bims-mihora 2026-06-14 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2026–06–14
seventeen papers selected by
Lisa Patel, Istesso

The integrated to developmental stress response (ISR-DASR) shift reveals a functional transition from cellular to stem cell organismal adaptation.
Integrated Stress Response and Necroptosis Drive Epithelial Dysfunction in Crohn's Disease: Repurposing Cancer Drugs for Permeability Barrier Healing.
eIF3 Orchestrates a Biphasic Stress Response Linking Translational Control to Mitochondrial Integrity in Skeletal Muscle.
Mitophagy: an emerging therapeutic target in mitochondrial diseases.
Mitochondrial complex I deficiency-associated diseases and models.
Mitochondrial homeostasis in bone aging: Unraveling dysfunctional pathways and developing precision therapies.
Reductive Stress in Myocardial Ischemia: Mechanisms, Pathophysiology, and Therapeutic Perspectives.
The UPR drives gametogenesis via an unexpected response, coordinating translation and ER structure.
Fibro-Adipogenic Progenitor Cell Alterations in Skeletal Muscle: Pathological Dysfunction or Adaptive Reprogramming?
Targeting Mitochondria in Aging-Related Diseases: Therapeutic Potential and Obstacles.
Multi-omics analysis of long COVID (post-COVID-19 condition) reveals persistent mitochondrial dysfunction, suppressed oxidative phosphorylation, and immune dysregulation.
Enhancers integrate microenvironmental signals in muscle stem cells during regeneration in health, disease, and aging.
Mitochondrial capsules mitigate mitochondrial dysfunction.
The mechano-immune-vesicle regulatory circuit: a systems framework for bone homeostasis and regeneration.
Mitoception Via the Metabokine GDF15 and Human Health.
Stem cell dysfunction and rejuvenation strategies in ageing: emerging advances in regenerative medicine.
Hormesis and the Golden Ratio: Toward a Universal Estimator of Adaptive Capacity.

Sci Rep. 2026 Jun 10.

The integrated to developmental stress response (ISR-DASR) shift reveals a functional transition from cellular to stem cell organismal adaptation.

Ximena Ruden, Campbell Coddington, Lynessa Asplund, Awoniyi Awonuga, Douglas Ruden, Steven Korzeniewski, Lijun Zhang, Elizabeth Puscheck, Daniel Rappolee.

  Stress responses are essential for cellular survival and organismal, developmental progression. In somatic cells and embryonic stem cells (ESC), there exists the sequential transcriptional programs of the integrated stress response (ISR) and senescence-associated secretory phenotype (SASP), which enable stepwise adaptation to adverse conditions. We recently identified a distinct developmentally associated stress response (DASR) in mouse ESC that hypothetically emerges only after successful completion of cellular adaptation (ISR), reflecting a shift toward organismal-level adaptation. In explanation, a cellular response is a cell autonomous cell survival response, and it enables a stem cell response leading to organismal development and survival. Here, we test whether placental trophoblast stem cells (TSC), also undergo this ISR-DASR transition. Using transcriptomic profiling of mouse TSC exposed to strong, hyperosmotic stress (at 400mM sorbitol), we find that early responses (0.5-2 h) are dominated by biosynthetic and metabolic gene functions characteristic of cellular adaptation, whereas later responses (6-24 h) are enriched for developmental and differentiation pathways, consistent with DASR activation. These findings suggest that the ISR-DASR transition is a general feature of the response of stressed, developmental stem cells. They also highlight potential biomarkers for improving in vitro fertilization, understanding miscarriage, and advancing regenerative medicine.

Keywords:  Cellular stress response; Developmentally associated stress response (DASR); Embryonic stem cells (ESC); Integrated stress response (ISR); Organismal homeostasis; Pluripotency; Transcriptomics; Trophoblast giant cells (TGC); Trophoblast stem cells (TSC)

DOI:  https://doi.org/10.1038/s41598-026-55295-1
Gastro Hep Adv. 2026 ;5(7): 100950

Integrated Stress Response and Necroptosis Drive Epithelial Dysfunction in Crohn's Disease: Repurposing Cancer Drugs for Permeability Barrier Healing.

