bims-mihora 2026-07-05 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2026–07–05
twelve papers selected by
Lisa Patel, Istesso

The role of ATF4 in neurons under mitochondrial stress.
The dual role of ATF4 in neurons: from stress adaptation to therapeutic intervention.
Mitochondria-sarcoplasmic reticulum crosstalk as a modulator of skeletal muscle mass.
ATPIF1, the rheostat in mitochondrial bioenergetics and dysfunction in diseases.
Mitochondria in the middle of inter- organellar cross talk: insights from yeast to humans.
Mitochondrial Complex I Modulator Restores Network Resilience in Advanced Alzheimer's Disease Through Metabolic Reprogramming.
Mapping bioenergetic mechanisms across aging hallmarks: a systematic evidence map and secondary conceptual synthesis.
Addressing bioenergetic deficits and restoring mitochondrial health in transplanted islets using mesenchymal stem cells.
When mitochondria lose their fold: matrix proteostasis and stress signaling.
Patterns in motion: Choreographing dynamic cell behaviours during tissue repair.
Allosteric disordering of eIF2B regulates the integrated stress response.
Mitochondrial stress markers associate with phenotypic variability in Fabry disease.

NAR Genom Bioinform. 2026 Sep;8(3): lqag069

The role of ATF4 in neurons under mitochondrial stress.

Maria Bilen, Yubing Liu, Imane Chakroun, Mohamed Ariff Iqbal, Bensun C Fong, Jingwei Chen, Smitha Paul, Alexandre Blais, Ruth S Slack.

Mitochondrial dysfunction and fragmentation are observed in various circumstances, such as neurodegeneration and aging. Studies have shown that altered mitochondrial function activates the integrated stress response (ISR), with ATF4 serving as a major mediator of adaptation to stress. Presently, little is known about the role of ATF4 in neurons under mitochondrial stress. Using primary cortical neurons, we demonstrate that inhibiting ATF4 under OPA1-mediated mitochondrial stress accelerates the impairment of neuronal differentiation, as evidenced by smaller dendrites and lower dendritic spine density. To better understand the role of ATF4 in this context, we investigated the global binding sites of ATF4 using chromatin immunoprecipitation sequencing (ChIP-seq) and examined the chromatin accessibility changes that occur following the loss of ATF4 in neurons under conditions of mitochondrial stress. We found that ATF4 binds to a wide range of targets and alters the chromatin accessibility of genes involved in metabolism, neuronal fate, and neuron maturation. The downstream targets of ATF4 identified in this study can reveal novel and direct targets of ATF4 in neuronal survival and maturation. These adaptations are the hallmarks of stress response in mitochondrial dysfunction-mediated neurodegeneration.

DOI: https://doi.org/10.1093/nargab/lqag069
Front Mol Neurosci. 2026 ;19 1816333

The dual role of ATF4 in neurons: from stress adaptation to therapeutic intervention.

Hua Huang, Yao Xu, Xingyi Li, Chenggang Li, Wuxue Peng.

  Activating transcription factor 4 (ATF4) functions as the central transcriptional arbiter of the integrated stress response (ISR) in neurons. Its translation is gated by diverse upstream kinases via the eIF2α pathway, while its functional output is critically shaped by context-dependent interactions with specific protein partners (e.g., C/EBPβ or CHOP). We conceptualize ATF4 as a spatiotemporal rheostat whose regulatory mandate is stage-specific: it acts as a physiological switch during neocortical development and maintains synaptic and mitochondrial integrity in the adult brain. However, this precise regulation fails in neurological disorders, including Alzheimer's disease, Parkinson's disease, cerebral ischemia, and epilepsy. Chronic, maladaptive ATF4 signaling-often driven by pathological heterodimerization-catalyzes neuroinflammation, ferroptosis, and circuit failure. Crucially, contemporary challenges in clinical translation highlight a "therapeutic paradox," where broad or untimely pathway inhibition may inadvertently dismantle essential neuroprotective shields. We therefore advocate for a paradigm shift toward "kinetic recalibration"-the development of precision interventions designed to restore the proteostatic and information-processing homeostasis of the stressed nervous system.

Keywords:  ATF4; homeostatic rheostat; integrated stress response; neurodegeneration; synaptic plasticity

DOI:  https://doi.org/10.3389/fnmol.2026.1816333
J Physiol Biochem. 2026 Jun 30. pii: 60. [Epub ahead of print]82(1):

Mitochondria-sarcoplasmic reticulum crosstalk as a modulator of skeletal muscle mass.

