bims-mihora 2026-05-24 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2026–05–24
fourteen papers selected by
Lisa Patel, Istesso

The Integrated Stress Response Protein, eIF2α, Modulates UPRmt Signaling and Cell Death in Doxorubicin Treated Human Cardiac Cells.
CTRP3 alleviates neuropathic pain by improving mitochondrial biogenesis and mitochondrial unfolded protein response via spinal SIRT1 in rats.
Inhibition of the mitochondrial pyruvate carrier attenuates the integrated stress response activation in a cellular model of Huntington's disease.
A mitochondrial-stress adipocyte-macrophage circuit sustaining metaflammation in human type 2 diabetic adipose tissue.
Mitochondrial Dynamics and Transfer in Mesenchymal Stromal Cells: Redox Regulation, Therapeutic Mechanisms, and Engineering Strategies.
An aging hallmark, Alzheimer's disease, and APOE nexus.
Mitochondrial respiratory capacity in kidney podocytes is high, age-dependent, and sexually dimorphic.
The progress of mitochondrial function and transfer in stem cell regulation and therapy.
Mitochondrial metabolic reprogramming, quality control, and intercellular transfer in regulating macrophage plasticity.
Therapeutic potential of stem cell-derived extracellular vesicles in aging and regeneration.
Damage-Driven Irreversibility and Emergent Senescence in Age-Structured Cell Populations.
The epigenetic landscape of skeletal muscle in response to exercise and aging.
Mitoredox Shifts in Mitochondrial Dysfunction.
Stress granules and RNA modifications in blood development and erythroid regeneration.

Cardiovasc Toxicol. 2026 May 20. pii: 53. [Epub ahead of print]26(6):

The Integrated Stress Response Protein, eIF2α, Modulates UPRmt Signaling and Cell Death in Doxorubicin Treated Human Cardiac Cells.

Kienan P O'Dwyer, Perry E Bauer, Subhankhi Pal, Kathleen Brundage, Sundararajan Venkatesh.

  Doxorubicin (DOX), is an indispensable first-line chemotherapeutic. Despite this first-line indication, clinical use of DOX is limited by severe, off-target, and often irreversible cardiotoxicity. DOX induces cytotoxicity in rapidly dividing cancer cells via inhibition of Topoisomerase IIα. However, the underlying mechanisms by which DOX causes cell death in non-replicative, terminally differentiated cardiomyocytes remain poorly understood. Emerging evidence suggests that mitochondrial uptake of DOX is contributory to cardiotoxicity. Whether mitochondrial stress pathways, including the mitochondrial unfolded protein response (UPRmt), are activated and critical for mediating DOX cardiotoxicity is poorly understood. Moreover, whether phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), a mediator of the Integrated Stress Response, regulates potential UPRmt signaling during DOX treatment is also unknown. Here, using human AC-16 cardiac cells, we examined the role of eIF2α phosphorylation during DOX treatment. Our data suggest that DOX triggers a transient increase in eIF2α phosphorylation, followed by a progressive decline. Further, knockdown of eIF2α decreased key transcriptional regulators of UPRmt signaling such as C/EBP Homologous Protein and ATF5, blunted the induction of UPRmt genes (AFG3L2, CLPP, HSPA9, HSPD1, LONP1, SPG7), and aggravated DOX induced cytotoxicity. Together, these findings identify eIF2α as a critical upstream regulator of UPRmt signaling, and suggest that activation of the UPRmt may confer cardio-protection against DOX-induced mitochondrial stress in human cardiac cells.

Keywords:  ATF5; CHOP; Cardiomyocytes; Cardiotoxicity; Doxorubicin; Mitochondria; UPRmt ; eIF2α

DOI:  https://doi.org/10.1007/s12012-026-10124-9
Int J Mol Med. 2026 Jul;pii: 197. [Epub ahead of print]58(1):

CTRP3 alleviates neuropathic pain by improving mitochondrial biogenesis and mitochondrial unfolded protein response via spinal SIRT1 in rats.