Debasish Halder, Ritwika Biswas Lanford, Amin Esmaeilniakooshkghazi, Jason Ken Hou, Yaohong Wang, Seema Khurana.

   Background and Aims: Intestinal permeability dysfunction is a central pathogenic driver of Crohn's disease (CD), fueling microbial translocation, chronic inflammation, and progressive tissue injury. While current therapies suppress inflammation, none directly restore epithelial barrier function. Importantly, in patients with CD, epithelial barrier healing rather than mucosal healing is associated with long-term remission and a reduced risk of disease complications. Yet permeability barrier healing remains an unaddressed therapeutic target in CD. Here, we investigated whether pharmacologic inhibition of the integrated stress response (ISR) and RIPK3-mediated necroptosis, 2 convergent pathways of epithelial injury, can promote epithelial viability, regeneration, and barrier integrity in CD.
Methods: We employed villin-1/gelsolin double knockout mice with epithelial-intrinsic ISR activation, Tnf ΔARE/+ mice with chronic inflammation, and CD patient-derived enteroids (PDEs). Animals and PDE were treated with integrated stress response inhibitor, RIPK3 inhibitor necrostatin-1, or US Food and Drug Administration-approved cancer drugs pazopanib and ponatinib, repurposed as potent RIPK3 inhibitors. Epithelial survival, regenerative growth (enteroid formation, budding), and barrier function (transepithelial electrical resistance) were assessed.
Results: Chronic ISR activation and necroptosis were prominent in both murine models and CD PDEs, causing epithelial death, Paneth cell expansion, impaired enteroid survival, and regenerative failure. Pharmacologic inhibition with integrated stress response inhibitor, necrostatin-1, pazopanib, or ponatinib restored villus architecture, reduced inflammation, enhanced epithelial survival and regeneration, and significantly improved transepithelial electrical resistance.
Conclusion: ISR activation and RIPK3-mediated necroptosis converge to drive epithelial injury and barrier dysfunction in CD. Repurposing pazopanib and ponatinib offers a potentially translatable approach to restore barrier integrity in CD.

Keywords:  Crohn’s Disease; Integrated Stress Response; Necroptosis; Permeability Barrier Healing; RIPK3 Inhibitors

DOI:  https://doi.org/10.1016/j.gastha.2026.100950
FASEB J. 2026 Jun 30. 40(12): e71972

eIF3 Orchestrates a Biphasic Stress Response Linking Translational Control to Mitochondrial Integrity in Skeletal Muscle.

Yingying Lin, Jianing Xia, Man Li, Junhao Zhang, Yonghao Mu, Lenian Ling, Minghao Lu, Jiahuan Wang, Kexin Liao, Yefeng Cai.

  Skeletal muscle adaptation to physiological and pathological stressors requires precise coordination of protein synthesis and mitochondrial function. While the roles of canonical translation regulators such as eIF2α and 4E-BP1 in exercise-induced protein synthesis modulation are well established, the contribution of eIF3, the largest eukaryotic initiation factor complex, to muscle stress responses remains poorly understood. Eukaryotic initiation factor 3 (eIF3) regulates mRNA translation and mitochondrial homeostasis, yet how individual eIF3 subunits respond to distinct modes of skeletal muscle stress remains unclear. Here, we systematically characterized eIF3 dynamics and mitochondrial function using two complementary mouse models: acute exhaustive training and dexamethasone (DEX)-induced atrophy. Integrated proteomic, transcriptional, and imaging analyses revealed a biphasic regulatory pattern: DEX treatment caused broad downregulation of eIF3a, eIF3b, eIF3c, eIF3g, and eIF3l, concurrent with comprehensive mitochondrial electron transport chain (ETC) impairment, while acute training selectively decreased eIF3d, eIF3e, eIF3g, and eIF3l but uniquely preserved eIF3f expression alongside adaptive ETC remodeling. This differential response pattern distinguishes eIF3 from other stress-responsive translation factors, as eIF2α phosphorylation typically causes global translation suppression whereas eIF3 dysregulation selectively impairs mitochondrial protein synthesis. Notably, eIF3f preservation under both conditions suggests a compensatory mechanism to maintain translational capacity. siRNA-mediated knockdown of eIF3e or eIF3f in C2C12 myotubes demonstrated their differential effects on mitochondrial protein expression and atrophy signaling, with eIF3f knockdown causing more severe mitochondrial protein suppression. Seahorse XF analysis confirmed that eIF3 subunit loss directly impairs mitochondrial oxygen consumption, while SUnSET assays demonstrated attenuated global protein synthesis upon eIF3e or eIF3f depletion. Furthermore, eIF3 knockdown suppressed mTORC1 signaling (p-mTOR, p-4EBP1, p-S6K, p-S6) and differentially modulated ubiquitin-proteasome activity without altering bulk autophagy. These findings establish eIF3 as a molecular integrator linking translational control to mitochondrial integrity in skeletal muscle physiology, positioning this complex as a potential therapeutic target for conditions ranging from exercise-induced adaptation to muscle wasting disorders.

Keywords:  ETC complex; eIF3; mitochondria; muscle adaptation; skeletal muscle; translation regulation

DOI:  https://doi.org/10.1096/fj.202600161R
Biochem J. 2026 Jul 08. 483(7): 1193-1220

Mitophagy: an emerging therapeutic target in mitochondrial diseases.

Brígida R Pinho, Michael R Duchen, Jorge M A Oliveira.

  Mitophagy is a crucial autophagic process that degrades dysfunctional or unnecessary mitochondria, thereby maintaining cellular homeostasis. Mitophagy occurs through both basal mitophagy and stress-induced pathways, highly regulated by a complex network of proteins. In mitochondrial diseases, which are genetic disorders lacking effective treatments, mitophagy is often defective or insufficient. This permits the accumulation of dysfunctional mitochondria that negatively impact cell homeostasis. While some experimental therapeutic strategies have enhanced mitophagy in mitochondrial disorders by targeting broadly acting signaling pathways, such as mTORC1 inhibition or AMPK activation, pharmacological approaches directly targeting the mitophagy process remain underexplored in these disorders. Given the growing understanding of mitophagy regulation, targeting key proteins involved in this process may offer novel therapeutic opportunities for mitochondrial diseases. Here, we explore the molecular mechanisms of mitophagy, examining distinct pathways and regulatory checkpoints that might present potential therapeutic targets. Additionally, we review recent studies evaluating the effects of mitophagy modulation in mitochondrial diseases.

Keywords:  autophagy; mitochondria; pathway; pharmacology; receptors; ubiquitins

DOI:  https://doi.org/10.1042/BCJ20260161
Cell Mol Life Sci. 2026 Jun 10. pii: 249. [Epub ahead of print]83(1):

Mitochondrial complex I deficiency-associated diseases and models.

Lena Jentsch, Natascia Ventura.

  Mitochondrial complex I is the first and largest enzyme of the mitochondrial respiratory chain and thus plays a crucial role in cellular energy metabolism. Defects in the mitochondrial respiratory chain, and in particular CI deficiency, are the primary cause of human mitochondrial associated diseases, which most often presents as severe neurometabolic disorders with fatal outcome. Up to this date the diagnosis and treatment of CI deficiency-associated diseases is challenging, only limited symptomatic therapies exist and no cures are available. This review aims at summarizing current knowledge on the genetic basis of CI deficiency-associated diseases and available experimental disease models. Most common human disorders caused by CI deficiency range from Leigh syndrome to MELAS and LHON, all characterized by genetic and symptomatic heterogeneity. So far, in vivo studies on non-mammalian organisms and mouse models, as well as in vitro studies on patient derived fibroblasts, cybrids and human-induced pluripotent stem cells have mainly facilitated the research of CI deficiency. These model systems provide insights on molecular mechanisms in mitochondrial disease and approaches for potential therapeutic intervention strategies. However, current research is limited by translational relevance of existing disease models, varying degrees of heteroplasmy and tissue specific effects characteristic of mitochondrial diseases, so that basic disease mechanisms still remain poorly understood. To overcome these challenges there is an urgent need for in vivo and in vitro human relevant models to aid the development of effective therapeutic interventions and potential cures of CI deficiency-associated diseases.