Rafael A Casuso.

  Preservation of skeletal muscle mass and function is a key feature of healthy ageing and relies on the tight coordination between protein synthesis and breakdown to maintain proteostatic balance. These processes impose a substantial energetic demand, highlighting the importance of mitochondrial function in skeletal muscle homeostasis. Increasing evidence indicates that mitochondria and the sarcoplasmic reticulum are functionally interconnected. Effective crosstalk between these organelles contributes to the integration of bioenergetic supply, Ca²⁺ handling, and proteostasis. Disruption of this communication network may impair adaptive stress responses, compromise protein quality control, and favour the development of anabolic resistance during ageing. This review synthesizes current evidence on mitochondria-sarcoplasmic reticulum communication. It further discusses how disruption of this crosstalk may promote anabolic resistance and skeletal muscle atrophy, with particular emphasis on its implications for age-related muscle decline.

Keywords:  Atrophy; Calcium; Endoplasmic reticulum; Organelle crosstalk; Sarcopenia; Unfolded protein response

DOI:  https://doi.org/10.1007/s13105-026-01198-8
Mitochondrion. 2026 Jun 27. pii: S1567-7249(26)00077-2. [Epub ahead of print]91 102187

ATPIF1, the rheostat in mitochondrial bioenergetics and dysfunction in diseases.

Jing Huang, Cheng Xue, Huangmin Li, Yan Wu, Qingqing Wei.

  ATP synthase inhibitory factor 1 (ATPIF1) is a critical regulator of the activity of F1F0-ATPase, a central enzyme in mitochondrial ATP production. Accumulating evidence highlights ATPIF1 as a master modulator of mitochondrial morphology, function, cellular metabolism, and stress responses in diverse physiological and pathological conditions. In this review, we first provide a brief overview of mitochondrial structure and ATP production. We then focus on the cellular and molecular mechanisms of mitochondrial bioenergetics regulated by ATPIF1 and emphasize the role of ATPIF1 in energy preservation, mitophagy and redox balance. Furthermore, we comprehensively summarize recent advances about the pathological function of ATPIF1 in various mitochondrial dysfunction related diseases, including ischemia/reperfusion injury, aging, cancer, sepsis and chronic inflammation, and neurodegenerative disorders. ATP1IF1, the mitochondrial rheostat, emerges as a novel therapeutic target to combat mitochondrial dysfunction across multiple organ systems.

Keywords:  ATPIF1; Bioenergetics; Mitochondria; Mitochondrial dysfunction; Mitophagy; Redox signaling

DOI:  https://doi.org/10.1016/j.mito.2026.102187
Front Cell Dev Biol. 2026 ;14 1820168

Mitochondria in the middle of inter- organellar cross talk: insights from yeast to humans.

Nicoletta Guaragnella, Maria Antonietta Di Noia, Giampaolo Morciano, Angela Primavera.

  Mitochondria are multifaceted organelles acting as energy, metabolic and signaling hubs in the cells. Their role as sensors, integrators and transducers of intra and extracellular inputs can drive many processes of stress response. Mitochondrial signal integration can occur at different levels involving functional and physical interactions. An example of functional interaction is the mitochondria-cytosol-nucleus cross talk, named retrograde pathway, which is evolutionary conserved from yeast to humans and allows metabolic rewiring in the presence of. mitochondrial dysfunction. On the other hand, Physical Interactions, such as mitochondria associated membranes (MAMs), specialized contact sites between mitochondria and the endoplasmic reticulum (ER), play pivotal roles in calcium signaling and stress response. Calcium is tightly regulated at MAMs and functions both as stress sensor and mediator. Impaired mitochondrial function can lead to dysregulated calcium flux, particularly from the ER to mitochondria, triggering retrograde signaling pathways that alter nuclear gene expression and support cell adaptation. In yeast, the ER-mitochondria encounter structure (ERMES) complex exemplifies conserved mechanisms facilitating organelle tethering and metabolic cross talk. Dysfunctional mitochondria have significant repercussion on MAMs architecture, and viceversa, which impact on cell stress response particularly in, but not limited to, neurodegenerative disorders and cancer. In this review, we provide an overview of mitochondria-centered inter-organellar cross talk underpinning stress adaptation across eukaryotes, from yeast to humans. This comparative approach allows us to focus on key regulatory nodes, which are emerging as potential therapeutic targets. Components, such as calcium-dependent effectors, transcription factors, tethering proteins, or mitochondrial carriers could enable selective modulation of stress responses.

Keywords:  ERMES complex; MAMS; inter-organellar cross talk; mitochondria; retrograde signaling pathway

DOI:  https://doi.org/10.3389/fcell.2026.1820168
bioRxiv. 2026 Jun 17. pii: 2026.06.14.732179. [Epub ahead of print]

Mitochondrial Complex I Modulator Restores Network Resilience in Advanced Alzheimer's Disease Through Metabolic Reprogramming.

Esraa Gabal, Thi Kim Oanh Nguyen, Tetiana Kovalenko, Huanyao Gao, Noa Rappaport, Cory Funk, Priyanka Baloni, Eugenia Trushina.

Mitochondrial dysfunction and lipid dysregulation are among the earliest abnormalities in Alzheimer's disease (AD), yet their mechanistic interplay and therapeutic potential remain poorly understood. Here, we investigated whether restoration of mitochondrial function can reverse metabolic dysfunction and promote resilience in advanced-stage AD. Female APP/PS1 mice were treated with the brain-penetrant mitochondrial complex I (mtCI) modulator CP2 beginning at 19 months of age, when pathology and cognitive deficits were well established. To define the metabolic mechanisms underlying therapeutic response, we developed iMiceBrain , the first brain-specific genome-scale metabolic model of the mouse brain, and integrated transcriptomics, targeted metabolomics, lipidomics, and metabolic network analyses. CP2 treatment broadly reprogrammed AD-associated molecular signatures and restored pathways involved in mitochondrial function, glucose utilization, lipid metabolism, synaptic activity, and cellular stress responses. Metabolic modeling identified enhanced mitochondrial substrate flexibility, activation of fatty acid utilization, restoration of pyruvate dehydrogenase flux, and normalization of cholesterol metabolism as key features of the therapeutic response. Lipidomic analyses further demonstrated correction of disease-associated alterations in cholesteryl esters, phospholipids, and sphingolipids. Together, these findings demonstrate that mild mtCI modulation restores metabolic resilience by coordinating mitochondrial and lipid metabolism, establishing it as a disease-modifying therapeutic strategy for AD.

DOI: https://doi.org/10.64898/2026.06.14.732179
Front Physiol. 2026 ;17 1868353

Mapping bioenergetic mechanisms across aging hallmarks: a systematic evidence map and secondary conceptual synthesis.

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

   Background: Mitochondrial dysfunction is widely recognized as a feature of aging, but the term encompasses heterogeneous processes, including altered energy production, redox imbalance, substrate handling, respiratory capacity, and mitochondrial quality control. Biological resilience depends on the capacity to respond to stressors, restore homeostasis, and preserve maintenance and repair. However, within mechanism-oriented aging literature, how mitochondrial and bioenergetic mechanisms are represented across aging hallmark domains, and whether they can be organized along a continuum of impairment, remains incompletely defined.
Methods: This study used a secondary evidence map and narrative synthesis based on a previously curated, mechanism-oriented literature dataset; it was not designed as a comprehensive hallmark-by-hallmark systematic review. The original search captured stress adaptation, bioenergetic regulation, systemic dysfunction, and metabolic strain. Included reports were recategorized by hallmark domain, stage of mitochondrial or bioenergetic impairment, mechanistic domain, evidence type, and evidence tier. The final synthesis included 433 reports.
Results: Within this mechanism-enriched dataset, mapped evidence was concentrated in regulatory and systems-level hallmark domains, particularly altered intercellular communication, chronic inflammation, and deregulated nutrient sensing. The most frequent mechanistic labels involved redox imbalance, substrate reallocation, oxidative throughput limitation, limited adenosine triphosphate availability, and mitochondrial quality-control impairment. Stage-based mapping showed that functional, adaptive, and structural labels often coexisted across hallmark domains rather than forming discrete categories.
Conclusion: These findings identify recurrent co-representation of mitochondrial and bioenergetic mechanisms with selected aging hallmark domains visible within a mechanism-oriented evidence set. The results support a cautious, hypothesis-generating interpretation in which bioenergetic constraint may provide a conceptual lens for organizing stage-like patterns, rather than reducing mitochondrial aging biology to a binary distinction between "function" and "dysfunction." However, this analysis does not establish biological centrality, causal direction, temporal sequence, tissue specificity, or generalizability across the broader aging literature.Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/view/, identifier CRD420251033154.

Keywords:  aging hallmarks; bioenergetics; biological resilience; evidence mapping; inflammaging; mitochondrial dysfunction; nutrient sensing; redox imbalance

DOI:  https://doi.org/10.3389/fphys.2026.1868353
Stem Cells Transl Med. 2026 May 18. pii: szag038. [Epub ahead of print]15(7):

Addressing bioenergetic deficits and restoring mitochondrial health in transplanted islets using mesenchymal stem cells.

Rosita Primavera, Abantika Ganguly, Reza Yarani, Lili Bettencourt, Shobha Regmi, Shashank Chetty, Jing Wang, Michele Guindani, Ramasamy Paulmurugan, Avnesh S Thakor.

  During the process of islet transplantation, islets undergo isolation and are then introduced into a new microenvironment where they need to adapt and revascularize. This transition imposes substantial stress on islets, leading to mitochondrial dysfunction and oxidative stress, adversely affecting islet function and vitality. Mesenchymal stem cells (MSCs) offer a promising therapy to mitigate these adverse effects by restoring their bioenergetic capacity and overall functionality of islets. Our study investigates how human MSCs (hMSCs) from different sources-adipose tissue (AD), bone marrow (BM), and umbilical cord (UC)-can restore the bioenergetic capacity of inflamed pancreatic islets. We assess how hMSCs can improve islet survival, function, and mitochondrial health, by analyzing key mitochondrial oxidative stress-related genes. In addition, this study examines the functional effect of co-transplanting islets with hMSCs in vivo in diabetic mice. hMSCs, particularly those from UC and BM, can effectively sustain islet viability, enhance mitochondrial function, and alleviate oxidative stress, as evidenced by increased expression of key mitochondrial markers such as PPARGC1A, TOMM20, and Sod2. Furthermore, co-transplantation of hMSCs with sub-therapeutic islet numbers leads to long-term improvements in glucose regulation, with UC-hMSCs showing better short-term efficacy (100% of diabetic mice receiving islets with UC-hMSCs recovered their blood glucose levels back to normal at 4 weeks post-transplantation, vs. 80% of those transplanted with BM-hMSCs, 60% with AD-hMSCs, and 16% for islets alone). These findings highlight the potential of hMSC-therapies for islet transplantation, underscoring the need to select the optimal MSC source to maximize the therapeutic outcome of transplanted islets.

Keywords:  bioenergetics; diabetes; islet transplantation; mesenchymal stem cells; mitochondria transfer; oxidative stress; pancreatic islets

DOI:  https://doi.org/10.1093/stcltm/szag038
Front Physiol. 2026 ;17 1873221

When mitochondria lose their fold: matrix proteostasis and stress signaling.

Nils Bertram, Dejana Mokranjac.

  A dedicated network of chaperones and proteases is present in the mitochondrial matrix that orchestrates import, folding, disaggregation and eventually degradation of proteins. When this network is overwhelmed, unfolded or misfolded proteins accumulate in different types of aggregates which may either support recovery of functional proteins, initiate spatial sequestration or drive toxic aggregation. Here, we discuss mitochondrial protein aggregation and how mitochondrial proteostasis stress is communicated to the rest of the cell.

Keywords:  Hsp70; mitochondria; mitochondria-nuclear signaling; protein aggregation; proteostasis

DOI:  https://doi.org/10.3389/fphys.2026.1873221
Curr Opin Cell Biol. 2026 Jun 27. pii: S0955-0674(26)00059-1. [Epub ahead of print]101 102671

Patterns in motion: Choreographing dynamic cell behaviours during tissue repair.

Helen Weavers.

Tissue repair is a dynamic, multicellular response that relies on the precise spatiotemporal coordination of diverse cell types. Here, we discuss how recent advances have accelerated our mechanistic understanding of these collective cellular behaviours, particularly in epithelial barrier tissues like the skin. We highlight studies unravelling the intricate crosstalk that patterns cell behaviours across the repairing tissue and how vulnerable cells are endowed with striking stress resilience and memory. The integration of cutting-edge live imaging, single-cell profiling and computational approaches are now revealing the complexities of effective and pathological repair at an unprecedented resolution, opening new avenues for therapeutic intervention.

DOI: https://doi.org/10.1016/j.ceb.2026.102671
Nat Chem Biol. 2026 Jun 29.

Allosteric disordering of eIF2B regulates the integrated stress response.

Udit Dalwadi, Advait Subramanian, Aniliese Deal, Julia E Conrad, Tamara Nadjsombati, Meera Venkatesh, