bims-mihora 2026-05-10 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2026–05–10
ten papers selected by
Lisa Patel, Istesso

Harnessing mitohormesis: A thiazole-based mitochondrial respiration inhibitor restores metabolic homeostasis in type 2 diabetes.
Stress is inevitable; recovery is conditional: bioenergetic limits of resilience in aging and disease.
MG53, a Regenerative Myokine Linking Skeletal Muscle to Cardiac Repair.
Cellular senescence in skeletal muscle regeneration.
Role of external forces in the mechanobiology of stem and differentiated chondrogenic cells embedded in a tissue-engineered construct for cartilage repair.
Methylene blue protects hair follicle stem cells from oxidative and metabolic stress to enhance hair regeneration.
Metformin lowers blood glucose by targeting intestinal mitochondrial complex I.
A Predictive Model for Coupling Cell Division Orientation to Tissue Mechanics During Epithelial Morphogenesis.
Polyamines and autophagy as a dynamic regulatory network in skeletal muscle regeneration and aging.
A new perspective on mesenchymal stem cells and their derivatives in alleviating cerebral ischemia-reperfusion injury dynamically regulating mitochondrial function to remodel the immune network.

Bioorg Chem. 2026 Apr 26. pii: S0045-2068(26)00461-X. [Epub ahead of print]177 109925

Harnessing mitohormesis: A thiazole-based mitochondrial respiration inhibitor restores metabolic homeostasis in type 2 diabetes.

Yang Zhang, Jie Guo, Jie Jin, Ci-An Cheng, Yixin Hu, Shihao Chen, Chen Wang, Xinwei Meng, Binglu Jiang, Zhihao Jia, Yixue Qiao, Jinxin Gu, David A Tyvoll, James P Collman, Lei Fu.

  Mitohormesis, an adaptive cellular response to moderate mitochondrial stress, represents a promising therapeutic paradigm. To pharmacologically harness this phenomenon, we developed mitochondrial respiration inhibitors by conjugating a thiazole-based pharmacophore to a triphenylphosphonium (TPP) cation. Here, we report three TPP-thiazole conjugates which are distinguished by their hydrolytically labile linkers, comprising an ester (Compound 1), a more labile thioester (Compound 2), and a more stable amide (Compound 3). In vitro evaluation demonstrated that the hydrolytic stability of the linkers correlated inversely with inhibitory potency, where Compound 2 exhibited the strongest inhibition, followed by Compound 1. In contrast, Compound 3 showed negligible activity, lacking a clear dose-response relationship. As therapeutic mitohormesis requires a mild stress induction within a beneficial hormetic window, Compound 1 was selected for further investigation based on its intermediate inhibition and pronounced biphasic effects. Compound 1 activated the mitochondrial unfolded protein response (UPRmt) in Caenorhabditis elegans (C. elegans) and stimulated transcription of mitokines in both C. elegans and mice. In a murine model of diet-induced type 2 diabetes, Compound 1 significantly improved systemic metabolism, ameliorating glucose intolerance, insulin resistance, and hepatic steatosis. Furthermore, it outperformed metformin at an equivalent dose without observed toxicity. Collectively, these findings establish the rationally tuned inhibition of mitochondria as a viable small-molecule strategy for the treatment of metabolic disorders through mitohormesis.

Keywords:  Metabolic disorders; Mitochondria; Mitohormesis; TPP-thiazole; UPR(mt)

DOI:  https://doi.org/10.1016/j.bioorg.2026.109925
Biogerontology. 2026 May 04. pii: 96. [Epub ahead of print]27(3):

Stress is inevitable; recovery is conditional: bioenergetic limits of resilience in aging and disease.

Torsak Tippairote, Pruettithada Hoonkaew, Aunchisa Suksawang, Prayfan Tippairote.