Tianzhu Liu, Longqing Zhang, Wei Mei.

  Neuropathic pain arises from an intricate network of interconnected pathophysiological mechanisms, yet the arsenal of effective therapeutic strategies remains frustratingly limited. Accumulating evidence has linked mitochondrial dysfunction to the progression of neuropathic pain. C1q‑tumor necrosis factor‑related protein‑3 (CTRP3), a newly identified adipokine with diverse cytoprotective capacities, has not been previously explored for its role in nociceptive processing. To explore the role of CTRP3 in pain hypersensitivity, pain‑related behavioral assessments were conducted using von Frey filaments and acetone drop method in male rats subjected to spared nerve injury (SNI). To unravel the underlying mechanisms, spinal cord tissues were subjected to western blotting, reverse transcription‑quantitative PCR, immunofluorescence staining, dihydroethidium staining, small interfering RNA (siRNA) technologies and biochemical assays for quantifying oxidative markers. The findings showed that SNI markedly reduced endogenous CTRP3 expression in spinal neurons. Intrathecal administration of recombinant CTRP3 (rCTRP3) alleviated mechanical allodynia and cold hyperalgesia in SNI‑induced rats. Additionally, rCTRP3 treatment enhanced PGC‑1α‑mediated mitochondrial biogenesis, ATF5‑triggered mitochondrial unfolded protein response (UPRmt), and mitigated spinal oxidative stress. Mechanistically, pharmacological inhibition of SIRT1 with EX‑527, or siRNA‑mediated silencing of PGC‑1α or ATF5, reversed the effects of CTRP3 on pain hypersensitivity, mitochondrial biogenesis, UPRmt and oxidative stress. The present study demonstrates that CTRP3 mitigates mechanical allodynia and cold hyperalgesia in male SNI rats by activating spinal SIRT1, thereby enhancing PGC‑1α‑mediated mitochondrial biogenesis and ATF5‑induced UPRmt. CTRP3 may therefore represent a novel therapeutic target for the management of neuropathic pain.

Keywords:  C1q‑tumor necrosis factor‑related protein‑3; mitochondrial biogenesis; mitochondrial unfolded protein response; neuropathic pain

DOI:  https://doi.org/10.3892/ijmm.2026.5868
Mol Cell Biochem. 2026 May 21.

Inhibition of the mitochondrial pyruvate carrier attenuates the integrated stress response activation in a cellular model of Huntington's disease.

Ângela Oliveira, Liliana M Almeida, Jorge M A Oliveira, Brígida R Pinho.

  Mitochondrial pyruvate carrier (MPC) inhibition was found protective in models of neurodegenerative diseases, such as Alzheimer's and Parkinson's. However, little is known about MPC as a potential therapeutic target in Huntington's disease (HD), a neurodegenerative disorder with dysregulation of the pro-survival pathway integrated stress response (ISR). Here, we investigate if MPC inhibition modulates the ISR and mitigates mutant huntingtin (mut-Htt) proteotoxicity in a cellular HD model. We treated cells expressing N-terminal fragments of wild-type- (wt-) or mut-Htt with two MPC inhibitors (mitoglitazone and UK5099) or solvent control. Metabolism was assessed analysing resazurin reduction, oxygen consumption, extracellular acidification, and ATP levels. ISR activation and huntingtin proteostasis were assessed using western-blot and filter-trap assays. Mut-Htt-expressing cells showed decreased resazurin reduction and ATP levels, and increased eIF2α phosphorylation, indicating metabolic stress and ISR activation. MPC inhibitors (100 µM) increased resazurin reduction and decreased respiration. The latter was rescued by the membrane-permeant methyl pyruvate, which bypasses MPC inhibition. In wt-Htt-expressing cells, MPC inhibitors increased levels of ATP and ISR markers, suggesting metabolic adaptation and ISR activation. In mut-Htt-expressing cells, MPC inhibitors preserved ATP levels and attenuated mut-Htt-induced eIF2α phosphorylation but without changing soluble or aggregated mut-Htt levels. This work showed that MPC inhibition differentially modulates the ISR: it activates ISR in control cells and attenuates overactive ISR in mut-Htt-expressing cells. However, MPC inhibition did not impact the proteostasis of N-terminal fragment mut-Htt. Further studies are essential to explore MPC inhibition in less severe full-length mut-Htt-expressing models to better understand its therapeutic potential in HD.

