bims-mihora 2026-05-31 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2026–05–31
twenty-six papers selected by
Lisa Patel, Istesso

Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.
A transport-independent role for SLC25A12 in mitochondrial stress signalling.
A multilayered stress-response circuit: The mammalian mitochondrial UPR.
A Stress-Responsive Nuclear Factor, GLDI-8, Mediates Mitochondrial Stress Responses to ETC Dysfunction.
Mitochondrial drivers of stem cell aging and inflammaging.
CHOP promotes the transition to chronic integrated stress response signaling with suppression of hepatocyte identity.
Mesenchymal Stromal Cell-Mediated Intercellular Communication: Mapping the Interactome for Skeletal Muscle Homeostasis and Regeneration.
Mapping the GDF15 arm of the integrated stress response in human cells and tissues.
Mitochondrial Metabolism Governs Spermatogonial Stem Cell Fate Decisions.
Pharmacological targeting of the integrated stress response by 2BAct improves object recognition memory and reduces neuroinflammation in the 5xFAD model of Alzheimer's disease.
A paradoxical relationship between mitochondrial calcium regulation and retinal ganglion cell degeneration after axon damage.
Mitochondrial complex I as a master regulator of redox signaling: From structural architecture to directionality of electron transport.
From Mesenchymal Stromal Cells to Extracellular Vesicles: Scalable Strategies for Ovarian Stroma Regeneration.
Mitochondrial extracellular vesicles between pathology and regeneration.
Mitochondrial Stress Orchestrates Tumor Immune Evasion and Immunotherapy Resistance.
Nuclear Receptor Liver Receptor Homolog-1 drives Intestinal Stem Cell regeneration and UPR/ER stress response after gut injury.
Targeting the Skeletal Muscle Microenvironment: A Novel Therapeutic Strategy for Skeletal Muscle Aging.
Immunometabolic Modulation of the Bone Marrow Niche by Bioactive Materials to Rescue Impaired Fracture Healing.
Trans-kingdom coupling of redox signaling to environmental cell stress responses through multiphase partitioning.
Regenerative potential of muse cells in ROS-mediated cardiac injury: An in vitro oxygen-glucose deprivation/reoxygenation model.
Metabolite Damage and Repair in Health and Disease.
Mitochondria-Associated mRNAs Restore ATP During Oxidative Stress via Cytosolic Translation.
Mesenchymal drift: A convergent framework for the hallmarks of aging.
Multicellular senescence impairs skeletal muscle recovery following disuse in aging.
Sestrin regulates cellular homeostasis through modulating mitochondrial function.
Intraosseous therapy: harnessing the potential of tissue regeneration and repair.

Muscles. 2026 May 22. pii: 39. [Epub ahead of print]5(2):

Unfolding Resilience: Molecular Integration of the Integrated Stress Response and Mitochondrial UPR in Skeletal Muscle Homeostasis.

Victoria C Sanfrancesco, Daniella Della Mea, David A Hood.

  To maintain homeostatic conditions and optimal function during stressors, mitochondria initiate retrograde signaling. The mitochondrial integrated stress response (ISR) and unfolded protein response (UPRmt) are critical quality control mechanisms activated during instances of mitochondrial perturbations. Restoration of mitochondrial homeostasis is orchestrated by three transcription factors, ATF4, CHOP, and ATF5, which upregulate protective genes to counteract stress. As the health and function of skeletal muscle are heavily dependent on a highly adaptive mitochondrial network, defining how mitochondrial health is maintained across various conditions is essential. Although several studies demonstrate the importance of these responses following instances of stress, the signaling mechanisms required to initiate such pathways remain poorly characterized in skeletal muscle. This review examines how the mitochondrial ISR/UPRmt and related transcription factors respond to organellar stress by emphasizing the molecular events that occur during exercise, aging and muscle disuse. By consolidating the literature, this work aims to highlight the current understanding of mitochondrial stress response signaling within skeletal muscle and thus emphasize areas for future research and potential therapeutic strategies during divergent metabolic conditions.

Keywords:  ATF4; ATF5; CHOP; adaptation; aging; exercise; integrated stress response; mitochondria; muscle inactivity; skeletal muscle; stress response; unfolded protein response

DOI:  https://doi.org/10.3390/muscles5020039
Nat Cell Biol. 2026 May 27.

A transport-independent role for SLC25A12 in mitochondrial stress signalling.

Liu Jiang, Lan Li, Jialiang Guan, Ying Liu.

Mitochondria are central hubs for energy production and cellular adaptation to stress. When mitochondria are damaged, cells activate protective signalling pathways to restore homeostasis and ensure survival. One such pathway, known as the integrated stress response (ISR), reduces overall protein synthesis while enhancing the production of stress-responsive proteins. The mitochondrial carriers SLC25A12 and SLC25A13 transport similar metabolites but are expressed in different tissues and linked to distinct genetic diseases. Here we show that SLC25A12 plays a previously unrecognized role in stress signalling that is independent of its transport activity. SLC25A12 interacts with the mitochondrial protease OMA1, enabling activation of ISR during mitochondrial damage. This signalling function is disrupted by a disease-linked mutation but preserved in transport-deficient variants. Our findings reveal SLC25A12 as a dual-function mitochondrial protein, acting as both a metabolite transporter and a regulator of stress signalling, and suggest that defective ISR activation may contribute to certain SLC25A12-associated pathologies.

DOI: https://doi.org/10.1038/s41556-026-01973-1
FEBS J. 2026 May 29.

A multilayered stress-response circuit: The mammalian mitochondrial UPR.

Paulina Czechowicz, Anna Więch-Walów, Sylwia Kozioł, Jakub Dudzik, James F Collawn, Rafal Bartoszewski.