  Aging, stress-related disorders, and chronic disease are often examined across separate domains-stress physiology, nutrition, psychiatry, and geroscience-despite converging on shared phenotypes of functional decline and reduced resilience. Although adaptive responses to stress are well characterized, why comparable exposures yield sustained resilience in some individuals but progressive dysfunction in others remains insufficiently explained. We propose that the missing unifying constraint is not stress exposure itself, but the bioenergetic capacity to complete recovery. We reframe stress adaptation as a cyclical process comprising response, adaptation, and recovery, emphasizing that recovery is an active, ATP-dependent phase conditionally funded within a finite bioenergetic system. When mitochondrial processing capacity and redox flexibility are constrained, adaptive programs may persist beyond their functional window, contributing to mitochondrial congestion, epigenetic gridlock, and progressive loss of physiological plasticity-even in the absence of overt pathology. Within this perspective, we introduce Exposure-Related Malnutrition (ERM) as a proposed conceptual model describing a clinically interpretable and potentially reversible phenotype of unresolved bioenergetic triage. ERM is proposed to describe a state of relative undernutrition arising from chronic mismatch between energetic demand and recovery capacity, often occurring despite nominal intake and laboratory values within reference ranges. Distinct from frailty, sarcopenia, cachexia, metabolic syndrome, and classical malnutrition, ERM may reflect an upstream constraint in ATP-dependent recovery rather than structural loss, inflammatory wasting, metabolic thresholds, or inadequate intake. By integrating evolutionary allocation theory, developmental calibration, stress physiology, and mitochondrial mechanics, ERM is proposed to offer a unifying integrative framework for functional decline across aging and chronic disease. Clinically, this perspective shifts risk assessment from isolated thresholds toward coordinated biomarker patterns, trajectories, and recovery kinetics, potentially enabling recognition of vulnerability before incomplete resolution consolidates into irreversible pathology. We further outline translational implications of a recovery-centered approach, positioning mitochondrial processing capacity and intercellular bioenergetic support as modifiable determinants of long-term resilience.

Keywords:  Aging and chronic disease; Bioenergetic resilience; Exposure-Related Malnutrition (ERM); Mitochondrial capacity; Stress adaptation and recovery

DOI:  https://doi.org/10.1007/s10522-026-10445-w
Biomolecules. 2026 Apr 01. pii: 524. [Epub ahead of print]16(4):

MG53, a Regenerative Myokine Linking Skeletal Muscle to Cardiac Repair.

Yuchen Chen, Kyung Eun Lee, Jongsoo Kim, Jae-Kyun Ko, Ki Ho Park.

  Mitsugumin 53 (MG53, also TRIM72) is a muscle-enriched tripartite motif protein with a well-established role in acute membrane repair and cytoprotection in striated muscle and other stressed tissues. MG53 is a core component of cellular repair machinery, rapidly sensing membrane disruption and coordinating membrane resealing, mitochondrial preservation, and anti-inflammatory modulation. In contrast to its high expression in skeletal muscle, endogenous MG53 expression in the adult human heart is minimal, raising the question of how MG53 exerts cardioprotective effects in the human heart. Recent studies help address this by identifying MG53 as a circulating regenerative myokine. MG53 is secreted from skeletal muscle into the bloodstream and can reach distal organs, including the heart. These findings support a muscle-to-heart endocrine model in which MG53 mediates tissue crosstalk and helps provide repair capacity to the myocardium when intrinsic cardiac MG53 is low. Here, we summarize recent advances in MG53 biology, emphasizing molecular mechanisms and inter-organ communication underlying cardioprotection. We further highlight translational strategies leveraging recombinant MG53- and MG53-based therapeutics and discuss challenges that must be addressed for future clinical applications. Collectively, these insights support MG53 as an endocrine repair factor linking skeletal muscle to cardiac repair and a potential regenerative cardiovascular target.

Keywords:  MG53; TRIM72; cardioprotection; inter-organ communication; membrane repair; mitochondrial protection; muscle-derived myokine; regenerative medicine

DOI:  https://doi.org/10.3390/biom16040524
Cell Regen. 2026 May 07. pii: 15. [Epub ahead of print]15(1):

Cellular senescence in skeletal muscle regeneration.