Keywords:  Aggregation; Huntingtin; Huntington’s disease; Integrated stress response; Metabolism; Mitochondrial pyruvate carrier

DOI:  https://doi.org/10.1007/s11010-026-05573-3
Front Immunol. 2026 ;17 1768845

A mitochondrial-stress adipocyte-macrophage circuit sustaining metaflammation in human type 2 diabetic adipose tissue.

Haibin Ji, Tian Cao, Zixuan Tan, Rui Zheng, Jinhui Bian, Wenfeng Lin, Xiufan Xu, Chunze Yuan, Yongfeng Shao, Huanhuan Chen, Junjie Du.

  Type 2 diabetes mellitus (T2D) features chronic low-grade inflammation in white adipose tissue (WAT), where adipocytes and innate immune cells engage in immunometabolic crosstalk. Mitochondrial damage-associated molecular patterns (mtDAMPs) released from stressed adipocytes are thought to sustain metaflammation, but how they are handled by specific macrophage subsets in human T2D WAT is unclear. We hypothesized that in T2D subcutaneous white adipose tissue (scWAT), the mitochondrial stress-clearance circuit between adipocytes and macrophages becomes maladaptive. scWAT biopsies from 6 patients with T2D and 7 non-diabetic controls were profiled by single-nucleus RNA sequencing (snRNA-seq). We integrated transcriptomic data across donors, annotated adipocyte and immune cell states, and performed differential expression analysis along with pathway and immunometabolic module scoring. To map intercellular communication and mitochondrial waste handling, we applied metabolic flux inference (COMPASS), mitochondrial-derived vesicle (MDV) and phagocytosis gene signatures, ligand-receptor analysis (CellChat), and pseudotime trajectories of lipid-associated macrophages. Macrophages and adipocytes showed the strongest T2D-associated transcriptional and metabolic rewiring. We identified a stress-enriched adipocyte state (AD3) with upregulated mitophagy, vesicle and MDV trafficking, and inflammatory signaling, whose mitochondrial-stress module overlapped genes enriched in adipocyte-derived extracellular vesicles. Among lipid-associated macrophages, we resolved a LAM-ST1 subset with immunometabolic activation but downregulation of receptors and lysosomal programs for MDV uptake and degradation. Cell-cell communication and trajectory analyses indicated that AD3 engages LAM-ST1 through inflammatory and vesicular signaling and that LAM-ST1 occupies a terminal, clearance-incompetent branch along the LAM continuum, consistent with a maladaptive mitochondrial stress-clearance response. Our human snRNA-seq analysis delineates an adipocyte-macrophage immunometabolic circuit in which mitochondrial stress in AD3 adipocytes and defective MDV clearance by LAM-ST1 macrophages jointly sustain metaflammation in T2D scWAT. These findings highlight mitochondrial waste handling by tissue-resident macrophages as a potential checkpoint for restoring adipose immune homeostasis and reducing cardiometabolic risk.

Keywords:  immunometabolism; lipid-associated macrophages; metaflammation; mitochondrial stress; mitochondrial-derived vesicles; single-nucleus RNA sequencing; subcutaneous white adipose tissue; type 2 diabetes

DOI:  https://doi.org/10.3389/fimmu.2026.1768845
Free Radic Biol Med. 2026 May 20. pii: S0891-5849(26)00771-9. [Epub ahead of print]

Mitochondrial Dynamics and Transfer in Mesenchymal Stromal Cells: Redox Regulation, Therapeutic Mechanisms, and Engineering Strategies.

