s disease

DOI:  https://doi.org/10.1007/s11064-025-04591-9
Int J Mol Sci. 2025 Oct 29. pii: 10497. [Epub ahead of print]26(21):

Mitochondrial Dysfunction in the Cardiovascular Disease Continuum: Problems of Studying the Progression During the Follow-Up of the Pathologies.

Ganna Nevoit, Maksim Potyazhenko, Ozar Mintser, Gediminas Jarusevicius, Alfonsas Vainoras.

  This perspective piece extrapolates knowledge of mitochondriology to the clinical aspects of cardiovascular disease (CVDs) development. The aim was to deepen the understanding of the etiopathogenesis of CVDs by conceptualizing the systemic involvement of mitochondrial dysfunction mechanisms in their follow-up. A theoretical comparison of mitochondrial status and mitochondrial dysfunction across stages of the cardiovascular continuum was performed based on a systematic analysis of the scientific literature data using general scientific, theoretical, and logical methods and normative rules. Conceptual aspects of the involvement of mitochondrial dysfunction (MD) mechanisms at each stage of the CVDs continuum were identified. MD is a dynamic, complex, multifactorial process that is characterized by quantitative and qualitative changes in the mitochondrial pool of human body cells during the development of CVDs. MD is a fundamental participant in the pathogenesis of CVDs, predetermining the nature and features of the clinical manifestation and course of the disease in each patient. MD has distinctive features at each stage of the catamnesis of CVDs and can be classified according to this principle. The development of objective methods for assessing the degree of MD and its classification criteria is a promising task for future scientific research.

Keywords:  cardiovascular continuum; cardiovascular diseases; mitochondrial dysfunction

DOI:  https://doi.org/10.3390/ijms262110497
EMBO J. 2025 Nov 10.

Iron-deplete diet enhances Caenorhabditis elegans lifespan via oxidative stress response pathways.

Priyanka Das, Ravi, Jogender Singh.

  Gut microbes play a crucial role in modulating host lifespan. However, the microbial factors that influence host longevity and their mechanisms of action remain poorly understood. Using the expression of Caenorhabditis elegans FAT-7, a stearoyl-CoA 9-desaturase, as a proxy for lifespan modulation, we conduct a genome-wide bacterial mutant screen and identify 26 Escherichia coli mutants that enhance host lifespan. Transcriptomic and biochemical analyses reveal that these mutant diets induce oxidative stress and activate the mitochondrial unfolded protein response (UPRmt). Antioxidant supplementation abolishes lifespan extension, confirming that oxidative stress drives these effects. The extension of lifespan requires the oxidative stress response regulators SKN-1, SEK-1, and HLH-30. Mechanistically, these effects are linked to reduced iron availability, as iron supplementation restores FAT-7 expression, suppresses UPRmt activation, and abolishes lifespan extension. Iron chelation mimics the pro-longevity effects of the mutant diets, highlighting dietary iron as a key modulator of aging. Our findings reveal a bacterial-host metabolic axis that links oxidative stress, iron homeostasis, and longevity in C. elegans.

Keywords:  HLH-30; Iron; Lifespan; Oxidative Stress; SKN-1

DOI:  https://doi.org/10.1038/s44318-025-00634-7
Aging Dis. 2025 Nov 06.

Rethinking Muscle Aging Through the Lens of Fibro-Adipogenic Progenitors.

Feng-Min Zhang, Xian-Zhong Zhang, Zhen Yu, Cheng-Le Zhuang, Li-Li Han.

Aging of skeletal muscles is accompanied by a progressive deposition of adipose and fibrotic tissue within the interstitial compartment. This process profoundly disrupts the structural integrity and contractile function of the muscle. Such maladaptive remodeling not only compromises muscle performance but also impairs its regenerative capacity, predisposing old individuals to frailty and sarcopenia. Fibro-adipogenic progenitors (FAPs) have been identified as the principal cellular source of the pathological adipogenic and fibrogenic remodeling. These stromal cells integrate mechanical, biochemical, and immune signals within the muscle niche, ultimately determining whether muscle repair leads to effective regeneration or maladaptive remodeling. In young muscle, transient FAP activation supports satellite cell-mediated myogenesis through extracellular matrix remodeling and pro-regenerative signaling. However, in aging muscle, this precise regulation is disrupted. The aged niche is characterized by chronic inflammatory stress, altered matrix composition, and impaired immune-stromal communication. These changes drive FAPs toward maladaptive phenotypes that promote fibrosis, intramuscular fat accumulation, and regenerative failure. FAP dysfunction is increasingly recognized as a central mechanism contributing to age-related sarcopenia, increased susceptibility to injury, and delayed recovery. Given their dual ability to promote both regeneration and degeneration, understanding how aging reprograms FAP fate and function offers a promising avenue to rejuvenating the aged muscle niche. Here, we summarize current insights into the roles and dynamics of FAPs in aged muscle and discusses their potential as therapeutic targets to restore regenerative capacity and mitigating muscle aging.

DOI: https://doi.org/10.14336/AD.2025.1162
Adv Exp Med Biol. 2026 ;1492 669-685

Functions of Macrophages in Periodontal Disease Progression and Gingival Tissue Homeostasis.

Tsuguno Yamaguchi.

  Macrophages play pivotal roles in the immune response, acting as antigen-presenting cells that influence both inflammation and tissue homeostasis. This chapter explores the versatile functions of macrophages in periodontal disease, a chronic inflammatory condition characterized by the destruction of periodontal tissues. Macrophages are primarily derived from circulating monocytes and exhibit distinct polarization states, notably M1 and M2. In the context of periodontal disease, M1 macrophages are closely associated with pro-inflammatory responses and tissue destruction, while M2 macrophages facilitate tissue repair and resolution of inflammation. Evidence demonstrates that macrophage polarization is a dynamic continuum influenced by various environmental cues such as cytokines. Notably, an increase in M1 macrophages correlates with the active stages of periodontal disease, whereas M2 macrophages are more prevalent during the recovery phase. Furthermore, macrophages significantly contribute to bone metabolism by regulating osteoclastogenesis, with M1 macrophages promoting bone resorption through the secretion of inflammatory cytokines. This chapter also addresses the role of macrophages in the interaction between systemic diseases and periodontal disease and potential therapeutic strategies aimed at targeting macrophage polarization to mitigate inflammation and enhance periodontal regeneration. Overall, macrophages play various roles in the progression of periodontal disease and gingival homeostasis. Further understanding of the multifaceted roles of macrophages is essential for developing effective host modulation therapies that restore immune balance, improve treatment outcomes, and advance our comprehension of the complex mechanisms underlying oral health and disease. This knowledge holds promise for the development of innovative therapeutic approaches in the management of periodontal disease.

Keywords:  Host modulation; Inflammation; Innate immunity; Macrophage; Periodontal disease

DOI:  https://doi.org/10.1007/978-3-032-03176-1_32
Cell Rep. 2025 Nov 07. pii: S2211-1247(25)01293-8. [Epub ahead of print]44(11): 116522

A retrograde, non-canonical integrated stress response cascade maintains synaptic strength under amino acid deprivation.

Megumi Mori, Grant Kauwe, Ammar Aly, Edward H Liao, Gary Scott, A Pejmun Haghighi.

  Neuronal response to changes in nutrient availability is critical for maintaining metabolic homeostasis and organismal survival. Nevertheless, we know little about the molecular players that regulate and maintain neurotransmission under nutritional stress. We demonstrate that, under acute amino acid restriction, the maintenance of normal synaptic strength at the Drosophila larval neuromuscular junction critically depends on the integrated stress response (ISR) machinery. Our findings indicate that amino acid restriction triggers a non-canonical ISR cascade in muscle via GCN2 and eIF2α phosphorylation but independently of ATF4. We have identified Still life (Sif), an ortholog of human TIAM1, as a translational target of the ISR and show that it is required in muscle for mediating the action of the ISR. Our results reveal an intricate non-canonical ISR signaling cascade at the synapse and offer a new framework to separate the role of the ISR in proteostasis from its synaptic actions.

Keywords:  CP: metabolism; CP: neuroscience; GCN2; amino acid sensing; eIF2alpha; integrated stress response; presynaptic release; regulation of translation; retrograde signaling; synaptic set point

DOI:  https://doi.org/10.1016/j.celrep.2025.116522
Cells. 2025 Oct 27. pii: 1678. [Epub ahead of print]14(21):

Caspase-8 and BID Caught in the Act with Cardiolipin: A New Platform to Provide Mitochondria with Microdomains of Apoptotic Signals.

Patrice X Petit.

  Mitochondria play a central role in cellular bioenergetics. They contribute significantly to ATP production, which is essential for maintaining cells. They are also key mediators of various types of cell death, including apoptosis, necroptosis, and ferroptosis. Additionally, they are one of the main regulators of autophagy. This brief review focuses on BID, a molecule of the BCL-2 family that is often overlooked. The importance of the cardiolipin/caspase-8/BID-FL platform, which is located on the surface of the outer mitochondrial membrane and generates tBID, will be emphasized. tBID is responsible for BAX/BAK delocalization and oligomerization, as well as the transmission of death signals. New insights into the regulation of caspase-8 and BID have emerged, and this review will highlight their originality in the context of activation and function. The focus will be on results from biophysical studies of artificial membranes, such as lipid-supported monolayers and giant unilamellar vesicles containing cardiolipin. We will present the destabilization of mitochondrial bioenergetics caused by the insertion of tBID at the mitochondrial contact site, as well as the marginal but additive role of the MTCH2 protein, not forgetting the new players.

Keywords:  BH3 interacting domain death agonist (also BID-FL); BID; CLOOH; Cell death; DISC; GUV; MTCH2; Mitochondria; Mitochondrial Carrier Homolog 2; OMM outer mitochondrial membrane; cardiolipin peroxidized; death inducing signalling complex; giant unilamellar-vesicles; p15); tBID (truncated BID at the n terminal end

DOI:  https://doi.org/10.3390/cells14211678
Int J Mol Sci. 2025 Oct 22. pii: 10257. [Epub ahead of print]26(21):

Urolithin A Alleviates Doxorubicin-Induced Senescence in Mesenchymal Stem Cells.

Alexander Kalinin, Ekaterina Zubkova, Mikhail Menshikov, Yelena Parfyonova.

  The accumulation of senescent cells, characterized by a pro-inflammatory secretory phenotype (SASP), metabolic dysfunction, and irreversible cell cycle arrest, is a driving force behind numerous age-related pathologies and directly undermines the therapeutic potential of mesenchymal stem cells (MSCs). In this study, we explore the senotherapeutic potential of urolithin A, a renowned antioxidant compound, in human adipose-derived MSCs (AD-hMSCs). Our findings reveal that urolithin A is non-cytotoxic to senescent AD-hMSCs and significantly suppresses the SASP by reducing the secretion of key pro-inflammatory mediators, including MCP1, PAI2, and IL1B. In addition, it was demonstrated that urolithin A was capable of reversing the decline in H3K9me3 levels induced by Doxorubicin treatment, restoring them to levels observed in untreated cells. The results of this study suggest that urolithin A functions as a senomorphic agent, capable of modulating cellular senescence. Moreover, its combination with senolytic therapies has the potential to yield novel and effective treatment strategies for regenerative medicine.

Keywords:  aging; autophagy; cellular senescence; doxorubicin; mesenchymal stem cells; senotherapeutics

DOI:  https://doi.org/10.3390/ijms262110257
Cells. 2025 Oct 30. pii: 1704. [Epub ahead of print]14(21):

Preventive Effect of Fisetin on Follicular Granulosa Cells Senescence via Attenuating Oxidative Stress and Upregulating the Wnt/β-Catenin Signaling Pathway.

Juan Dong, Zhaoyu Yang, Qiongyu Yuan, Weidong Zeng, Yuling Mi, Caiqiao Zhang.

  Oxidative stress-mediated dysfunction of granulosa cells (GCs) is recognized as a pivotal driver of prehierarchical follicular atresia in poultry, contributing substantially to the reduced egg production in aged laying hens. Here, we investigated the protective effects of the natural flavonol, fisetin, on aged chicken follicular GCs. A D-galactose (D-gal)-induced aging model of GCs was established to evaluate the protective role of fisetin against cellular senescence. Small yellow follicles (SYFs) from 580-day-old hens were cultured with fisetin for 72 h to verify its ameliorative effect on naturally aged follicles. Fisetin reduced the typical characteristic of senescence in D-gal-induced GCs, as reflected by decreased senescence-associated β-galactosidase (SA-β-gal) activity and increased expression of proliferation-related proteins, including cyclin D1 (CCND1), cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 1 (CDK1), and Cyclin B1. Furthermore, fisetin enhanced the activity of antioxidant enzymes by activating the Nrf2/HO-1 signaling pathways, while attenuating mitochondrial dysfunction and promoting ATP production in senescent GCs. Additionally, fisetin significantly promoted nuclear translocation of β-catenin, and suppressed the expression of senescence marker proteins p53 and p21, thereby alleviating cell cycle arrest in D-gal-induced senescent GCs. Simultaneous inhibition of Nrf2/HO-1 and β-catenin signaling also abolished the beneficial effects of fisetin on oxidative stress and cell proliferation in naturally senescent follicles. These findings indicate that fisetin prevents follicular atresia by suppressing GCs oxidative damage and improving cell cycle arrest via activating the Nrf2/HO-1 and Wnt/β-catenin signaling pathways.

Keywords:  chicken; fisetin; follicular atresia; oxidative stress; β-catenin

DOI:  https://doi.org/10.3390/cells14211704
Immunol Res. 2025 Nov 15. 73(1): 166

MYC affects mitochondrial function in IgA nephropathy by promoting the degradation of MFN1 through HRD1.

Xueping Wu, Lei Liu, Ruiping Zhao, Weidong Chen.

  IgA nephropathy is characterized by the deposition of IgA and complement C3 in the glomerular mesangial region. Recent research has pointed out the critical role of mitochondrial damage during the occurrence and development of IgAN. During IgAN progression, elevated myc promotes the transcription of HRD1, which in turn induces the ubiquitination of MFN1, leading to mitochondrial dysfunction. We found that the expression levels of myc and HRD1 were elevated in IgAN. Down-regulation of HRD1 and myc successfully alleviated IgAN progression by promoting cell survival, reducing renal injury and improving mitochondrial homeostasis. Additionally, we observed reduced levels of MFN1 expression in IgAN. Overexpression of MFN1 significantly inhibited IgAN progression, while the deficiency of MFN1 exacerbated IgAN injury. In summary, our findings revealed that myc plays a critical role in regulating mitochondrial function in IgAN by promoting HRD1 transcription and inducing MFN1 ubiquitination. These results suggested that targeting myc/HRD1/MFN1 axis may offer a novel therapeutic strategy to combat IgAN progression.

Keywords:  HRD1; IgA nephropathy; MFN1; Mitochondrial; Myc

DOI:  https://doi.org/10.1007/s12026-025-09695-6
Geroscience. 2025 Nov 13.

Mitochondrial dysfunction drives age-related degeneration of the thoracic aorta.

Arjune S Dhanekula, Benjamin R Harrison, Gavin Pharaoh, Aurora Mattson-Hughes, Stefano Tarantini, Rudolph Stuppard, Scott C DeRoo, Christopher R Burke, Billiana Hwang, Jay D Pal, Michael S Mulligan, David J Marcinek.

  This study investigated the role of mitochondrial function in aortic aging. As the aorta ages, it becomes stiffer and less compliant, increasing the risk of aneurysmal disease, hypertension, and diastolic dysfunction. Given the role of mitochondrial dysfunction in non-age related aortopathies and as a hallmark of aging, we investigated its contribution to the aging aorta. Both male and female young (5-6 month) and aged (24-25 month) C57Bl/6 J mice received mitochondrial-targeted peptide elamipretide (ELAM; SS-31) for 8 weeks. ELAM restored complex II-linked respiration in aged mice to values seen in young mice, while also improving relative phosphorylative flux. ELAM treatment also reduced inflammatory MMP9 expression and elastin breaks in aged mice. Bulk RNAseq analysis revealed that ELAM treatment significantly affected the aortic transcriptome in an age-dependent manner, reducing the expression of senescent and associated pro-inflammatory genes. Mitochondrial dysfunction thus drives aortic aging and is a potential therapeutic target for future study.

Keywords:  Aorta; Mitochondria; Senescence; Vascular biology

DOI:  https://doi.org/10.1007/s11357-025-01937-7
Cell Signal. 2025 Nov 07. pii: S0898-6568(25)00636-9. [Epub ahead of print]138 112221

Idebenone alleviates rotenone-induced mitochondrial dysfunction through mitophagy and mitochondrial biogenesis in muscle cells.

Chen Zhang, Mei Li, Liying Meng, Wei Xia, Guanzhao Wu.

  Idebenone, a synthetic quinone analog of coenzyme Q10, is a well-characterized antioxidant with clinical applications in treating diseases associated with mitochondrial dysfunction. However, it remains unclear whether idebenone can mitigate rotenone-induced oxidative stress and mitochondrial dysfunction in muscle cells. In this study, exposure of C2C12 myoblasts to rotenone resulted in a significant increase in cell death, intracellular and mitochondrial reactive oxygen species, and the activation of mitophagy and autophagy, as evidenced by altered expression levels of PINK1, PARKIN, and p62/SQSTM1. Additionally, elevated mitochondrial fission (measured by DRP1 and FIS1 expression) and a decrease in energy production (assessed via Seahorse analysis) were observed compared to untreated cells. The translocation of cytoplasmic DRP1 to the mitochondria was further demonstrated by its colocalization with TOM20. Remarkably, treatment with idebenone reversed these effects, and pharmacological inhibition of PGC1A abolished the protective effects of idebenone on mitochondrial biogenesis and function. Our findings suggest that idebenone ameliorates rotenone-induced apoptosis, oxidative stress, and mitochondrial damage in C2C12 cells, supporting its potential therapeutic role in the treatment of skeletal muscle atrophy.

Keywords:  C2C12; Idebenone; Mitochondrial dysfunction; Oxidative stress; Rotenone

DOI:  https://doi.org/10.1016/j.cellsig.2025.112221
J Cell Mol Med. 2025 Nov;29(21): e70937

Enterococcus faecalis Translocation in Sepsis: Fibrinolysis and Mitochondrial Dysfunction Drive Lung Injury.

Chenfei Wang, Dan Lv, Yuan Gao, Xinhui Xu, Changqing Zhu, Song Zhang, Keji Zhang.

  Sepsis frequently progresses to acute lung injury (ALI), characterised by inflammation, extracellular matrix degradation, and mitochondrial dysfunction. This study identifies Enterococcus faecalis as a gut-derived bacterium that exploits the host fibrinolytic system for pulmonary translocation, resulting in mitochondrial damage and exacerbating lung injury. Utilising the cecal ligation and puncture (CLP) mouse model combined with E. faecalis pulmonary infection, we demonstrated that E. faecalis exacerbates lung injury by activating fibrinolysis, disrupting intestinal barrier integrity, and impairing mitochondrial function. Key findings include elevated plasmin activity, increased fibrin degradation products (FDP), and reduced expression of tight junction proteins ZO-1 and occludin. Mitochondrial dysfunction was confirmed by disrupted ultrastructure, impaired ATP synthesis, and increased ROS levels. Histological analyses revealed severe alveolar damage, neutrophil infiltration, and edema. Treatment with the fibrinolysis inhibitor aminocaproic acid or the mitochondrial protector MitoTEMPO alleviated fibrinolytic activity, preserved mitochondrial function, and reduced lung damage. Notably, combination therapy showed the most significant protective effects, improving lung histology and decreasing inflammation markers. This study provides novel insights into sepsis-induced lung injury, highlighting E. faecalis and the fibrinolytic system as potential therapeutic targets.

Keywords:   Enterococcus faecalis ; fibrinolytic system; gut‐lung axis; lung injury; mitochondrial dysfunction; sepsis

DOI:  https://doi.org/10.1111/jcmm.70937
Rev Col Bras Cir. 2025 ;pii: S0100-69912025000100215. [Epub ahead of print]52 e20253880

Liver regeneration: Literature review.

Edimar Leandro Toderke, Jorge Eduardo Fouto Matias.

Liver regeneration is a highly organized tissue growth process and is the livers most important reaction to aggression. The complex mechanisms involved in this process encompass a variety of regenerative pathways that are specific to the different types of aggression. The most studied form of liver regeneration is that which occurs after the loss of hepatocytes in an acute injury, such as in the regenerative process of rodents after partial hepatectomy or administration of harmful chemicals (CCl4, paracetamol, allyl alcohol). These experimental models revealed extracellular and intracellular signaling pathways that are used to return the liver to the size and weight equivalent to those prior to the injury. Understanding the liver regeneration process is a challenge that is justified by the numerous interactions of different cellular components, various mitogenic factors (complete and incomplete), complex mitogenic pathways, and acute phase inflammatory proteins. Hepatocytes, cholangiocytes, and liver progenitor cells have been shown to have regenerative behavior. The regenerative activities of hepatocytes and cholangiocytes are typically characterized by phenotypic fidelity (multiplication), however, when normal regeneration is thwarted, hepatocytes and cholangiocytes function as facultative stem cells (dedifferentiate) or transdifferentiate to restore normal liver structure. This review traces the path taken in recent decades in the study of liver regeneration and highlights new concepts in the area.

DOI: https://doi.org/10.1590/0100-6991e-20253880-en
Redox Biol. 2025 Nov 01. pii: S2213-2317(25)00425-2. [Epub ahead of print]88 103912

Redox homeostasis in ferroptosis and aging: a causal role for fard-1 and dhs-25 in Caenorhabditis elegans.

Roberta Pensotti, Barbara Sciandrone, Federica Bovio, Laura Schröter, Silvia Maglioni, Leonie Thewes, Matilde Emma Forcella, Andrea Rossi, Paola Alessandra Fusi, Carsten Berndt, Natascia Ventura, Maria Elena Regonesi.

  Aging is a natural process characterized by a progressive physiological decline that undermines health and well-being in the elderly population. Oxidative stress is a widely accepted hallmarks of aging, and its role as one of the main drivers of ferroptosis is quite recent. Ferroptosis is an iron-dependent cell death caused by massive phospholipid peroxidation. The excessive accumulation of intracellular reactive oxygen species and iron, as well as the failure of the main cellular antioxidant systems, cause ferroptotic cell death. While clear roles for ferroptosis in pathological conditions such as cancer or neurodegeneration have been described, its physiological roles and regulators are less understood. Here, using Caenorhabditis elegans as a powerful model organism for aging studies, we uncover a role for ferroptosis in physiological aging mediated by disturbed redox homeostasis. We evaluated healthspan parameters in C. elegans highlighting how several age-related features differentially decline during physiological aging. A progressive loss of the capability to contrast external stressors, with an increase in hydroxyl radicals and a decrease of glutathione demonstrated the disruption of redox homeostasis in older age. Moreover, transcription of selected genes involved in redox metabolism is downregulated with aging. Among them, loss of the fatty acyl-CoA reductase encoded by fard-1 and of the dehydrogenase encoded by dhs-25 display higher sensitivity to ferroptosis, increased lipid peroxidation, lower total glutathione levels and reduced lifespan. Accordingly, the expression of hydroxysteroid 17-beta dehydrogenase 8, one of the closest mammalians dhs-25 homologs, is downregulated in cells which are more sensitive to ferroptosis. Our results clearly prove a causal role for ferroptosis in C. elegans aging driven by mitochondrial redox unbalance, unveiling novel genes involved in this connection that may constitute targets for possible interventions to improve healthy aging.