Xingyuan Liu, Huating Wang.

  Skeletal muscle possesses a remarkable capacity for regeneration, driven by the activation and proliferation of Pax7-positive muscle stem cells within a dynamic niche that includes immune cells, fibro-adipogenic progenitors, endothelial cells, pericytes, and neural elements. Cellular senescence, a stress-induced program featuring stable cell-cycle arrest and the senescence-associated secretory phenotype (SASP), has emerged as a critical yet paradoxical regulator of this process. Accumulating evidence indicates that transient senescence, particularly in FAPs, macrophages, and other niche cells during acute muscle injury, plays a beneficial role in supporting muscle regeneration. These senescent cells promote cellular plasticity, enhance myoblast differentiation, facilitate phagocytic clearance of debris, and modulate inflammation and repair via timely SASP factor secretion. However, conflicting findings suggest that senescent cells exert detrimental effects, impairing regeneration by establishing a sustained pro-inflammatory and pro-fibrotic niche, especially when senescence persists in aged or dystrophic muscle. This review synthesizes the complex and contradictory roles of cellular senescence in skeletal muscle regeneration, underscores the distinction between transient pro-regenerative and persistent deleterious senescence, highlights the importance of cell-type-specific contributions, and emphasizes the need for precise characterization of senescent cell dynamics and fate. Resolving these discrepancies will be critical for developing targeted senotherapeutic strategies to enhance muscle regeneration in aging and degenerative diseases.

Keywords:  Cellular senescence; SASP; Skeletal muscle regeneration

DOI:  https://doi.org/10.1186/s13619-026-00287-9
J Biomed Sci. 2026 May 04. pii: 44. [Epub ahead of print]33(1):

Role of external forces in the mechanobiology of stem and differentiated chondrogenic cells embedded in a tissue-engineered construct for cartilage repair.

Maria Carolina Cordeiro, Andrea Barbero, Ivan Martin, Martin J Stoddart.

  Articular cartilage, as a mechanosensitive tissue, supports and distributes various mechanical forces-including compression, shear, hydrostatic pressure, and tensile strain-during joint loading and motion. These external forces deform not only the chondrocytes but also their pericellular matrix and the surrounding extracellular matrix (ECM). Those mechanical cues are detected by mechanosensors on the plasma membrane (e.g., integrins) and transmitted through the cytoskeleton, ultimately being converted into biochemical signals. These signals activate key mechanoresponsive intracellular pathways-including TGF-β-induced SMAD, Rho-GTPase, MAPKs (ERK, JNK, p38), PI3K/AKT/mTOR, MRTF-SRF, and YAP/TAZ-that regulate chondrogenic differentiation and cartilage-specific matrix synthesis. This field of study is known as mechanobiology. Over the past decades, it has gained increasing recognition, particularly with the emergence of tissue-engineering constructs as a novel strategy for cartilage repair. However, progress in chondrogenic mechanobiology has primarily centred on intrinsic substrate- or matrix-derived cues, while overlooking the role of extrinsic mechanical forces. This review therefore provides an updated perspective on chondrogenic mechanobiology, with a particular focus on the cellular responses to external mechanical stimuli. It also emphasizes the therapeutic potential of incorporating mechanical stimulation into tissue-engineering strategies for cartilage repair, an emerging filed referred to as Regenerative Rehabilitation (RR). Since this concept has so far been investigated mainly in vitro, we highlight only those studies and refer to it as In vitro Regenerative Rehabilitation. Moreover, this review also addresses post-traumatic osteoarthritis (PTOA), a common joint disorder that frequently results from traumatic cartilage damage. It explores the mechanobiological mechanisms underlying OA and discusses in vitro regenerative rehabilitation studies, highlighting how external forces could serve as an alternative to conventional biochemical treatments for preventing OA progression.