Keywords:  Mammalian cell models; Mitochondrial complex I; Mitochondriopathies; Model organisms

DOI:  https://doi.org/10.1007/s00018-026-06169-2
Fundam Res. 2026 May;6(3): 1893-1912

Mitochondrial homeostasis in bone aging: Unraveling dysfunctional pathways and developing precision therapies.

Yu Zhang, Xishui Liu, Zijie Xiang, Yuqing Yang, Lei Xing, Yu Chen, Siming Zhang, Shixiang Zhao, Youzhi Hong, Yusen Qiao, Jiaxiang Bai.

  Mitochondria have complex functional and information-processing networks that play key roles in both health regulation and disease progression. However, the multiple properties and complex thresholds of mitochondrial dysfunction and quality control make the contribution of mitochondria to bone aging elusive. These factors prevent mitochondria from being among the most important precision therapies. Currently, many strategies that target mitochondrial homeostasis have entered clinical trials. In mitochondria, mitochondrial DNA (mtDNA) and its associated proteins are potential therapeutic agents for immunometabolic diseases and tissue injury, with the aim of enhancing mitochondrial function. Here, we comprehensively review the intrinsic mechanisms of mitochondrial dysfunction and quality control leading to bone aging and summarize current strategies for the treatment of skeletal aging disorders and the clinical translation of relevant agents in terms of unraveling dysfunctional pathways and developing precision therapies. In this review, we offer a general overview of the progress of clinical application in the treatment of skeletal senescence diseases, and we also provide prospects for the challenges associated with the role of mitochondrial dysfunction in bone senescence in clinical application and future trends in this field.

Keywords:  Bone aging; Clinical application; Mitochondrial DNA (mtDNA); Mitochondrial dysfunction; Precision therapy; Quality control

DOI:  https://doi.org/10.1016/j.fmre.2025.12.021
Biochimie. 2026 Jun 08. pii: S0300-9084(26)00135-5. [Epub ahead of print]

Reductive Stress in Myocardial Ischemia: Mechanisms, Pathophysiology, and Therapeutic Perspectives.

Gino A Kurian.

  Reductive stress (RS), characterized by excessive accumulation of reducing equivalents including NADH, NADPH, and glutathione, is increasingly recognized as a potential contributor to myocardial ischemic heart disease. Conventional models of ischemia reperfusion injury primarily focus on oxidative stress and reactive oxygen species (ROS) mediated damage; however, excessive reductive redox imbalance may also influence myocardial susceptibility to injury. During ischemia, metabolic disruption and accumulation of electron carriers constrain mitochondrial electron transport, promote reverse electron transport associated ROS generation during reperfusion, and lower the threshold for mitochondrial permeability transition pore opening. Together, these changes may increase vulnerability to reperfusion associated injury and maladaptive remodeling. This review presents RS as an ischemia associated metabolic priming state that influences mitochondrial redox biology and modifies the response to reperfusion in different metabolic settings. Evidence linking ischemia induced metabolic alterations with mitochondrial dysfunction, inflammatory signaling, and fibrosis is examined in the context of existing oxidative stress centered models. Therapeutic strategies aimed at restoring redox balance are also discussed, including mitochondria targeted antioxidants, NAD+ centered metabolic interventions, and modulation of Nrf2 and sirtuin signaling pathways. In addition, the review highlights the current absence of standardized biomarkers for RS and discusses the potential value of RS guided phenotyping for improving therapeutic precision in ischemic heart disease. This framework proposes experimentally testable concepts intended to support future mechanistic studies and biomarker development.

Keywords:  Calcium dysregulation; Ischemia-reperfusion injury; Mitochondrial dysfunction; Myocardial ischemia; Redox homeostasis; Reductive stress

DOI:  https://doi.org/10.1016/j.biochi.2026.06.003
bioRxiv. 2026 Jun 01. pii: 2026.05.29.728519. [Epub ahead of print]

The UPR drives gametogenesis via an unexpected response, coordinating translation and ER structure.