  Mitochondrial proteotoxic stress activates the mammalian UPRmt through a multilayered mechanistic architecture rather than a linear pathway. At its core lies an import-gated sensing logic: reduced preprotein import and mito-nuclear stoichiometric imbalance activates the integrated stress response (ISR) toward the translation of ATF4, CHOP, and the mitochondria-targeted transcription factor ATF5. These factors cooperatively reprogram transcription to expand the chaperone-protease capacity while transiently reducing the nuclear-encoded OXPHOS load. Parallel translational mechanisms that include eIF2α-dependent repression, stress-granule triage, and miRNA-driven selective silencing reduce the mitochondrial precursor import and maintain proteostatic symmetry between the cytosol and mitochondria. Within the organelle, LONP1- and CLPP-dependent proteolysis, mitoribosome pausing, and tRNA-processing checkpoints further dampen nascent chain pressure. Epigenetic licensing by demethylases and acetyltransferases links metabolic and bioenergetic status to promoter accessibility at UPRmt loci. Together, these import-gated, translational, and epigenetic control layers form a coherent mechanistic circuit ensuring that mitochondrial recovery is matched to folding, assembly, and metabolic capacity. We propose a unified framework explaining how these layers cooperate to determine adaptive versus maladaptive outcomes.

Keywords:  Integrated stress response (ISR); Mitochondrial protein import stress; Mitochondrial proteostasis; Mitochondrial stress signaling; Mitochondrial unfolded protein response (UPRmt)

DOI:  https://doi.org/10.1111/febs.70607
Int J Mol Sci. 2026 May 14. pii: 4387. [Epub ahead of print]27(10):

A Stress-Responsive Nuclear Factor, GLDI-8, Mediates Mitochondrial Stress Responses to ETC Dysfunction.

Yung Wu, Hongyun Tang.

  Mitochondrial electron transport chain (ETC) impairment triggers mitochondrial unfolded protein response (UPRmt) that promotes mitochondrial homeostasis, yet the nuclear factors that mediate these responses remain incompletely defined. Here, we identify GLDI-8 as a nuclear factor required for robust activation of the hsp-6p::gfp UPRmt reporter induced by ETC dysfunction in Caenorhabditis elegans. Depletion of gldi-8 markedly compromises mitochondrial stress-induced hsp-6p::gfp reporter activation, and transgenic rescue restores the response, supporting a specific requirement for GLDI-8 in this pathway. Mitochondrial stress promotes nuclear accumulation of GLDI-8; however, a GLDI-8 transcriptional (promoter) reporter shows no detectable induction under the same conditions, suggesting that regulation occurs at the post-transcriptional level. Genetic analysis further shows that stress-induced nuclear translocation of GLDI-8 is not abolished by atfs-1 knockdown, and GLDI-8 is dispensable for DVE-1 nuclear translocation under mitochondrial stress. Together, these findings establish GLDI-8 as a mitochondrial stress-responsive nuclear factor that contributes to ETC impairment-induced transcriptional responses and adds to the complex regulatory network underlying the UPRmt.

Keywords:  Caenorhabditis elegans; GLDI-8; electron transport chain dysfunction; mitochondrial unfolded protein response

DOI:  https://doi.org/10.3390/ijms27104387
NPJ Aging. 2026 May 28.

Mitochondrial drivers of stem cell aging and inflammaging.

Jhommara Bautista, Andrés López-Cortés.

Mitochondria are increasingly recognized as master regulators of aging, integrating bioenergetics, redox control, stem cell fate, and innate immune signaling. This review synthesizes evidence that mitochondrial dysfunction is not only a hallmark but also an upstream driver of stem cell exhaustion and inflammaging. We discuss how age-associated mitochondrial DNA (mtDNA) mutations and clonal mosaicism impair respiration and reshape metabolite availability, thereby reprogramming long-lived epigenetic states that govern quiescence, lineage commitment, and regenerative output. In parallel, erosion of mitochondrial quality control (MQC), including fission-fusion balance, mitophagy, and the mitochondrial unfolded protein response (UPRmt), permits the persistence of reactive oxygen species (ROS)-producing organelles and lowers containment of mitochondrial danger signals. A central advance is that mitochondrial damage can be decoded as inflammation: cytosolic mtDNA and other mitochondrial damage-associated molecular patterns (mtDAMPs) activate cGAS-STING and NF-κB pathways, reinforcing senescence-linked cytokine circuits and chronic inflammatory tone. We further highlight nicotinamide adenine dinucleotide (NAD⁺) depletion as a metabolic bottleneck that compromises sirtuin-dependent resilience and can enforce mitochondrial dysfunction-associated senescence (MiDAS), linking redox collapse to altered senescence phenotypes and regenerative decline. Finally, we evaluate emerging mitochondria-targeted rejuvenation strategies, NAD⁺ repletion, mitophagy enhancers, mitochondrial transplantation/engineering, and precision elimination of mutant mtDNA using mitochondria-targeted transcription activator-like effector nucleases (mitoTALENs) or zinc-finger nucleases (mitoZFNs), emphasizing tissue-specific thresholds and context dependence for effective healthspan extension.

DOI: https://doi.org/10.1038/s41514-026-00422-5
bioRxiv. 2026 May 15. pii: 2026.05.13.724984. [Epub ahead of print]

CHOP promotes the transition to chronic integrated stress response signaling with suppression of hepatocyte identity.

Theo F Velarde, Kaihua Liu, Zewei Zhang, Reed C Adajar, Chaoxian Zhao, Huojun Cao, D Thomas Rutkowski.

The transcription factor CHOP promotes cell death during ER stress, but it is strongly induced even by moderate stresses that do not result in appreciable cell death. Its role during less severe stresses-especially in intact tissues in vivo -is poorly understood. Here, we both deleted and restored CHOP specifically in hepatocytes and challenged animals with ER stress in vivo . We found that CHOP influenced stress-dependent hepatocyte gene expression through two previously unappreciated mechanisms. It directly suppressed the expression of transcriptional master regulators of hepatocyte identity and metabolism. And more broadly, it exacerbated ER stress through the promotion of protein synthesis, which led to persistent activation of the integrated stress response (ISR) despite dephosphorylation of eIF2α. This shift to second-phase ISR signaling was phenocopied by deletion of the protective UPR sensor ATF6α, suggesting that it reflects a transition from an acute stress response to a chronic one. Our findings show that CHOP augments the capacity of the ISR and UPR to continue to mount a protective response even after eIF2α phosphorylation has been suppressed. In vivo , where ISR signaling intersects with hepatocyte gene regulatory networks, this transition favors lipid dysregulation, highlighting a pathway through which CHOP impacts tissue function independent of cell death.

DOI: https://doi.org/10.64898/2026.05.13.724984
Adv Sci (Weinh). 2026 May 29. e07444

Mesenchymal Stromal Cell-Mediated Intercellular Communication: Mapping the Interactome for Skeletal Muscle Homeostasis and Regeneration.