Keywords:  Articular cartilage; Mechanical stimuli; Mechanobiology; Post-traumatic osteoarthritis; Regenerative rehabilitation; Tissue engineering

DOI:  https://doi.org/10.1186/s12929-026-01247-w
Aging (Albany NY). 2026 May 05. 18(1): 455-465

Methylene blue protects hair follicle stem cells from oxidative and metabolic stress to enhance hair regeneration.

Kavitha Sadashivaiah, Huijing Xue, Kan Cao.

  Hair follicle stem cells (HFSCs) are vital for maintaining hair growth and regeneration. Their dysfunction, often caused by oxidative stress or metabolic imbalance, leads to hair loss and scalp aging. β-catenin is a key protein in the Wnt signaling pathway, and its activity is crucial for HFSC maintenance and regeneration. In this study, we show that methylene blue (MB), a mitochondrial-targeted antioxidant, promotes HFSC proliferation and viability by both reducing reactive oxygen species (ROS) and activating the β-catenin signaling pathway. Functional tests demonstrated that MB significantly sped up wound healing in HFSC cultures, indicating enhanced regenerative ability. Although co-treatment with antioxidants like vitamins A and C improved ROS scavenging, it surprisingly reduced MB-induced β-catenin activation. Conversely, minoxidil, a clinically approved hair growth stimulant, synergized with MB to further activate β-catenin signaling and enhance HFSC viability. Lastly, exposure to glucagon-like peptide-1 receptor agonists (GLP-1 RAs) resulted in a dose-dependent decrease in HFSC survival, consistent with emerging reports of treatment-related hair loss. Remarkably, pre-treatment with MB protected HFSCs from GLP-1 RA-induced metabolic stress and premature cell death. Overall, these findings identify methylene blue as a multifunctional therapeutic candidate that reduces oxidative and metabolic stress while supporting HFSC-mediated hair regeneration.

Keywords:  GLP-1 RA; HFSCs; Wnt/β-catenin; methylene blue; minoxidil

DOI:  https://doi.org/10.18632/aging.206376
Nat Metab. 2026 May 08.

Metformin lowers blood glucose by targeting intestinal mitochondrial complex I.

DOI: https://doi.org/10.1038/s42255-026-01532-w
bioRxiv. 2026 Apr 21. pii: 2026.04.17.719304. [Epub ahead of print]

A Predictive Model for Coupling Cell Division Orientation to Tissue Mechanics During Epithelial Morphogenesis.

Somiealo Azote Epse Hassikpezi, Rajendra Singh Negi, No Arnold Chen, M Lisa Manning.

Stratified epithelial tissues such as the skin epidermis maintain barrier integrity during development and homeostasis through the coordinated action of cell proliferation, differentiation, delamination, and tissue-scale mechanical forces. During development, the orientation of cell division within the basal layer plays a pivotal role in tissue stratification; however, the mechanical principles linking the orientation of the division plane to these processes across developmental stages remain poorly understood. Here, we expand a recently developed three-dimensional vertex model for stratified epithelia, composed of the basement membrane, basal, and suprabasal layers, to study the mechanical and structural impact of cell divisions with a wider range of orientations. The model integrates developmental stage via specific changes in heterotypic interfacial tensions (arising from actomyosin cortical contractility and adhesion molecules at the basal-suprabasal interface) and tissue stiffness that have been quantified previously in experiments. By systematically varying background mechanical parameters, we investigate how heterotypic tension, division orientation, and tissue fluidity collectively influence the outcome of cell division. Our goal is to uncover the strategies that the embryo may employ to generate stratified phenotypes at different developmental stages, recognizing that these strategies might evolve over time. Although our focus is on the embryonic developmental stages of the epidermis, this framework may also be extended to investigate transformed cells, such as in cancer, to explore how altered division orientation contributes to precancerous or transformed phenotypes.

DOI: https://doi.org/10.64898/2026.04.17.719304
Mech Ageing Dev. 2026 May 03. pii: S0047-6374(26)00040-0. [Epub ahead of print]231 112188

Polyamines and autophagy as a dynamic regulatory network in skeletal muscle regeneration and aging.

Lavinia Attili, Marianna Nicoletta Rossi, Rachele Di Santo, Guglielmo Duranti, Roberta Ceci, Manuela Cervelli.

  Autophagy is a core cellular mechanism that preserves tissue homeostasis by removing damaged proteins and organelles. In skeletal muscle, proper regulation of autophagic flux is essential for maintaining metabolic and structural integrity, whereas its disruption contributes to muscle atrophy, metabolic dysfunction, and age-related functional decline. Increasing evidence identifies polyamines, particularly spermidine (Spd), as important modulators of autophagy and cellular resilience, with beneficial effects on stress responses, metabolic regulation, and lifespan extension. Physical exercise likewise acts as a physiological inducer of autophagy, promoting muscle remodelling, mitochondrial quality control, and adaptive responses to stress. Within this framework, spermine oxidase (SMOX) has emerged as a relevant regulator of muscle homeostasis. SMOX expression is maintained in healthy muscle but declines in atrophic conditions. By converting spermine into spermidine, SMOX may help sustain autophagy-related pathways and support muscle mass under physiological conditions. This review explores the interplay between exercise, spermidine, and SMOX, highlighting autophagy as a unifying regulatory axis. We summarize current evidence on their individual and combined roles in preserving muscle function and discuss their potential relevance for promoting healthy muscle aging and counteracting sarcopenia.

Keywords:  Atrophy; Autophagy; Polyamine metabolism; Skeletal muscle; Spermidine

DOI:  https://doi.org/10.1016/j.mad.2026.112188
Cell Death Dis. 2026 May 08.

A new perspective on mesenchymal stem cells and their derivatives in alleviating cerebral ischemia-reperfusion injury dynamically regulating mitochondrial function to remodel the immune network.

Lizheng Huang, Yuqian Wang, Chunyi Li, Xiaojing Wang, Anqi Xiao, Fanglei Han, Jinlan Jiang.

Cerebral Ischemia-Reperfusion Injury (CIRI) is a common pathological process in ischemic stroke. Its core detriment lies in the cascade of subsequent injuries triggered by blood flow restoration after cerebrovascular recanalization, primarily including oxidative stress burst, calcium overload, immune-inflammatory imbalance, and mitochondrial dysfunction, ultimately leading to massive neuronal apoptosis and necrosis. Mitochondria, as central hubs of cellular energy metabolism and apoptosis regulation, exhibit functional disturbances that represent the initiating and core link in CIRI. CIRI triggers complex remodeling of the immune network. This dysregulated immune-inflammatory response forms a vicious cycle with mitochondrial dysfunction, exacerbating brain tissue damage. Mesenchymal Stem Cells (MSCs) and their derivatives have demonstrated significant potential in treating CIRI due to their potent paracrine and immunomodulatory functions. MSCs can repair neuronal functional basis by enhancing mitochondrial biogenesis, improving energy metabolism, inhibiting mitochondrial pathway-mediated apoptosis, restoring dynamic balance, and promoting normal mitophagy. Although existing reviews have explored the role of MSCs or mitochondrial function in CIRI, few studies have systematically integrated the bidirectional regulatory relationship between dynamic mitochondrial function and immune network remodeling. Furthermore, an in-depth analysis of the temporal therapeutic effects of MSCs and their derivatives across different pathological stages of CIRI is lacking. To address this gap, this review proposes a therapeutic strategy: MSCs exert synergistic neuroprotective effects by improving mitochondrial function through multiple targets while systematically reshaping the imbalanced immune network. This review summarizes the latest evidence regarding the temporal therapeutic role of MSCs via the "immune-mitochondrial" axis at different stages of CIRI. It elucidates the pivotal role of mitochondria as a central hub connecting metabolic crisis and immune storm, and untangles novel mechanisms such as MSC-mediated mitochondrial transfer and immune cell metabolic reproprogramming, providing a theoretical foundation for developing novel stroke therapies based on cell therapy.

DOI: https://doi.org/10.1038/s41419-026-08834-7