Constantine Bartolutti, Alena Bishop, Yanzhe Ma, Kelsey Van Dalfsen, Elçin Ünal, Marko Jovanovic, Gloria Ann Brar.

Stress responses, including the unfolded protein response (UPR), are commonly studied via induction with harsh exogenous stressors, leaving endogenous functions of these pathways less well understood. We found that the endogenous UPR that precedes meiosis in budding yeast is required for gamete production but diverges dramatically from previously defined UPR outputs, with only a few characterized UPR targets induced, and mildly. The role of this UPR can be replaced by increasing ER chaperones, reducing bulk translation, or impairing the machinery for protein translocation into the ER. ER integrity appears compromised in pre-meiotic cells lacking the UPR, as foci of reticulon proteins are seen and correlate strongly with an inability of cells to enter meiosis. These findings indicate that physiological UPR activation supports proteostasis and normal ER structure, preparing cells for meiotic entry by reducing the load of proteins that enter the ER. Overall, our study reveals surprising features of a physiological UPR induction that enables a cell fate decision.

DOI: https://doi.org/10.64898/2026.05.29.728519
Int J Mol Sci. 2026 Jun 02. pii: 5016. [Epub ahead of print]27(11):

Fibro-Adipogenic Progenitor Cell Alterations in Skeletal Muscle: Pathological Dysfunction or Adaptive Reprogramming?

Margarita Y Sorokina, Oksana A Ivanova, Anna A Kostareva, Renata I Dmitrieva.

  In skeletal muscle, there are two main progenitor populations crucial for growth, maintenance, and repair: satellite cells (SCs) and interstitial cells, of which fibro-adipogenic progenitor cells (FAPs) are the best characterized fraction. However, data on how specific diseases or physiological conditions affect the biological properties of FAPs are limited. In this review we analyze data obtained with FAPs purified from skeletal muscle tissue from Duchenne muscular dystrophy (both human patients and mdx mice models), hindlimb functional unloading (rats), and type 2 diabetes (T2DM, human patients). Here we discuss how disuse/disease affect FAP's properties: the adaptive metabolic remodeling; the alterations in adipogenic differentiation in vitro; the possible role of particular subpopulations of FAPs in disease development; the role of FAPs in cell-to-cell interactions during skeletal muscle degeneration and regeneration. Current research has outlined how different physiological and pathological conditions alter FAPs' behavior, highlighting FAPs as a potential target for clinical protocols aimed at treating or mitigating skeletal muscle disorders. Future studies should clarify how FAPs govern cell-to-cell interactions during skeletal muscle degeneration and regeneration, offering critical insights for therapies targeting diverse neuromuscular diseases.

Keywords:  adipogenesis; duchenne muscular dystrophy; fibro/adipogenic progenitors; metabolic flexibility; myogenesis; skeletal muscle; skeletal muscle unloading

DOI:  https://doi.org/10.3390/ijms27115016
MedComm (2020). 2026 Jun;7(6): e70790

Targeting Mitochondria in Aging-Related Diseases: Therapeutic Potential and Obstacles.

Zijie Xiang, Yu Chen, Xishui Liu, Haowen Lu, Yuqing Yang, Lei Xing, Yu Zhang, Chuandong Lang, Siming Zhang, Shixiang Zhao, Youzhi Hong, Jiaxiang Bai, Yusen Qiao.