Xingyu Liu, Edgar E Perez Carbajal, Yih-Chii Hwang, Sahil A Mapkar, Benjamin W Gilman, Sarah A Bliss, Lam B Tran, Kalgi T Mehta, Jacob O Banyasz, Ming Yu, Reynold R Liu, Matthew N Ly, Christapher S Morrissey, Michael N Wosczyna.

  Mesenchymal stromal cells (MSCs) support tissue homeostasis and regeneration, yet their molecular signals remain largely enigmatic. In skeletal muscle (SkM), MSCs, known as fibroadipogenic progenitors (FAPs), are essential for maintenance and repair, orchestrating these processes through intricate cellular communication networks. Given the critical role of SkM in lifelong health and longevity, FAP signaling has drawn significant interest as a potential therapeutic target and a model for MSC interactions. However, deciphering FAP-derived regulatory signals remains challenging due to their pleiotropic complexity. Here, we employ a systems-level approach to construct a comprehensive FAP interactome in both homeostatic and regenerating SkM. By integrating unique single-cell RNA sequencing atlases with advanced computational analyses, we identify putative FAP-mediated signaling pathways and validate their biological relevance through FAP depletion experiments, assessing disruptions in key pathways. This approach reveals novel signaling networks across diverse SkM cell populations, corroborates key FAP interactions from recent studies, and provides a valuable dataset for modeling MSC interactions and their roles in SkM homeostasis and regeneration.

Keywords:  fibroadipogenic progenitor; intercellular communication; maintenance and regeneration; mesenchymal stem cell; skeletal muscle

DOI:  https://doi.org/10.1002/advs.202507444
Commun Biol. 2026 May 27.

Mapping the GDF15 arm of the integrated stress response in human cells and tissues.

Janell L M Smith, Kamaryn T Tanner, Jack Devine, Anna S Monzel, Taivan Batjargal, Maxwell Z Wilson, Alan A Cohen, Martin Picard.

Mitochondrial stress activates the integrated stress response (ISR) and triggers cell-cell communication through the secretion of the metabokine growth differentiation factor 15 (GDF15). However, the gene network underlying the ISR remains poorly defined across metabolically diverse cellular states and tissues. Using RNAseq data from fibroblasts subjected to eleven metabolic perturbations, including genetic and pharmacological mitochondrial OxPhos defects, we show that the ISR has multiple arms. To quantify the GDF15 arm of ISR activation in human cells, we developed an ISRGDF15 index. We validate the ISRGDF15 index in datasets from optogenetic and small molecule activation of ISR kinases, demonstrating its rapid kinetics preceding to GDF15 gene expression. We then deploy the ISRGDF15 index across 44 postmortem human tissues, confirm its correlation with age, and report that the ISRGDF15 is upregulated in the heart of individuals with acute causes of death in the emergency room, whereas it was upregulated in the brain of individuals who died after protracted hospital inpatient stays. These data highlight distinct arms of the ISR and clarify genes related to the GDF15 ISR arm, yielding an ISRGDF15 index that can be used to investigate tissue-specific and age-related ISR activation in both in vitro cultures and human tissues.

DOI: https://doi.org/10.1038/s42003-026-10312-x
Andrology. 2026 May 25.

Mitochondrial Metabolism Governs Spermatogonial Stem Cell Fate Decisions.

Zhimin Ma, Qi Geng, Huaibing Zhu, Dingfeng Zou, Dingyao Chen, Kai Li, Wei Song.

   BACKGROUND: Spermatogonial stem cells (SSCs) sustain lifelong spermatogenesis through their unique capacity for self-renewal and differentiation. While transcriptomic regulation has long been emphasized, recent advances in multi-omics have highlighted mitochondrial metabolism as a pivotal regulator of SSC fate.
OBJECTIVE: This review aims to summarize current advances in how mitochondrial metabolism regulates SSC fate decisions and to explore its pathological alterations and potential therapeutic targets in obesity-associated male infertility.
METHODS: This review delves deeper into the core mechanisms by which mitochondria govern SSC fate decisions, integrating findings from multi-omics, metabolic assays, and animal models. We also provide a comprehensive overview of published literature on mitochondrial dysfunction in obesity-related infertility.
RESULTS AND CONCLUSION: Quiescent SSCs predominantly rely on glycolysis within a hypoxic niche, whereas differentiation is accompanied by a metabolic shift toward oxidative phosphorylation (OXPHOS), alongside mitochondrial maturation and remodeling. Beyond energy production, mitochondria function as critical signaling hubs that integrate redox regulation, mitochondrial dynamics, and metabolite-dependent epigenetic mechanisms to dictate SSC fate. Conversely, in the context of obesity, mitochondrial dysfunction, characterized by excessive reactive oxygen species (ROS) production, mitochondrial fragmentation, and impaired quality control, severely disrupts SSC homeostasis and drives male infertility. Maintaining mitochondrial metabolic integrity is essential for normal SSC function. Targeting mitochondrial quality control and restoring metabolic balance represent promising emerging therapeutic strategies for the treatment of obesity-related male infertility.

Keywords:  male infertility; mitochondrial metabolism; obesity; oxidative stress; spermatogonial stem cells (SSCs)

DOI:  https://doi.org/10.1111/andr.70241
J Alzheimers Dis. 2026 May 25. 13872877261450638

Pharmacological targeting of the integrated stress response by 2BAct improves object recognition memory and reduces neuroinflammation in the 5xFAD model of Alzheimer's disease.

Daegeon Kim, Hojung Jeong, Hye Kyung Lim, Soo Min Ahn, Minseok Song.

  BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia. The integrated stress response (ISR) contributes to impaired synaptic plasticity, neuronal dysfunction, and cognitive deficits in AD. However, research targeting the ISR as a therapeutic strategy for AD remains limited due to insufficient mechanistic insight.ObjectiveThis study aimed to evaluate the effects of 2BAct, an ISR inhibitor, on behavioral symptoms, amyloid-β (Aβ) and tau accumulation, and neuroinflammation in 5xFAD mice.MethodsTen-month-old 5xFAD mice received daily intraperitoneal (IP) injections of either 2BAct (10 mg/kg/day), donepezil (2 mg/kg/day; positive control), or vehicle for 23 consecutive days. Anxiety-like behavior and cognitive function were assessed using the open field test (OFT), novel object recognition test (NORT), and Morris water maze (MWM). Amyloid-β (Aβ), tau, and neuroinflammation markers were analyzed by immunofluorescence staining. ISR inhibition was evaluated by examining the phosphorylation level of eukaryotic initiation factor 2 alpha (eIF2α) using immunofluorescence staining and by analyzing ISR-related markers via RNA sequencing.Results2BAct treatment significantly improved object recognition performance and attenuated microglial activation and tau accumulation, without reducing Aβ burden. Reduced levels of phosphorylated eIF2α were also confirmed by immunofluorescence staining.ConclusionsThese findings suggest that 2BAct treatment improves cognitive performance and mitigates neuroinflammation while reducing tau accumulation. Although the therapeutic effects are limited, targeting the ISR with inhibitors such as 2BAct represents a potential therapeutic approach for AD. Further studies are required to elucidate the underlying molecular mechanisms and to address the limitations of ISR-based interventions.

Keywords:  2BAct; 5xFAD; Alzheimer's disease; cognitive impairment; integrated stress response; microglial activation; tau pathology

DOI:  https://doi.org/10.1177/13872877261450638
bioRxiv. 2026 May 15. pii: 2026.05.13.724793. [Epub ahead of print]

A paradoxical relationship between mitochondrial calcium regulation and retinal ganglion cell degeneration after axon damage.

Sean McCracken, Minglei Zhao, Kyler Squirrell, Christopher Zhao, Saman Behboodi Tanourlouee, Michelle Aum, Philip R Williams.

Retinal ganglion cells (RGCs) degenerate in optic neuropathies like glaucoma and traumatic optic nerve injury leading to irreversible vision loss. Higher levels of homeostatic Ca 2+ and canonical Ca 2+ regulated signaling promote RGC survival in animal models of glaucoma and optic nerve injury. Mitochondrial dysfunction is also a hallmark of degenerating neurons, including RGCs. Here, we investigate the intersection of mitochondrial function, Ca 2+ homeostasis, and cellular resilience by performing an optic nerve crush model of RGC degeneration while monitoring and manipulating mitochondrial Ca 2+ levels (mito-Ca 2+ ). We find that mito-Ca 2+ is predicative of RGC survival in that surviving RGCs are enriched for higher homeostatic mito-Ca 2+ levels. Mitochondrial dysfunction was observed where mito-Ca 2+ was reduced in RGCs after injury, regardless of survival. We then examined the importance of higher mito-Ca 2+ in surviving RGCs by altering mito-Ca 2+ levels and Ca 2+ transit using pharmacological and AAV-mediated approaches. Paradoxically, treatment to decrease mito-Ca 2+ increased survival to ONC. We then manipulated mito-Ca 2+ permeability by altering the expression levels of the mitochondrial calcium uniporter (MCU) pore forming subunit that allows Ca 2+ to enter mitochondria from the cytoplasm. Overexpressing MCU reduced RGC survival to injury, while shRNA knockdown of MCU increased RGC survival. These results reveal a complex relationship between mito-Ca 2+ and RGC degeneration and suggest that well-surviving RGCs may be under chronic mitochondrial stress due to higher homeostatic mito-Ca 2+ levels.

DOI: https://doi.org/10.64898/2026.05.13.724793
Free Radic Biol Med. 2026 May 25. pii: S0891-5849(26)00791-4. [Epub ahead of print]253 221-237

Mitochondrial complex I as a master regulator of redox signaling: From structural architecture to directionality of electron transport.

Ehsaneh Khodadadi, Bingwei Lu.

  Mitochondrial complex I (MCI) is the largest enzyme of the electron transport chain, catalyzing oxidation of NADH, reduction of ubiquinone, and translocation of protons across the inner mitochondrial membrane (IMM). In addition to driving ATP synthesis through oxidative phosphorylation (OxPhos), MCI is a dynamic redox regulator that couples bidirectional catalysis with redox signaling. MCI conducts electron transfer in both the forward and reverse directions. While forward electron transport (FET) is essential for OxPhos and ATP synthesis, reverse electron transport (RET), driven by high membrane potential and ubiquinol pool, transfers electrons from ubiquinol to NAD+ and produces excessive ROS. MCI-derived ROS and NAD+/NADH changes act as physiologically regulated signals mediating hypoxia sensing, immune activation, stem-cell metabolism, but they can also contribute to pathology when dysregulated as in ischemia-reperfusion, cancer, neurodegeneration, and aging. Recent cryo-EM structures, time-resolved studies, and multiscale molecular dynamics (MD) simulations have provided near-atomic views of MCI architecture and operational mechanics. Here we review these developments from a redox-centered perspective. By positioning MCI as a dynamic redox regulator within a spatially organized mitochondrial network, we aim to provide a unifying framework for understanding how directional electron transfer, proton translocation, and redox signaling are intertwined in mitochondrial biology.

Keywords:  Mitochondrial Complex I; Proton-coupled electron transfer; Reactive oxygen species (ROS); Redox signaling; Reverse electron transport (RET)

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.311
Mol Reprod Dev. 2026 May;93(5): e70113

From Mesenchymal Stromal Cells to Extracellular Vesicles: Scalable Strategies for Ovarian Stroma Regeneration.

Stefhani Martins Barcelos, Amandda Évelin Silva-Carvalho, Felipe Perecin, Juliana Lott Carvalho.

  Ovarian aging is characterized by the reduction of the follicular pool and a progressive loss in oocyte quality. Although these changes have initially been attributed to oocyte alterations, increasing evidence indicates that stromal deterioration plays a central role in this process. Stromal remodeling involves complex interactions among structural, molecular, and cell communication disruptions. This review discusses the main ovarian stroma shifts related to aging, emphasizing ECM remodeling, biomechanical changes, and cell signaling dysfunction. In light of the multifactorial nature of ovarian aging, no single therapeutic strategy is likely to fully address stromal dysfunction. In this context, Mesenchymal Stromal Cells (MSCs) and their secreted Extracellular Vesicles (EVs) have emerged as promising approaches, given their ability to deliver a diverse and functionally complementary set of bioactive molecules that collectively modulate inflammation, support extracellular matrix remodeling, and restore cell communication. Notably, EVs retain key paracrine effects of MSCs while offering advantages in safety and manufacturability, supporting the transition from cell-based to cell-free therapies. Accordingly, this review also examines this therapeutic shift, highlighting the role of MSCs and EVs in stromal regeneration. By integrating ovarian biology with biotechnological bioprocesses, we discuss key translational challenges-including scalability, quality control, and regulatory considerations-that are critical for the development of effective stroma-targeted interventions aimed at preserving or restoring ovarian function.

Keywords:  extracellular vesicles; mesenchymal stromal cells; ovarian aging; ovarian stroma; regenerative medicine; scale‐up

DOI:  https://doi.org/10.1002/mrd.70113
Neural Regen Res. 2026 May 14.

Mitochondrial extracellular vesicles between pathology and regeneration.

Paola Margutti, Silvia Zamboni.

  Mitochondria are central regulators of cellular energy production, metabolic homeostasis, and stress responses, and their dysfunction represents a critical hallmark of neurodegenerative and neuroinflammatory diseases. To preserve mitochondrial integrity, cells rely on an intricate mitochondrial quality control system encompassing mitochondrial dynamics, mitophagy, biogenesis, and vesicle-mediated pathways. Emerging evidence highlights the pivotal role of mitochondria-derived vesicles as vehicles for trafficking mitochondrial components within cells, thereby contributing significantly to intracellular communication and mitochondrial quality control. In parallel, mitochondrial extracellular vesicles have been identified as dynamic mediators of intercellular communication, enabling the transfer of mitochondrial proteins, lipids, and even mitochondrial DNA between cells. Mitochondria-derived vesicles selectively remove damaged mitochondrial components and coordinate intracellular stress responses, whereas mitochondrial extracellular vesicles can transfer mitochondrial material, including proteins, mitochondrial DNA, and even intact mitochondria, between cells, thereby modulating inflammation, immune activation, and cellular bioenergetics. Interestingly, mitochondrial extracellular vesicles play a dual, context-dependent role: they can exacerbate pathology when carrying damaged or dysfunctional mitochondrial cargo, or promote cellular resilience when delivering healthy, functional mitochondrial components. Likewise, extracellular vesicles derived from mesenchymal stem cells, including larger extracellular vesicle populations capable of transferring functional mitochondria, are emerging as promising cell-free therapeutic candidates with the potential to restore mitochondrial function and promote tissue repair across multiple diseases, including neurodegenerative disorders. Collectively, these insights establish mitochondrial vesicular trafficking as a transformative frontier for diagnostic innovation, biomarker development, and novel therapeutic strategies in neurodegenerative and mitochondria-related central nervous system disorders. Implications for the field include: the recognition of mitochondrial vesicular pathways as fundamental regulators of central nervous system homeostasis highlights their crucial roles in sustaining neuronal function, cellular resilience, and overall brain health. When enriched with dysfunctional mitochondrial cargo, mitochondrial extracellular vesicles are emerging as key contributors to the etiopathogenesis of neurodegenerative and neuroinflammatory diseases, thereby driving disease initiation and progression. In parallel, their ability to reflect mitochondrial status positions mitochondrial extracellular vesicles - particularly those containing mitochondrial DNA and mitochondrial proteins - as promising biomarkers for monitoring mitochondrial stress, disease activity, and therapeutic response. At the translational level, advancing mitochondrial extracellular vesicles and mitochondrial vesicular pathways as therapeutic tools opens new opportunities to restore mitochondrial integrity, modulate neuroinflammation, and potentially modify disease trajectories. The objectives of this review are to: (1) delineate the mechanisms of mitochondrial dysfunction and mitochondrial quality control failure in neurodegenerative and neuroinflammatory diseases; (2) comprehensively characterize the biogenesis, trafficking pathways, and functional roles of mitochondria-derived vesicles; (3) evaluate experimental and clinical evidence supporting the role of mitochondrial extracellular vesicles as mediators of neuroimmune communication and mitochondrial transfer; (4) critically assess the therapeutic potential of mesenchymal stem cell-derived mitochondrial extracellular vesicles.

Keywords:  autophagy; extracellular vesicles; lysosome; mesenchymal stem cells; mitochondria; mitochondrial damage-associated molecular patterns; mitochondrial transfer; mitophagy; neurodegeneration; neuroinflammation

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00964
Cells. 2026 May 13. pii: 890. [Epub ahead of print]15(10):

Mitochondrial Stress Orchestrates Tumor Immune Evasion and Immunotherapy Resistance.

Ayhan Bilir, Berna Yıldırım, Mete Hakan Karalök.

  Mitochondrial stress has emerged as a key regulator of tumor-immune interactions, extending beyond its classical bioenergetic role to coordinate metabolic adaptation and immune regulation. Rather than merely accompanying tumor progression, mitochondrial dysfunction contributes to immune evasion and resistance to immunotherapy. Here, we propose that mitochondrial stress functions as a unifying axis governing three key determinants of anti-tumor immunity: immune visibility, immune cell fitness, and the metabolic architecture of the tumor microenvironment. Mechanistically, mitochondrial reactive oxygen species, mitochondrial DNA release, and mitophagy modulate antigen presentation and T cell function. We further highlight emerging experimental platforms, including 3D spheroid and organoid systems, that enable physiologically relevant investigation of mitochondria-driven tumor-immune interactions. Together, this perspective provides a mechanistic framework for understanding and targeting resistance to immune checkpoint blockade.

Keywords:  3D tumor models; PD-1/PD-L1 axis; immune checkpoint blockade; immunotherapy resistance; metabolic competition; mitochondria; mitochondrial stress; mitophagy; mtDNA–cGAS–STING; organoids; tumor immune evasion; tumor microenvironment

DOI:  https://doi.org/10.3390/cells15100890
bioRxiv. 2026 May 17. pii: 2026.05.15.725547. [Epub ahead of print]

Nuclear Receptor Liver Receptor Homolog-1 drives Intestinal Stem Cell regeneration and UPR/ER stress response after gut injury.

Hsi-Ju Chen, Kristina N Braverman, Bohan Yu, James R Bayrer.

Stem cell renewal and crypt survival are tightly controlled processes critical for gut repair. Defining key regulators of intestinal healing is critical for the development of new epithelial-targeted therapies. We previously showed that the nuclear receptor LRH-1 (NR5A2) maintains intestinal epithelial health and protects against inflammatory damage. Here, using lineage tracing and selective LRH-1 knockout in the Atoh1 + secretory lineage we show LRH-1 is vital for intestinal stem cell (ISC) regeneration in complementary in vivo and ex vivo injury-recovery models. Transcriptomic profiling and pathway analysis reveal downregulation of ER stress and unfolded protein response (UPR) programs. Using a new in vivo model to ascertain how LRH-1 directly impacts intestinal cell responses, we identify key ER stress response genes Ire1α and Xbp1 as potential LRH-1 targets. Together our results uncover a novel mechanism whereby LRH-1 sustains the IRE1α-XBP1 arm of the UPR to support injury-induced dedifferentiation and ISC regeneration. Our findings highlight LRH-1 as a promising therapeutic target for restoring epithelial integrity in inflammatory intestinal disorders.

DOI: https://doi.org/10.64898/2026.05.15.725547
FASEB J. 2026 May 31. 40(10): e71936

Targeting the Skeletal Muscle Microenvironment: A Novel Therapeutic Strategy for Skeletal Muscle Aging.

Yujia Yu, Yu He, Yan Wang, Chunhua Wu, Rui Zhou, Feng Chen, Wen Ma.

  Sarcopenia, a hallmark of skeletal muscle aging, is a significant public health concern that substantially compromises the quality of life in the elderly. While conventional research has predominantly focused on intrinsic pathological alterations within muscle fibers, it has often overlooked the diverse cell-cell and interorgan communications mediated by nonmuscle cells in the skeletal muscle microenvironment. This microenvironment, comprising the extracellular matrix, multiple cellular components, secreted factors, and metabolites, plays a crucial role in regulating muscle homeostasis and regeneration, serving as a key driver of skeletal muscle aging. As the microenvironment undergoes profound remodeling with advancing age, this review systematically examines novel intervention strategies targeting it. By aiming to achieve coordinated multipathway remodeling of this niche, these approaches offer a fresh theoretical foundation and novel clinical avenues for delaying or reversing sarcopenia. Future research should prioritize elucidating these microenvironmental regulatory mechanisms, refining personalized intervention protocols, and rigorously validating translational applications.

Keywords:  cytokines; extracellular matrix; intervention strategies; sarcopenia; skeletal muscle aging; skeletal muscle microenvironment

DOI:  https://doi.org/10.1096/fj.202601360R
Stem Cell Rev Rep. 2026 May 28.

Immunometabolic Modulation of the Bone Marrow Niche by Bioactive Materials to Rescue Impaired Fracture Healing.

Dong Li, Shaolong Ma.

  Despite advancements in mechanical fixation, impaired fracture healing remains a significant clinical challenge, largely driven by immunometabolic dysregulation within the bone marrow niche. Conditions such as prolonged M1 macrophage activation, disrupted metabolic homeostasis, and mitochondrial dysfunction collectively stall the regenerative cascade and push skeletal progenitors toward senescence or adipogenesis. This review comprehensively explores the paradigm shift from purely mechanical stabilization to immunometabolic reprogramming using bioactive materials to rescue impaired bone repair. We systematically categorize biomaterial-driven interventions into three core pillars: metal ion-releasing systems that orchestrate immune-osteogenic crosstalk, metabolism-targeted delivery platforms that suppress aerobic glycolysis to alleviate inflammatory stress, and mitochondria-protective strategies that scavenge reactive oxygen species to restore cellular bioenergetics. Furthermore, we emphasize the critical importance of spatiotemporal design-such as phase-matched degradation kinetics, sequential drug release, and localized deployment-to synchronize material function with physiological healing stages while minimizing ectopic ossification. Ultimately, integrating these advanced biomaterial strategies with emerging diagnostic tools, such as single-cell profiling, offers a promising framework for personalized, precision-guided therapies to overcome complex bone regeneration failures in compromised clinical scenarios.

Keywords:  Bioactive materials; Bone marrow niche; Bone nonunion; Fracture healing; Immunometabolism

DOI:  https://doi.org/10.1007/s12015-026-11162-0
bioRxiv. 2026 May 15. pii: 2025.05.09.653213. [Epub ahead of print]

Trans-kingdom coupling of redox signaling to environmental cell stress responses through multiphase partitioning.

Elsy Ngwa, Xi Chen, Stefanie Schmieder, Aaron Maurais, Victor Svistunov, Qianni Peng, Ian Moore, Wayne I Lencer, Eranthie Weerapana, Krishnan Raghunathan, Jay R Thiagarajah.

Reactive Oxygen Species (ROS) signaling is a conserved biological process with parallel functions in all evolutionary branches of life. Here, we identify Receptor for Activated C Kinase 1 (RACK1) as a conserved redox-regulated hub that integrates ROS signals to coordinate cellular stress responses. Using cysteine reactivity profiling in intestinal epithelial cells, we demonstrate that RACK1 undergoes NOX1-dependent oxidation at multiple residues, with C286 serving as a key regulatory site. Functional studies reveal that RACK1 negatively regulates NFκB signaling through redox-dependent interactions with upstream signaling complexes. Upon stress stimulation, RACK1 dynamically redistributes into membrane-less condensates that act as redox-privileged microenvironments enriched for hydrogen peroxide. We find that oxidized RACK1 condensates are conserved through evolution with analogous stress response behavior in bacteria and yeast indicating a ubiquitous and ancient stress sensor-effector system. Functionally, redox-dependent RACK1 activity links environmental stress to translational control, with oxidation promoting inhibition of protein synthesis. Furthermore, RACK1 mediates responses to diverse pathogen-associated stimuli, including viral and bacterial infection, highlighting its role in epithelial innate immune responses. Collectively, these findings establish RACK1 as a cellular node for redox signaling, operating within condensate-based microdomains to spatially encode oxidative signals and regulate environmental stress pathways in cells.
Significance Statement: This study defines a mechanism by which cells achieve specificity in redox signaling through compartmentalization within condensates. By identifying RACK1 as a redox sensor-effector, we reveal an ancient and broadly conserved system linking environmental stress to innate immune signaling and translational control. The discovery of redox-privileged condensates provides a conceptual framework for understanding how transient ROS signals are stabilized and interpreted in epithelial biology, with implications for inflammatory diseases, host-pathogen interactions, and fundamental cellular stress responses.

DOI: https://doi.org/10.1101/2025.05.09.653213
Life Sci. 2026 May 28. pii: S0024-3205(26)00307-3. [Epub ahead of print] 124498

Regenerative potential of muse cells in ROS-mediated cardiac injury: An in vitro oxygen-glucose deprivation/reoxygenation model.

Abeer Sallam, Hala Salah Ibrahim Aly, Nihal Mohamed El-Habachi, Hagar Elkafrawy, Ashraf Awaad, Radwa A Mehanna.

   AIMS: Myocardial Ischemia-reperfusion injury produces excessive reactive oxygen species, leading to myocardial cell death and debilitated cardiac function. The regenerative properties of cardiac stem/progenitor cells, particularly the Sca-1+ population, remain narrow under ischemia-reperfusion injury conditions. Multilineage stress-enduring cells known as Muse cells, a distinguished subpopulation of SSEA-3+ mesenchymal stromal cells (MSCs), have shown promise in tissue repair due to their stress-enduring, non-tumorigenic, and pluripotent-like properties. This study questioned the regenerative potential of Muse cells in rescuing Sca-1+ cardiac stem cells exposed in vitro to oxygen-glucose deprivation/reoxygenation injury.
MATERIALS AND METHODS: Muse cells were first isolated from human adipose mesenchymal stromal cells using Magnetic-activated cell sorting for SSEA-3+ cells. Co-culture experiments were conducted to assess the impacts of Muse cells on Sca-1+ cardiac stem cells proliferation, apoptosis, oxidative stress. Spontaneous Cardiac differentiation of Muse cells was assessed using expression of cardiac markers (GATA-4, Myosin light chain 2, Connexin-43, Troponin C1, and Myosin heavy chain 6.
KEY FINDINGS: Muse cell co-culture with cells exposed to oxygen-glucose deprivation/reoxygenation injury significantly improved the survival and proliferation of Sca-1+ cardiac stem cells, while reducing apoptosis and oxidative stress compared to untreated cells. Additionally, Muse cells enhanced spontaneous cardiac differentiation, as indicated by the upregulation of assessed cardiac markers.
SIGNIFICANCE: Muse cells exert protective and supportive effects on cardiac stem cells under ischemic-like conditions and may represent a promising adjunct therapy to enhance endogenous cardiac repair. However, further studies are required to confirm functional cardiomyocyte differentiation and clinical applicability.
CLINICAL TRIALS: No applicable.

Keywords:  Cardiac differentiation; Ischemia-reperfusion injury; Muse cells; Oxidative stress; SSEA-3(+) cells; Sca-1(+) cardiac stem cells

DOI:  https://doi.org/10.1016/j.lfs.2026.124498
Annu Rev Nutr. 2026 May 28.

Metabolite Damage and Repair in Health and Disease.

Carole L Linster, Maria Veiga-da-Cunha, Thomas D Niehaus, Guido T Bommer, Emile Van Schaftingen.

Metabolite repair, or metabolite damage control, has emerged as a fundamental pillar of intermediary metabolism alongside catalysis and regulation. Enzyme promiscuity and spontaneous chemical reactions inevitably generate abnormal metabolites that can interfere with classical metabolic processes. Dedicated metabolite repair enzymes prevent or reverse such damage, thereby preserving metabolic integrity. Defects in these systems define a growing class of inborn errors of metabolism, several of which are now clinically recognized and, in some cases, treatable. We summarize recent advances in the discovery and characterization of metabolite damage and repair systems in the tricarboxylic acid cycle, glycolysis, and other pathways, highlighting examples with established or potential links to human disease. We outline strategies for identifying additional metabolite repair defects and discuss diagnostic challenges, therapeutic perspectives, and connections between metabolite repair and aging. Understanding metabolite repair exposes the mechanisms that safeguard metabolism and opens new paths toward molecular diagnosis and targeted therapy.

DOI: https://doi.org/10.1146/annurev-nutr-062024-123639
Antioxidants (Basel). 2026 May 03. pii: 580. [Epub ahead of print]15(5):

Mitochondria-Associated mRNAs Restore ATP During Oxidative Stress via Cytosolic Translation.

Dong-Bin Back, Gen Hamanaka, Ji-Hyun Park, Shin Ishikane, Masayoshi Tanaka, Takafumi Nakano, Yoshihiko Nakamura, Kazuhide Hayakawa.

  Mitochondrial transplantation has been proposed as a strategy to restore cellular bioenergetics after oxidative injury, but the mechanisms governing ATP recovery remain unclear. Using placental mitochondria, we examined ATP restoration following H2O2-induced oxidative stress. Unmodified mitochondria modestly increased ATP under baseline conditions but failed to restore ATP after injury. In contrast, lipid-coated mitochondria (MitoCoat) and lipid-encapsulated mitochondria-associated mRNAs (MitoCoat-mRNA) significantly increased ATP levels in injured cells. Transcriptomic analyses revealed that ATP recovery occurred without the normalization of canonical glycolytic or oxidative phosphorylation (OXPHOS) gene programs. Instead, unmodified mitochondria induced broad transcriptional responses associated with immune activation and cellular stress, whereas MitoCoat elicited a more restricted transcriptional profile. Notably, mitochondria-associated mRNAs alone restored ATP without detectable changes in host transcriptional programs. The removal of mitochondrial surface-associated ribosomes or the inhibition of cytosolic but not mitochondrial translation attenuated ATP recovery. The restoration of key metabolic enzymes through cytosolic translation, including PFKP, pyruvate dehydrogenase, and ATP synthase subunit ATP5A suggests that mitochondria-associated mRNAs promote recovery by re-establishing coupling between glycolysis and mitochondrial OXPHOS. Together, these findings identify encapsulated mitochondria-associated mRNAs as a potential strategy to restore cellular bioenergetics under oxidative stress.

Keywords:  MitoCoat; lipid modification; mRNA; mitochondria

DOI:  https://doi.org/10.3390/antiox15050580
Cell. 2026 May 28. pii: S0092-8674(26)00455-1. [Epub ahead of print]189(11): 3184-3213

Mesenchymal drift: A convergent framework for the hallmarks of aging.

Jinlong Y Lu, William B Tu, Shuai Ma, Zaijun Ma, Ivan Imaz-Rosshandler, Mingxi Weng, Jing Qu, Concepcion Rodriguez Esteban, Pradeep Reddy, Guang-Hui Liu, Juan Carlos Izpisua Belmonte.

  Aging is characterized by the loss of tissue homeostasis, traditionally captured by the hallmarks of aging, yet how these hallmarks integrate to drive organismal decline remains unresolved. We propose mesenchymal drift, a process in which cells progressively lose lineage identity and adopt mesenchymal features, as a convergent framework that integrates the hallmarks of aging. Accumulating evidence suggests that mesenchymal drift can both arise from and reinforce these hallmarks, forming a feedback network that drives systemic decline. Framing aging through mesenchymal drift shifts the focus from discrete molecular defects to interconnected disruptions in cellular identity and cell state regulation, providing a more cohesive view of aging biology. Mesenchymal drift may therefore represent a measurable and targetable mechanism underlying diverse age-related pathologies. Interventions such as partial reprogramming may restrain mesenchymal drift, restore cellular identity, and simultaneously counteract multiple hallmarks, positioning it as both a convergent nexus and a tractable therapeutic axis in aging biology.

Keywords:  Yamanaka factors; aging; biomarkers; cellular identity and plasticity; endothelial-to-mesenchymal transition; epithelial-to-mesenchymal transition; fibrosis; geroscience; partial reprogramming; rejuvenation

DOI:  https://doi.org/10.1016/j.cell.2026.04.020
Sci Adv. 2026 May 29. 12(22): eaed5255

Multicellular senescence impairs skeletal muscle recovery following disuse in aging.

Paul-Emile Bourrant, Elena M Yee, Zachary J Fennel, Robert J Castro, Chad M Skiles, Jonathan J Petrocelli, Naomi M M P de Hart, Lisa A Lesniewski, Anna E Beaudin, Katsuhiko Funai, Christopher S Fry, Micah J Drummond.

Aged skeletal muscle has a diminished capacity to recover after disuse. Although muscle regrowth requires coordinated interactions between immune and progenitor cells, the mechanisms of impaired remodeling in aged skeletal muscle remain poorly understood yet possibly involve the accumulation of senescent cells. We used a flow cytometry approach coupled with scRNAseq to determine the muscle senescent cell identity and transcriptional landscape during skeletal muscle recovery following disuse atrophy. Young and aged mice underwent 14 days of hindlimb unloading followed by reloading (7 or 14 days). At recovery, old mice showed smaller myofibers and abnormal muscle macrophage dynamics corresponding to greater collagen content. These outcomes coincided with elevated markers of muscle senescence (p21 and γH2AX) and increased SPiDER-β-Gal+ cells, which inversely correlated with muscle mass. Single-cell resolution of SPiDER+ cells unmasked several senescent interstitial muscle vascular and stromal populations. Senescent interstitial cell populations were enriched in aged muscle and displayed a senescence-associated secretory phenotype (SASP) across multiple stromal, vascular, and immune cell types. Senolytic treatment reduced overall senescent cell burden, attenuated macrophage accumulation, and restored muscle mass and function in aged mice following disuse. These findings identify a multicellular senescence environment within the muscle interstitial niche as a hallmark of impaired muscle recovery following disuse.

DOI: https://doi.org/10.1126/sciadv.aed5255
FEBS J. 2026 May 27.

Sestrin regulates cellular homeostasis through modulating mitochondrial function.

Alexander Haidurov, Andrei Budanov.

  For years, the function of Sestrin proteins has been assigned to antioxidant protection and regulation of mTOR complexes 1 and 2. However, recent data demonstrate that Sestrins have a new role in the regulation of mitochondrial functions through incompletely understood mechanisms. These include Sestrin involvement in the control of mitochondrial biogenesis, respiration and mitophagy. Machado et al. describe a key role of Sestrin2 in the regulation of mitochondrial function in myoblast C2C12 cells. Sestrin2 supports mitochondrial biogenesis and respiration through control of mitochondrial protein expression and tuning up mitophagy. These discoveries expand our understanding of the potential role of Sestrins in supporting muscle function through mitochondrial signalling.

Keywords:  ageing; mTOR; mitochondria; myoblasts; sestrin

DOI:  https://doi.org/10.1111/febs.70604
Front Med (Lausanne). 2026 ;13 1775823

Intraosseous therapy: harnessing the potential of tissue regeneration and repair.

Mikhail Yu Artamonov, Inessa A Minenko.

  Tissue regeneration and repair remain significant challenges in various medical fields, particularly in the context of musculoskeletal conditions. Intraosseous therapy has emerged as a promising approach, harnessing the body's intrinsic regenerative potential to promote bone and tissue regeneration. This review provides a comprehensive overview of intraosseous therapy, including its principles, strategies, and clinical applications. The bone biology and regeneration processes are discussed, along with the roles of cellular components such as osteoblasts, osteoclasts, osteocytes, and mesenchymal stem cells. Intraosseous therapy encompasses various approaches, including Bone marrow aspirate concentrate (BMAC), platelet-rich plasma (PRP), stem cell-based therapies (mesenchymal stem cells, induced pluripotent stem cells, and other sources), biomaterials and scaffolds, and growth factors. The clinical applications of intraosseous therapy span bone fracture repair and non-union, spinal fusion, craniofacial and maxillofacial reconstruction, osteonecrosis and avascular necrosis, and osteoporosis and bone defects. While intraosseous therapy holds significant promise, challenges related to regulatory and ethical considerations, standardization and quality control, clinical translation and commercial viability, and future research directions in personalized medicine, advanced biomaterials, combination therapies, and in vivo monitoring must be addressed. Ultimately, intraosseous therapy represents a rapidly evolving field with the potential to revolutionize tissue regeneration and repair, offering improved outcomes and enhanced quality of life for patients suffering from various musculoskeletal conditions.

Keywords:  biomaterials; bone fracture repair; bone regeneration; growth factors; intraosseous therapy; spinal fusion; stem cells; tissue regeneration

DOI:  https://doi.org/10.3389/fmed.2026.1775823