XueXia Liu, XiaoXin Wang, FuJun Liu.

  Mesenchymal stromal cells (MSCs) are metabolically active and redox-sensitive therapeutic cells, with their therapeutic potency tightly linked to mitochondrial integrity and function. Beyond paracrine and immunomodulatory actions, MSCs can transfer functional mitochondria to damaged cells, restoring bioenergetics, maintaining redox homeostasis via ROS regulation, and facilitating tissue repair and regeneration. This review summarizes recent progress in MSC mitochondrial biology, highlighting how metabolic reprogramming, mitochondrial biogenesis, fusion-fission dynamics and mitophagy coordinately regulate MSC stemness, differentiation, senescence and therapeutic capacity. It outlines core redox regulatory networks covering mitochondrial ROS production (ETC Complexes I/III and reverse electron transport), non-mitochondrial oxidases (NADPH oxidases), and canonical antioxidant signaling (Nrf2/Keap1, thioredoxin/peroxiredoxin and glutathione/glutaredoxin). Redox-dependent post-translational modifications governing mitochondrial transfer machinery are emphasized, including cysteine oxidation of connexin 43, redox-regulated Drp1 phosphorylation, and oxidative modulation of Miro1-mediated mitochondrial trafficking. Major intercellular mitochondrial transfer routes, such as tunneling nanotubes, connexin 43-based intercellular communication and extracellular vesicles, are discussed under inflammatory, hypoxic and metabolic stress conditions. Preclinical studies across pulmonary, cardiovascular, neurological, renal, hepatic and immune-mediated diseases validate that MSC-derived mitochondrial transfer preserves ATP production, mitigates oxidative injury and remodels recipient cell immunometabolic phenotypes. Emerging engineering strategies to improve mitochondrial delivery and therapeutic outcomes are also reviewed, alongside translational bottlenecks including cell source heterogeneity, mitochondrial quality control, in vivo tracking, dosage optimization and long-term biosafety. Overall, MSC mitochondrial dynamics and intercellular transfer bridge redox biology, metabolism and regenerative medicine, offering mechanistic insights for next-generation precision regenerative therapies.

Keywords:  Extracellular vesicles; Mesenchymal stromal cells; Mitochondrial transfer; Redox homeostasis; Regenerative medicine

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.291
J Alzheimers Dis. 2026 May 21. 13872877261452598

An aging hallmark, Alzheimer's disease, and APOE nexus.

Alexander P Gabrielli, Ian Weidling, Colton R Lysaker, Lesya Novikova, Amol Ranjan, Xiaowan Wang, Heather M Wilkins, Russell H Swerdlow.

  BackgroundThe commonality of Alzheimer's disease (AD) in the elderly suggests connections between aging and AD biology. APOE biology is also tied to AD.ObjectiveWe sought to link three aging hallmarks (loss of proteostasis, mitochondrial dysfunction, deregulated nutrient sensing) to APOE biology.MethodsWe altered SH-SY5Y cell proteostasis directly via heat shock, integrated stress response inhibition (ISRIB), or autophagy inhibition (chloroquine), and indirectly by perturbing mitochondria (mtDNA depletion; oligomycin). We also exposed induced pluripotent stem cell-derived neurons to ISRIB and chloroquine. Conversely, we mitigated protein stress with rapamycin. We assessed intervention impact on APOE expression.ResultsIncreasing protein stress elevated and decreasing protein stress lowered APOE expression. In SH-SY5Y cells rapamycin blocked oligomycin-induced mTOR 2448 phosphorylation, Akt 473 phosphorylation, and APOE expression. In chloroquine-treated neurons rapamycin reduced mTOR phosphorylation and APOE expression.DiscussionProtein stress initiates APOE expression and facilitates mitochondrial dysfunction's impact on APOE by engaging the mTOR pathway. Our findings link aging and AD biology.