  Aging is a complex biological process characterized by the functional decline of multiple cellular organelles, with mitochondrial dysfunction emerging as a predominant hallmark. Alterations in mitochondria within senescent cells primarily encompass two interrelated aspects: intrinsic mitochondrial dysfunction and compromised mitochondrial quality control systems, including mitophagy, dynamics, and biogenesis. However, a comprehensive synthesis that bridges mechanistic insights into mitochondrial dysfunction with an analysis of therapeutic obstacles remains lacking. Here, we systematically summarized the pathways leading to mitochondrial dysfunction in aging and deeply analyzed how this dysregulation, including mitochondrial DNA instability and mitochondria driving inflammation through the cGAS-STING pathway, contributed to the etiology of aging-related diseases, including muscle, bone, neurodegeneration, cardiovascular, and metabolic diseases. Additionally, we analyzed a series of mitochondrial targeted treatment strategies, from metabolism and kinetic regulation to disease-specific intervention and emerging technologies, such as mitochondrial transplantation and mitochondrial DNA base editing. Finally, we emphasized the key obstacles that must be overcome for clinical transformation, including tissue-specific mitochondrial heterogeneity. By combining the basic mechanism with the development of treatment and its potential challenges, this review provides a key perspective for promoting the emerging field of mitochondrial medicine to intervene in aging-related pathology more accurately and effectively.

Keywords:  aging; mitochondria; therapy

DOI:  https://doi.org/10.1002/mco2.70790
Front Immunol. 2026 ;17 1776555

Multi-omics analysis of long COVID (post-COVID-19 condition) reveals persistent mitochondrial dysfunction, suppressed oxidative phosphorylation, and immune dysregulation.

Alexia Tasoula, Shehbeel Arif, Ethan Waisberg, Lucas Bauer, Elizabeth Aslinger, Joseph W Guarnieri.

   Introduction: Post-COVID Syndrome (PCS), or long-COVID, is a major public health burden, but its underlying mechanisms remain poorly understood. Because acute SARS-CoV-2 infection induces marked suppression of mitochondrial oxidative phosphorylation (OXPHOS), we investigated whether persistent immunometabolic remodeling is a recurring transcriptional, metabolic, and proteomic feature of PCS.
Methods: We performed an integrated multi-omics analysis of transcriptomic, proteomic, and metabolomic datasets across multiple tissues from Syrian hamster models and human cohorts spanning acute infection through post-acute and PCS stages extending up to 12 months post-infection.
Results: Across species and tissues, we observed overlapping signatures of mitochondrial dysfunction, including sustained suppression of OXPHOS, activation of mitochondrial stress responses, and enrichment of inflammatory pathways. Skeletal muscle exhibited the most pronounced and persistent mitochondrial repression in both hamsters and PCS patient biopsies, consistent with fatigue-associated phenotypes. Hamster heart and kidney tissues also showed persistent OXPHOS suppression, while lung tissue demonstrated prolonged inflammatory signaling despite partial metabolic recovery. In the nervous system, transcriptional profiles revealed region-specific patterns, including persistent cortical mitochondrial repression and partial recovery in sensory-associated regions. Peripheral blood mononuclear cells (PBMCs) transcriptomics and serum metabolic datasets suggested prolonged downregulation of OXPHOS-associated programs up to 12 months post-infection, potentially contributing to persistent immune dysregulation in susceptible individuals with underlying conditions. Longitudinal serum proteomics in PCS patients revealed sustained mitochondrial stress responses, increased oxidative stress signatures, and persistent immune activation at 1 and 6 months post-infection compared to recovered controls.
Discussion: Together, these multi-omics results identify persistent mitochondrial repression and immune dysregulation as recurring features across PCS-associated datasets, providing a framework linking bioenergetic dysfunction with chronic immune activation and supporting future mechanistic and therapeutic investigation.

Keywords:  SARS-CoV-2 infection; bioenergetic dysfunction; metabolic remodeling; mitochondrial stress response; post-acute sequelae of COVID-19 (PASC); systemic inflammation; transcriptomic reprogramming

DOI:  https://doi.org/10.3389/fimmu.2026.1776555
Skelet Muscle. 2026 Jun 12.

Enhancers integrate microenvironmental signals in muscle stem cells during regeneration in health, disease, and aging.

Sarah Hachmer, F Jeffrey Dilworth.

  Effective skeletal muscle regeneration requires muscle stem cells (MuSCs) to continuously interpret and respond to signals from their surrounding microenvironment. These niche-derived cues, including inflammatory, extracellular matrix, paracrine, metabolic, and biomechanical signals, direct MuSC progression through quiescence, activation, proliferation, and differentiation by reshaping gene expression programs. Increasing evidence suggests that transcriptional enhancers serve as a key regulatory interface through which environmental information is translated into transcriptional output. Enhancer activity is governed by the coordinated action of lineage-defining transcription factors, histone modifiers, chromatin remodelers, transcriptional coactivators, and architectural proteins that together regulate chromatin accessibility, enhancer-promoter communication, and gene activation. Recent work has shown that enhancer landscapes and three-dimensional genome organization are highly dynamic during muscle regeneration and become altered in aging and disease. In this review, we examine how enhancer-associated mechanisms enable MuSCs to interpret niche-derived signals, highlighting the roles of transcription factor networks, chromatin remodeling complexes, and enhancer-promoter interactions in coordinating gene expression. We further discuss how disruption of enhancer regulation contributes to impaired regeneration in aging and muscular dystrophy, where altered chromatin states and genome organization lead to aberrant transcriptional responses. Understanding how these regulatory elements integrate complex environmental signals will be essential for defining the mechanisms underlying muscle regeneration and may provide new avenues for therapeutic intervention.

Keywords:  Gene Expression; Inflammation; Muscle Stem Cells; Myogenesis; Niche; Regeneration; Transcriptional Enhancers

DOI:  https://doi.org/10.1186/s13395-026-00434-5
Nat Genet. 2026 Jun;58(6): 1200

Mitochondrial capsules mitigate mitochondrial dysfunction.

Chiara Anania.

DOI: https://doi.org/10.1038/s41588-026-02651-6
Bioact Mater. 2026 Nov;65 94-106

The mechano-immune-vesicle regulatory circuit: a systems framework for bone homeostasis and regeneration.

Ting Yang, Zhili Dong, Lili Chen, Xiaoxing Kou.

  Bone remodeling is a mechanically adaptive process that integrates physical loading with immune regulation during homeostasis, repair, and disease. However, the traditional view fails to fully explain how mechanical and immune signals are coordinated across cellular compartments. Emerging evidence indicates that mechanical forces, immune responses, and extracellular vesicles (EVs) function as an integrated communication system rather than independent regulators. Here, we propose a systems-level framework termed the "mechano-immune-vesicle regulatory circuit". In this framework, biophysical cues regulate EV biogenesis and selective cargo sorting through mechanotransduction pathways. These mechanically primed EVs then serve as communication vectors that reprogram osteoimmune responses, specifically by directing macrophage polarization, adaptive immunity, and bone-resident cell differentiation. The resulting immune output feeds back to reshape EV signaling and mechanosensitivity, suggesting a closed regulatory circuit that governs bone remodeling. By synthesizing advances in mechanobiology, osteoimmunology and EV biology, this review reframes bone remodeling as a mechano-immune-vesicle regulatory circuit rather than as a collection of parallel pathways. We further discuss how this framework may guide the design of mechano-responsive biomaterials and engineered EV-based therapies with spatiotemporal control over inflammation and bone regeneration. This conceptual integration provides a mechanistic basis for understanding bone diseases and for developing next-generation regenerative strategies.

Keywords:  Bone diseases; Bone remodeling; Extracellular vesicles; Immune response; Mechanical forces

DOI:  https://doi.org/10.1016/j.bioactmat.2026.05.050
Biopsychosoc Sci Med. 2026 Jun 09.

Mitoception Via the Metabokine GDF15 and Human Health.

Cynthia C Liu, Qiuhan Huang, Evan D Shaulson, Caroline Trumpff, Elissa Epel, Lisa Feldman Barrett, Daniel W Belsky, Maxwell Z Wilson, Alan A Cohen, Eugene Mosharov, Nirosha J Murugan, Tor D Wager, Martin Picard.