Keywords:  Aging; Caenorhabditis elegans; Ferroptosis; Frataxin; Mitochondria; Redox homeostasis

DOI:  https://doi.org/10.1016/j.redox.2025.103912
Annu Rev Anim Biosci. 2025 Nov 11.

Mammalian Models of Adult Tissue Regeneration.

Kuo Liao, Yigit Koray Babal, Sebastian A Lewandowski.

Adult tissue regeneration is a rare phenomenon in mammals. Most mammals heal tissue through scarring, which quickly seals the wound and helps prevent blood loss and infection, but this comes at the cost of poor tissue regeneration. Regeneration is typically studied in worms, amphibians, or fish, which gives insights into the biology of respective species but provides limited translation for human therapies. However, several mammals develop adaptations, typically favored by natural selection pressures, to regenerate a specialized tissue (e.g., antlers in deer or skin in bats) or a systemically reduced scar formation that allows multiple tissues to restore their function (e.g., African spiny mice). In this review, we aim to summarize the examples of mammals that regenerate tissues and discuss potential cellular mechanisms that allow their regeneration. The future studies of these exceptional mammals can allow for a greater understanding of mammalian complexity and provide insights for future therapies.

DOI: https://doi.org/10.1146/annurev-animal-030424-071428
Int J Mol Sci. 2025 Nov 01. pii: 10660. [Epub ahead of print]26(21):

Distinct Molecular Mechanisms in Oral Mucosal Wound Healing: Translational Insights and Future Directions.

Priscila Chuhuaicura, Cynthia Rodríguez-Niklitschek, Gonzalo H Oporto, Luis A Salazar.

  Oral mucosal wound healing is a rapid, precisely regulated process distinct from cutaneous repair due to the specialized anatomical, microbial, and physiological features of the oral cavity. This review outlines the sequential healing phases-hemostasis, inflammation, proliferation, and remodeling-and examines the coordinated roles of keratinocytes, fibroblasts, endothelial cells, and immune cell subsets in tissue restoration. Central molecular pathways, including PI3K/Akt, JAK/STAT, Ras/MAPK, TGF-β/SMAD, and Wnt/β-catenin, along with growth factors such as TGF-β, FGF, EGF, and VEGF, are discussed in relation to their regulatory influence on cell behavior and extracellular matrix dynamics. Unique intraoral factors-namely saliva-derived histatins and a distinct resident microbiota-promote accelerated re-epithelialization and attenuated fibrosis. Systemic conditions such as diabetes, aging, and tobacco exposure are identified as key modulators that compromise repair efficiency. Emerging therapeutic strategies, including stem-cell-based interventions, microbiota modulation, bioengineered scaffolds, and photobiomodulation, offer translational potential to enhance clinical outcomes in oral tissue regeneration.

Keywords:  mouth mucosa; oral mucosa; signaling pathway; wound healing

DOI:  https://doi.org/10.3390/ijms262110660
Cell Mol Neurobiol. 2025 Nov 10. 45(1): 101

Research on the Application of Mesenchymal Stem Cells for Addressing Mitochondrial Damage in Neurodegenerative Diseases.

Li Zhang, Ying Ge, Jingjing Wu, Mei Wang, Nanqu Huang, Yong Luo.

  Neurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) pose serious threats to human health, and their pathogenesis is closely related to mitochondrial damage. Mitochondrial dysfunction includes abnormal energy metabolism, oxidative stress imbalance, disturbed calcium homeostasis and altered mitochondrial dynamics, which in turn trigger neuronal apoptosis and neuroinflammation. Mitochondrial dysfunction is a hallmark of many NDs. In addition to their multi-lineage differentiation potential, ability to promote neuronal repair, and capacity to modulate the neuroimmune microenvironment, Mesenchymal stem cells (MSCs) also hold potential for restoring mitochondrial dysfunction. MSCs have important therapeutic potential and mechanistic research value in the context of neurodegenerative disorders through the modulation of mitochondrial homeostasis and its transcellular transfer process. In this paper, we systematically summarize the mechanisms, technological advances, and translational challenges associated with mitochondrial damage in NDs and the role of MSCs in NDs through the modulation of mitochondrial damage and discuss their potential and limitations as a general therapeutic strategy.

Keywords:  Mesenchymal stem cells; Mitochondrial damage; Neurodegenerative diseases

DOI:  https://doi.org/10.1007/s10571-025-01624-3
Biomater Adv. 2025 Nov 09. pii: S2772-9508(25)00426-1. [Epub ahead of print]180 214599

Living biomaterials: A promising approach to promoting wound healing.

Qingxin Wu, Yibing You, Haiyan Hu, Lantao Wang, Zhengfeng Lu, Xiaofei Qin.

  Wound healing plays an important role in re-establishing the structure and physiological function of damaged tissues during the repair process. However, certain extrinsic factors (e.g., pathogenic infection or persistent inflammatory response) may interfere with this repair process and even trigger secondary tissue damage. Therefore, exploring innovative therapeutic strategies for wound recovery has become an important direction of current medical research. Living organism therapy is a promising technique that utilizes the unique biological activity of living organisms to modulate the wound microenvironment and promote tissue repair. Despite the current remarkable breakthroughs in the field of bioengineering and regenerative medicine, there are still some critical problems with living organism-based wound therapies, such as immune response, inability to control their proliferation, and poor targeting. Biomaterials are capable of interacting with biological systems and their good biocompatibility can be used as delivery vehicles for living organisms to enhance their therapeutic efficacy. Living biomaterials, which combine living organisms with biomaterials, show considerable promise in wound healing. In this review, we firstly describe the physiological process of wound healing and its conventional therapies, and provide an overview of the types of living organisms commonly used in wound healing. Then, we comprehensively summarize the different delivery systems used for living organisms. Moreover, the various strategies of living biomaterials in promoting wound healing are systematically summarized. Finally, we analyze the application of living biomaterials in clinical translation and discuss current challenges, potential solutions, and future research directions in this area.

Keywords:  Co-delivery; Living biomaterials; Living organism delivery; Living organisms; Wound healing

DOI:  https://doi.org/10.1016/j.bioadv.2025.214599
Biomaterials. 2025 Nov 01. pii: S0142-9612(25)00747-1. [Epub ahead of print]328 123828

Ultrasound-responsive piezoelectric hydrogel attenuates oxidative stress-induced nucleus pulposus senescence via AMPK-FOXO1a-mediated mitophagy for intervertebral disc regeneration.

Wenbo Wu, Zhangrong Cheng, Pengzhi Shi, Haiyang Gao, Yuhang Chen, Anran Zhang, Xianglong Chen, Wang Wu, Yukun Zhang.

  The progression of intervertebral disc degeneration (IDD) is closely linked to the nucleus pulposus cells (NPCs) senescence driven by oxidative stress and extracellular matrix (ECM) abnormalities. This study presents an ultrasound-responsive, temperature-sensitive piezoelectric hydrogel (TT@P-Gel) that enables dual therapy combining electrical stimulation (ES) and controlled drug release, fabricated by incorporating pyrrole/barium titanate nanoparticles (PB NPs) loaded with tannic acid (TA) and transforming growth factor-β (TGF-β). Experiments have demonstrated that TT@P-Gel can initiate the electrically controlled release of TGF-β and facilitate the gradual TA release to neutralize reactive oxygen species (ROS) via ultrasound in vitro, thereby reducing β-galactosidase expression and restoring the mitochondrial membrane potential ΔΨm in senescent NPCs. Under ultrasound stimulation (US), TT@P-Gel via ES activated the AMPK-FOXO1a signaling pathway and promoted FOXO1a nuclear translocation. Additionally, ES and TA released from the hydrogel enhance SIRT1 expression, which stabilizes nuclear FOXO1a through deacetylation, thereby regulating the expression of downstream genes. Furthermore, TT@P-Gel stimulated the BNIP3-PINK1-Parkin pathway via FOXO1a to augment mitophagy, eliminate defective mitochondria, and counteract TBHP-induced cellular senescence. In vivo investigations indicated that TT@P-Gel combined with ultrasound, markedly enhanced the disc height index and Pfirrmann score while diminishing the expression of p16/p21, a marker of senescence, in a rat model of intervertebral disc degeneration. This study introduces an "electro-chemical synergy" strategy to modulate energy metabolism and mitophagy in senescent NPCs under oxidative stress, utilizing an ultrasound-responsive piezoelectric hydrogel, thereby offering a novel approach for the repair and treatment of intervertebral disc degeneration.

Keywords:  Cellular senescence; Intervertebral disc degeneration; Mitophagy; Oxidative stress; Piezoelectric hydrogel

DOI:  https://doi.org/10.1016/j.biomaterials.2025.123828
Arterioscler Thromb Vasc Biol. 2025 Nov 13.

Senescence: An Overlooked VSMC Phenotype and Therapeutic Opportunity?

Allison B Herman, Katarina Gresova, Manolis Maragkakis, Michael V Autieri.

  Vascular smooth muscle cells (VSMCs) modulate their phenotype from a quiescent, contractile cell to a dedifferentiated, synthetic fibroproliferative cell in response to injury and cardiovascular risk factors. Senescence is a recognized phenotypically distinct cellular state characterized by cell cycle arrest and activation of the p16 and p53 damage response pathway and expression of the senescence-associated secretory phenotype. Low levels of senescence in healthy arteries contribute to vascular homeostasis by ensuring that only healthy VSMCs compose the artery, but they are not intended to be a persistent cellular component of the artery. However, when discussing VSMC phenotype modulation into foam-like cells, macrophages, mesenchymal cells, fibroblasts, adipocytes, and other VSMC-like cells, senescence is rarely included. This raises an intriguing question: can senescence be recognized as a phenotypic state of VSMCs? As understanding SMC phenotypic switching is crucial for developing therapies that can prevent and treat cardiovascular diseases, so is understanding mechanisms of senescence, and targeting the mechanisms that regulate this modulation could be a promising approach for managing conditions such as atherosclerosis, arterial calcification, and aortic aneurysms. This review aims to summarize recent findings about the molecular mechanisms of VSMC senescence and compare similarities and contrasts with the mechanisms known to regulate VSMC phenotype plasticity. Comparison of transcriptomic databases compelled us to also raise the interesting question: if VSMC can regain their contractile phenotype, can they also be coaxed to exit the senescent state and return to the contractile VSMC phenotype? We posit that senescent VSMCs may not be an end point but rather an intermediate or inflection point in VSMC cell fate decision.

Keywords:  atherosclerosis; cellular senescence; coronary vessels; hemodynamics; muscle, smooth, vascular; vascular remodeling

DOI:  https://doi.org/10.1161/ATVBAHA.125.323131
J Plast Reconstr Aesthet Surg. 2025 Oct 30. pii: S1748-6815(25)00631-X. [Epub ahead of print]

Unresolved challenges in wound healing: When science meets clinical need.

Paul Martin, Jason K F Wong, Gus McGrouther.

  Tissue damage is a natural consequence of mankind's interactions with the physical environment and leads to activation of endogenous repair mechanisms. Wound treatments developed over centuries, although largely empirical, have been incorporated into routine clinical practice while awaiting evidence of their efficacy. Based on a revisited and updated discussion from a 2013 Gordon Research Conference between basic scientists and clinicians, we outlined current knowledge of wound repair, emphasising the unique roles of diverse cell types including neutrophils, macrophages, keratinocytes, fibroblasts, and other previously overlooked lineages such as adipocytes and melanocytes. Five key clinical challenges remain unsolved: hypertrophic and keloid scarring, burns, wound infections, and chronic wounds. For each challenge, we reviewed recent basic science insights that offer potential therapeutic avenues, such as the role of inflammatory signals and mechanical cues in scarring, neutrophil dysfunction in burns, influence of the wound microbiome on infection, and epigenetic changes in chronic wounds. Although significant progress has been made, these topics remain problematic. We concluded by highlighting emerging research areas, including the overlooked roles of the nerves, fascia and fat tissue, and lessons from cancer biology, which may provide further opportunities to develop innovative strategies for wound care. By fostering greater collaboration and targeting a deeper understanding of mechanisms with unique models, the pathway to accelerate the translation of new therapies to improve patient outcomes is hopeful.

Keywords:  Basic science; Complex wounds; Keloids; Scarring; Wound healing; Wound infection

DOI:  https://doi.org/10.1016/j.bjps.2025.10.039
Clin Sci (Lond). 2025 Nov 10. pii: CS20256110. [Epub ahead of print]

Nanoparticle-mediated overexpression of RacGAP1 protects against renal ischemia/reperfusion-injury by maintaining mitochondrial homeostasis.

Weiran Zhou, Shiqiang Tong, Jinbo Yu, Jun Chen, Yi Fang, Yuxin Nie, Yiqin Shi, Nana Song, Xuesen Cao, Xiaoqiang Ding, Shuan Zhao.

  Acute kidney injury (AKI) is recognized as a critical clinical problem, and pharmacological therapeutic options for AKI remain limited. Our previous study confirmed that Rac GTPase-activating protein 1 (RacGAP1) effectively promoted the repair of tubular epithelial cells in vitro. Further investigation is needed to determine whether boosting the expression of RacGAP1 in vivo helps protect against AKI. Herein, lipid-coated calcium phosphate (LCP) nanoparticles loaded with RacGAP1 plasmids (pRacGAP1-LCP) were generated and subsequently characterized based on their size, zeta potential, and morphological features. Animal models of AKI induced by ischemia/reperfusion (I/R) injury (IRI) were established in C57BL/6 mice and pRacGAP1-LCP was injected into the tail vein to explore the role of RacGAP1 on renal IRI in vivo. The therapeutic efficacy of pRacGAP1-LCP against IRI was assessed through western blotting, real-time PCR, and histological analyses. The effects of RacGAP1 on mitochondrial homeostasis were further examined in mouse renal tubular epithelial cells (mRTECs). Serial administrations of pRacGAP1-LCP injections led to a significant increase in RacGAP1 expression in murine kidneys. This therapeutic intervention effectively attenuated AKI, as evidenced by downregulation of AKI biomarkers, amelioration of renal histopathological damage, and suppression of both apoptosis and inflammatory responses. Characteristic mitochondrial abnormalities, diminished ATP production, and excessive lipid droplet accumulation were observed in tubular cells of IRI mice. Notably, pRacGAP1-LCP treatment reversed these pathological alterations and up-regulated the expression of PGC-1α and CPT-1α, indicating that RacGAP1 exerted its reno-protective effects through enhanced mitochondrial biogenesis and fatty acid oxidation (FAO).To further investigate the role of RacGAP1 in mitochondrial homeostasis, we employed an ATP depletion-repletion (ATP D-R) model in mRTECs. Crucially, RacGAP1 effectively restored ATP production, mtDNA copy number, and oxygen consumption (OCR) in mRTECs after ATP D-R treatment. RacGAP1 overexpression also suppressed mitochondrial depolarization, fragmentation, and reactive oxygen species (ROS) generation. Conversely, RacGAP1 knockdown exacerbated mitochondrial defects in mRTECs exposed to ATP D-R. In summary, this study uncovers that RacGAP1 overexpression protects against renal injury and mitochondrial dysfunction, highlighting its therapeutic promise for AKI. The LCP nanoparticle exhibits potential as a precise and efficient delivery platform and presents a viable option for AKI therapy.

Keywords:  LCP; RacGAP1; acute kidney injury; mitochondrial homeostasis; nanoparticles

DOI:  https://doi.org/10.1042/CS20256110
J Transl Med. 2025 Nov 10. 23(1): 1250

Macrophages: pivotal orchestrators and emerging therapeutic targets in osteoarthritis pathogenesis.

Jia Hu, Jing Wang.

  Osteoarthritis (OA) is a heterogeneous total joint disease that can cause disability, affecting over 500 million people worldwide. Macrophages play an important regulatory role in OA progression through orchestrating synovial inflammation and degradation of the cartilage matrix. The polarization and inflammatory functions of macrophages are coordinately regulated by multiple signaling pathways, including PI3K/Akt, NF-κB, mTORC1, Wnt/β-catenin, and MAPK. At present, the pathogenesis of OA is not fully understood, and effective treatment methods are lacking. Therefore, clarifying the regulatory mechanism and therapeutic potential of macrophages in OA provides direction for the development of more effective pharmacological interventions. In this review, we summarize the epidemiology and pathogenesis of OA, highlights the role of macrophages in the development of OA and related molecular targets, and discusses the latest drug research progress in targeting macrophage-mediated pathways in OA.

Keywords:  Macrophage; Molecular targets; Osteoarthritis; Polarization

DOI:  https://doi.org/10.1186/s12967-025-07340-2
FASEB J. 2025 Nov 30. 39(22): e71228

Kynurenine Pathway Dysregulation Impairs Podocyte Morphology and Bioenergetics In Vitro and Leads to Glomerular Dysfunction.

Patricia Bolanos-Palmieri, Heiko Schenk, Heike Bähre, Patricia Schroder, Lynne Staggs, Hermann Haller, Mario Schiffer.

  Managing tryptophan (TRP) availability is important for cell homeostasis, and a dynamic balance between dietary intake and its catabolism is crucial. The enzymes of the kynurenine pathway (KP) mediate the main catabolic route for TRP. Its intermediary products, collectively known as kynurenines, are considered metabolically active and highly pleiotropic. Some progress has been made in the description of the biological function of the kynurenines, and despite the growing number of studies that show an association between TRP metabolism and kidney function, not much is known about the cellular mechanisms involved. To assess if the kynurenines play a role in glomerular dysfunction, we carried out a series of experiments aimed at describing the effect of changes in the relative abundance of the kynurenines on cells of the glomerulus, both in vivo and in vitro. We used a transgenic zebrafish line as a model to show that systemic changes in the KP either by morpholino knockdown, enzymatic inhibition, or kynurenine supplementation, lead to pericardial effusion, yolk sac edema, and excretion of high molecular weight proteins, all signs of impaired glomerular filtration. Cultured podocytes incubated with a KP inhibitor show changes in cell size, morphology and focal adhesions, leading to a higher detachment rate. Additionally, there is a change in the polarization status of the mitochondria, showing a loss of membrane potential and an alteration of bioenergetics parameters. Taken together, our results highlight the importance of kynurenine metabolite levels in the maintenance of a functioning filtration barrier.

Keywords:  cytoskeleton; kynurenine; kynurenine 3‐monooxigenase; mitochondria; podocyte; proteinuria

DOI:  https://doi.org/10.1096/fj.202502175R
Front Immunol. 2025 ;16 1670213

The mechanotransduction-immune axis in organ fibrosis: dual regulatory mechanisms and translational therapeutic perspectives.

Chao Lei, Dongjie Wu, Houyan Zhang, Zhiya Yang, Bohao Huang, Jie Wang, Yanbo Li, Wenliang Lv.

  Organ fibrosis represents a final common pathway of chronic tissue injury, characterized by persistent extracellular matrix (ECM) accumulation and progressive loss of organ function. While canonical inflammatory and profibrotic cascades have been extensively studied, emerging evidence highlights the pivotal role of mechanotransduction-the process by which cells sense and transduce biomechanical cues-in orchestrating immune responses and driving fibrotic remodeling. This review conceptualizes the mechanotransduction-immune axis as a dual regulatory network wherein mechanical forces not only activate profibrotic signaling in resident stromal cells but also dynamically reprogram immune cell phenotypes and functions. We systematically delineate the molecular and cellular mechanisms by which matrix stiffness, shear stress, and mechanical stretch engage integrins, focal adhesion kinase, Piezo1, and TRPV4 to coordinate inflammatory signaling and ECM remodeling. Additionally, we discuss how immune cells, including macrophages, T cells, and neutrophils, sense and respond to mechanical inputs to amplify profibrotic responses. Finally, we summarize emerging translational therapeutic perspectives targeting this mechanotransduction-immune interplay, encompassing small-molecule inhibitors, nanomedicine approaches, gene editing technologies, and cell therapies. By integrating mechanistic insights and translational strategies, this review aims to provide a comprehensive framework for understanding and therapeutically targeting the mechanotransduction-immune axis in organ fibrosis.

Keywords:  extracellular matrix; immune; mechanotransduction; organ fibrosis; therapeutic target

DOI:  https://doi.org/10.3389/fimmu.2025.1670213
Cells. 2025 Nov 05. pii: 1738. [Epub ahead of print]14(21):

Targeting Mitochondrial Dynamics via EV Delivery in Regenerative Cardiology: Mechanistic and Therapeutic Perspectives.

Dhienda C Shahannaz, Tadahisa Sugiura, Brandon E Ferrell, Taizo Yoshida.

  Mitochondrial dysfunction is a key contributor to cardiac injury and heart failure, and extracellular vesicles (EVs) have emerged as promising therapeutic agents due to their ability to deliver mitochondrial-targeted cargo. This review systematically maps the evidence on how EVs modulate mitochondrial dynamics-including fusion, fission, mitophagy, and biogenesis-in regenerative cardiology. We comprehensively searched PubMed, Scopus, and Web of Science up to September 2025 for original studies. A total of 48 studies were included, with most utilizing EVs from mesenchymal stem cells, induced pluripotent stem cells, or cardiac progenitors. The review found that EV cargo influences key pathways such as DRP1 and MFN2, restores mitochondrial membrane potential, reduces ROS accumulation, and improves cardiomyocyte survival. While engineered EVs showed enhanced specificity, a lack of standardized preparation and quantitative assessment methods remains a significant challenge. We conclude that EV-mediated mitochondrial modulation is a promising strategy for cardiac repair, but the field needs harmonized protocols, deeper mechanistic understanding, and improved translational readiness to advance beyond preclinical research. The future of this research lies in integrating systems biology and precision targeting.

Keywords:  EV-based drug delivery; cardiac regeneration; extracellular vesicles (EVs); heart failure therapy; mitochondrial biogenesis and mitophagy; mitochondrial dynamics; mitochondrial transfer; regenerative cardiology; stem cell-derived EVs; translational cardiovascular medicine

DOI:  https://doi.org/10.3390/cells14211738