Keywords:  APOE; Alzheimer's disease; mTOR; mitochondria; proteostasis; rapamycin

DOI:  https://doi.org/10.1177/13872877261452598
Kidney Int. 2026 May 21. pii: S0085-2538(26)00394-7. [Epub ahead of print]

Mitochondrial respiratory capacity in kidney podocytes is high, age-dependent, and sexually dimorphic.

Matthew D Campbell, Monica Sanchez-Contreras, Britta D Sibley, Phoebe Keiser, Carla Ruiz-Sanchez, Carolyn N Mann, Anna A Bakhtina, James E Bruce, David J Marcinek, Behzad Najafian, Mariya T Sweetwyne.

   INTRODUCTION: Whether and how podocytes depend on mitochondria across their long post-mitotic lifespan is unclear. With limited cell numbers and broad kidney distribution, isolation of podocyte mitochondria typically requires first isolating podocytes themselves. Disassociation of podocytes from their basement membrane, however, recapitulates an injured state and stresses mitochondria. Here, we devise a new strategy to examine mitochondria in podocytes.
METHODS: To address this, we crossed floxed hemagglutinin (HA)-mitochondria tagged (MITO-Tag) mice with those expressing Cre in either podocytes (NPHS2) or mixed tubules (CDH16), thus allowing for rapid, kidney cell-specific, isolation of mitochondria via immunoprecipitation.
RESULTS: Mitochondrial respiration in fresh isolates from young (4-7 months) and aged (22-26 months) mice of both sexes demonstrated several previously unreported significant differences between podocyte and tubule mitochondria. First, although podocytes contain fewer mitochondria than tubule cells, mitochondria isolated from podocytes averaged twice the respiratory capacity of tubule mitochondria when normalized to mitochondrial content by citrate synthase levels. Second, age-related decline in respiration was detected only in podocyte mitochondria and only in aged male mice. Third, disassociating podocytes for cell culture initiates functional decline in mitochondria as those from cultured primary podocytes have half the respiratory capacity, but twice the hydrogen peroxide production, of podocyte mitochondria isolated directly from fresh kidneys. Finally, conformation of electron transport chain proteins differed between podocyte and tubule mitochondria, suggesting that cell-specific mitochondrial protein conformations dictate cell-specific mitochondrial function.
CONCLUSIONS: Previous studies suggesting a limited role for mitochondrial regulation of podocytes relied on cell culture. This resulted in artifactual suppression of mitochondrial function and masks the roles of mitochondria in maintenance of podocyte health. Our approach shows that per organelle, podocytes maintain sexually dimorphic mitochondria with greater oxidative phosphorylation capacity than the mitochondria-dependent tubules.

Keywords:  animal model; distal tubule; mitochondria; podocyte

DOI:  https://doi.org/10.1016/j.kint.2026.04.016
J Physiol Biochem. 2026 May 21. pii: 53. [Epub ahead of print]82(1):

The progress of mitochondrial function and transfer in stem cell regulation and therapy.

Yubing Zhang, Zhuojian Qu, Zhiliang Guo, Lijuan Zhang, Hong Li, Xiaoyun Zhang, Xiumei Guan, Xiaodong Cui, Wenxu Wang, Min Cheng.

  Mitochondria, serving as central organelles for energy metabolism, play a critical regulatory role in stem cell self-renewal and differentiation-a function increasingly supported by accumulating evidence and closely linked to various aging-related diseases. Central to their function in stem cell pluripotency are several key mechanisms, such as the control of reactive oxygen species, mitophagy, and mitochondrial-endoplasmic reticulum communication. Mitochondrial transfer, as an emerging intercellular communication mechanism, can enhance stem cell pluripotency and function by replacing damaged mitochondria or activating mitophagy in recipient cells. However, different transfer mechanisms can induce distinct effects on recipient cells. The development of artificial mitochondrial transfer technology, compared to traditional cell transplantation, reduces immune rejection and offers new strategies for stem cell therapy. This review examines the interplay between mitochondrial function and stem cell fate determination, discusses the therapeutic potential of mitochondrial transfer in stem cell-based regenerative strategies, and establishes a theoretical framework for understanding and treating mitochondrial dysfunctions and aging-associated pathologies.