  To survive and thrive, living organisms must monitor and regulate cell-level energy supply, demand, and transformation. Metabolic energy is monitored through a set of brain-directed interoceptive processes we refer to as metaboception. Here, we review evidence for a specific metaboceptive signaling cascade mediated by the cytokine/metabokine growth differentiation factor 15 (GDF15), which we refer to as mitoception. Mitoception involves an afferent signaling arm initiated by the integrative stress response within cells, and an efferent signaling arm that simultaneously promotes systemic energy conservation and fuel mobilization. Afferent mitoceptive signaling is mediated by GDF15 released when cells face energy demand in excess of their energy transformation capacity, creating an energy gap. The efferent arm of mitoceptive signaling arises when GDF15 receptors in the brainstem receive the signal and initiate psychological experiences including fatigue and anxiety, together with neuroendocrine stress responses. Mitoceptive outputs thus reprioritize systemic energy metabolism to promote allostasis, survival, and long-term health. This article is an introduction to GDF15 psychobiology, and proposes a GDF15-driven mitoception cascade that makes predictions about modifiable processes shaping disease risk, mental health, mood, resilience, well-being, and aging.

Keywords:  GDF15; anxiety; behaviors; bioenergetics; energetic pain; fatigue; metaboception; mitoception; stress-disease cascade

DOI:  https://doi.org/10.1097/PSY.0000000000001498
Front Cell Dev Biol. 2026 ;14 1830358

Stem cell dysfunction and rejuvenation strategies in ageing: emerging advances in regenerative medicine.

Khuzin Dinislam, Anas Shamsi, Syed Tasqeruddin, Saleha Anwar, Moyad Shahwan.

  Ageing is a complicated phenomenon that is defined by the progressive decline in the body's functions that leads to weakened regenerative potential and greater vulnerability to various age-related diseases. There is evidence that highlights that stem cell dysfunction and exhaustion are the primary reasons for tissue degeneration that progresses with age and hence provide aid to regenerative therapeutic approaches. Stem cells have shown the ability to influence age-related cellular dysfunction in preclinical models mainly via paracrine signaling, immune modulation and tissue repair processes. Nonetheless, clinical evidence primarily confines to early-phase trials, showing inconsistent results based on cell type, delivery method and disease context. Several types of stem cells are being studied rigorously for their regenerative, immunomodulatory, and anti-ageing properties. Pre-clinical and early-phase clinical studies suggest potential benefits of stem cell-based interventions in musculoskeletal, cardiovascular and neurodegenerative disorders although effect sizes vary and long-term efficacy remains under investigation. Furthermore, emerging technologies such as tissue reprogramming, senolytics and niche modulation also contribute to improving therapeutic strategies. This review aims to provide a comprehensive overview of the existing knowledge of stem cell biology and therapies from various preclinical and clinical studies, along with rejuvenation approaches.

Keywords:  ageing; clinical trials; regenerative medicine; rejuvenation approaches; stem cell therapy; stem cells

DOI:  https://doi.org/10.3389/fcell.2026.1830358
IUBMB Life. 2026 Jun;78(6): e70118

Hormesis and the Golden Ratio: Toward a Universal Estimator of Adaptive Capacity.

Evgenios Agathokleous.

  Hormesis represents a universal feature of biological plasticity across species and environmental contaminants. Here I propose that the maximum stimulatory peak converges upon the golden ratio (φ = 1.618), representing a 61.8% increase above baseline, a value embedded within the empirically observed 30%-60% range but offering mathematical precision for a unifying quantitative reference. I further hypothesize that the internal architecture of the hormetic zone may follow the complementary proportion of φ (0.382), with the rising phase occupying the smaller fraction (steep ascent) and the falling phase the larger fraction (gradual decline), reflecting natural selection for rapid threat response followed by sustained benefit. This framework positions the golden ratio as a potential evolutionary optimum, a Pareto-efficient allocation where further investment yields diminishing returns. While the dose-width to toxicity remains variable and context-dependent, the peak magnitude may reveal a fundamental constraint on the adaptive capacity of life. Testing this hypothesis requires systematic meta-analysis of existing databases and targeted experiments manipulating resource availability, genetic background, and evolutionary history.

Keywords:  hormesis; life's golden formula; stress ecology; stress golden ratio; stress sweet spot

DOI:  https://doi.org/10.1002/iub.70118