Keywords:  Mitochondrial function; Mitochondrial transfer; Mitophagy; Reactive oxygen species; Stem cell regulation

DOI:  https://doi.org/10.1007/s13105-026-01192-0
Front Physiol. 2026 ;17 1721230

Mitochondrial metabolic reprogramming, quality control, and intercellular transfer in regulating macrophage plasticity.

Guanheng He, Qian Sun.

  Macrophage functional plasticity is intrinsically linked to metabolic reprogramming, including mitochondrial function, substrate utilization, and redox signaling. In response to hypoxia, infection, or tissue injury, macrophages rely on mitochondria not only for energy provision but, critically, for metabolic intermediates and reactive oxygen species (ROS) that serve as signaling molecules to guide gene expression reprogramming. While macrophage activation exists along a continuous spectrum, this review summarizes the distinct metabolic paradigms characterizing the classical M1-like (glycolysis-dominant) and M2-like (oxidative phosphorylation, OXPHOS-dominant) extremes, highlighting the molecular mechanisms where metabolic events-specifically tricarboxylic acid (TCA) cycle truncation and succinate accumulation-drive inflammatory polarization. Furthermore, we discuss the role of mitochondrial quality control, particularly dynamics and mitophagy, in maintaining macrophage homeostasis. Notably, recent evidence identifies "intercellular mitochondrial transfer" as a novel mode of immune microenvironment regulation, enabling damaged macrophages to restore function by acquiring exogenous mitochondria. A deeper understanding of these mechanisms offers new intervention targets for metabolic immunotherapy in sepsis, cancer, and chronic inflammatory diseases. Importantly, we emphasize that many of these metabolic and mitochondrial regulatory mechanisms are highly context-dependent, varying significantly across different tissues and disease microenvironments.

Keywords:  intercellular mitochondrial transfer; macrophage polarization; metabolic reprogramming; mitochondria; mitophagy

DOI:  https://doi.org/10.3389/fphys.2026.1721230
Front Aging. 2026 ;7 1752530

Therapeutic potential of stem cell-derived extracellular vesicles in aging and regeneration.

Isobel K Dunstan, Daniel C Anthony, Francesca Lugarini, Sherif Idriss.

  Aging is characterized by measurable reductions in tissue repair, immune balance, and metabolic regulation. Increasing evidence suggests that these changes may arise, in part, from an insufficiency or altered quality of endogenous extracellular vesicle (EV) signaling. EVs, including exosomes, carry regenerative and immunoregulatory cues, and age-related alterations in their abundance, cargo, and bioactivity have been linked to impaired cellular communication across organ systems. This has fueled growing interest in stem cell-derived EVs, which provide biologically more youthful vesicles that reproduce key paracrine functions of their parent cells while avoiding the limitations of cell transplantation. By transferring defined protein, lipid, and RNA cargoes, these vesicles influence pathways central to aging biology, including mitochondrial function, inflammatory control, and maintenance of stem cell niches. Preclinical studies support their efficacy in models of neurodegeneration, wound healing, musculoskeletal decline, and systemic inflammation. However, their function depends on stem cell origin, donor age, and environmental conditioning, variables that complicate standardization and clinical scalability. As interest expands across therapeutic and cosmetic domains, a comparative understanding of EV sources and their mechanistic actions is required. In this review, we examine stem cell-derived EVs across biological sources, outline how aging and environmental factors shape their regenerative potency, and evaluate current progress in clinical translation. The field has reached a point where future advances depend less on further demonstrations of efficacy and more on resolving challenges related to manufacturing, quality control, and regulatory alignment. Addressing these constraints will determine whether stem cell-derived EVs can progress from experimental promise to practical interventions for aging and regenerative medicine.

Keywords:  aging; exosomes; extracellular vesicles; immunomodulation; longevity; regenerative medicine; stem cells

DOI:  https://doi.org/10.3389/fragi.2026.1752530
Bull Math Biol. 2026 May 19. pii: 89. [Epub ahead of print]88(6):

Damage-Driven Irreversibility and Emergent Senescence in Age-Structured Cell Populations.

Koffi Enakoutsa.

Cellular aging is characterized by the progressive accumulation of intracellular damage, declining repair capacity, and altered mechanochemical signaling, ultimately leading to cellular senescence and loss of tissue homeostasis. Despite extensive experimental and theoretical efforts, the fundamental origin of senescence and its irreversible nature remain incompletely understood. In particular, it is unclear whether senescence must be imposed as a predefined cellular state or can instead emerge dynamically from more basic damage-repair mechanisms. In this work, we propose a unified age-damage structured mathematical framework for cellular aging that integrates intracellular damage accumulation, biochemical signaling, mechanical stress, and population renewal within a thermodynamically consistent variational structure. The model combines continuum thermodynamics with age-structured population dynamics, ensuring compliance with the second law of thermodynamics and providing a rigorous basis for irreversible aging processes. A central result of the model is the emergence of a damage-driven loss of homeostasis at a critical threshold of effective load, beyond which no steady intracellular damage state exists. This transition generates irreversibility at the single-cell level and propagates to the population scale through transport in age-damage space, leading naturally to the emergence of cellular senescence without introducing ad hoc senescence rules. Mechanical stress enters the model through a quadratic contribution to the effective damage load, producing a pronounced nonlinear sensitivity and predicting abrupt acceleration of aging beyond a critical stress level. To facilitate analysis and computation, we derive a reduced ODE-PDE system that retains the essential couplings between damage accumulation, biochemical signaling, mechanical stress, and population renewal. Analytical arguments and numerical illustrations demonstrate how transient mechanical or biochemical perturbations can induce persistent senescence at the population level. Overall, the proposed framework provides a mechanistic and thermodynamically grounded explanation of irreversible senescence as an emergent phenomenon in age-structured cell populations.

DOI: https://doi.org/10.1007/s11538-026-01653-z
FEBS J. 2026 May 18.

The epigenetic landscape of skeletal muscle in response to exercise and aging.

Sabrina Champsi, David A Hood.

  Skeletal muscle exhibits a remarkable level of plasticity that enables it to adapt to exercise training, as well as the deleterious effects of aging. Fundamental to this malleability are epigenetic processes, which collectively enhance chromatin remodeling and subsequently alter DNA availability for gene expression. A growing body of evidence has demonstrated that acute exercise is a powerful inducer of epigenetic remodeling, capable of stimulating gene-specific alterations, which transcriptionally activate exercise-responsive genes. These epigenetic processes, including DNA methylation and various histone modifications, are highly responsive to exercise-induced signaling cascades and mitochondrially-related metabolites, together indicating that exercise can modulate the nuclear and mitochondrial epigenome as a mechanism to regulate gene expression. However, aging is characterized by a unique epigenetic signature, which likely supports the alterations in gene expression observed with age. Yet, the effects of exercise on epigenetic regulation with age remain underexplored. To investigate the intersectionality of these two phenotypes and highlight significant gaps within the literature, this review aimed to discuss the different types of epigenetic modifications that have been reported within skeletal muscle and how they are altered with acute and chronic exercise. Furthermore, we aimed to analyze mitochondrial epigenetics and their role in mediating alterations in mitochondrial-nuclear crosstalk observed with exercise and age. Elucidating age-dependent adaptations in the epigenome and the differential effects of exercise in these populations will help uncover the complexity of gene regulation with age, and importantly, reveal how exercise can regulate many of these processes to improve muscle health.

Keywords:  aging; epigenetics; exercise; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1111/febs.70591
Free Radic Biol Med. 2026 May 21. pii: S0891-5849(26)00787-2. [Epub ahead of print]

Mitoredox Shifts in Mitochondrial Dysfunction.

Walter H Moos, Douglas V Faller, Ioannis P Glavas, Iphigenia Kanara, Krishna Kodukula, Julie Pernokas, Mark Pernokas, Carl A Pinkert, Whitney R Powers, Konstantina Sampani, Kosta Steliou, Demetrios G Vavvas.

  Mitochondrial dysfunction underlies a broad spectrum of primary and secondary disorders, yet current frameworks do not fully capture how diverse genetic, metabolic, and environmental stressors converge on shared pathological outcomes. Here, we propose that mitoredox shifts - bidirectional disruptions in mitochondrial redox homeostasis that alter mitochondrial quality control and genome-stability pathways - serve as a unifying axis linking oxidative stress, mitochondrial quality control failure, heteroplasmy dynamics, and regulated cell death. Both hyperactive and hypoactive mitochondrial states destabilize redox balance, altering PINK1/Parkin-dependent and receptor-mediated mitophagy, disrupting proteostasis, and reshaping mitochondrial network dynamics. These redox-driven perturbations influence the propagation of pathogenic mtDNA variants, modulate tissue-specific threshold effects, and bias cells toward apoptosis, ferroptosis, cuproptosis, and other regulated cell death pathways. We synthesize emerging evidence across mitochondrial genetics, bioenergetics, and redox signaling to outline how mitoredox shifts accelerate disease progression in both primary mitochondrial syndromes and secondary mitochondrial dysfunction. We further evaluate the expanding landscape of diagnostic biomarkers, including FGF21, GDF15, imaging-based oculomics, and high-throughput proteomic and genomic assays. In parallel, we highlight therapeutic strategies aimed at restoring redox balance, enhancing mitophagy, or shifting mitochondrial network composition by diluting dysfunctional organelles through mitochondrial transplantation. By emphasizing mitoredox imbalance as a recurrent feature of disease, this work synthesizes emerging diagnostic and therapeutic approaches across rare and common mitochondrial disorders.

Keywords:  Biomarkers; cuproptosis; ferroptosis; heteroplasmy; mitochondria; mitophagy; mitoredox medicine; oxidative stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.307
Curr Opin Hematol. 2026 May 18.

Stress granules and RNA modifications in blood development and erythroid regeneration.

Rajesh Gunage.

   PURPOSE OF REVIEW: Stress granules (SGs) are RNA and protein assemblies that form rapidly in the cytoplasm in response to cellular or environmental stress. SGs, traditionally recognized as transient repressors of translation, are now understood as versatile regulatory centers that shape RNA metabolism, signaling, proteostasis, and cell fate. In this review, we collate recent findings showing SGs' role in steady-state and regenerative stress in erythropoiesis.
RECENT FINDINGS: Blood loss, anemia caused by ribosomal mutations, has been reported to alter the SG axis and protein translation. During regeneration stress, SGs selectively capture lineage-defining RNAs to regulate their translation during recovery phases. This process ensures that blood progenitors and differentiating cells retain essential transcripts, supporting proper fate decisions and regeneration. Pathological SG accumulation disrupts RNA metabolism and translational reprogramming, key to blood cell regeneration.
SUMMARY: SGs regulate the transcriptome to endure stress via translational control mechanisms during erythropoiesis. SG deregulation can undermine these adaptive processes. Therapies modulating SG formation, dissolving pathological SGs, or influencing RNA sorting via genetics or targeted small molecules promise new directions to restore blood health, treat anemia, and regeneration in a range of blood disorders.

Keywords:  ATXN2; DBA; RNA modification; stress granules; translation

DOI:  https://doi.org/10.1097/MOH.0000000000000930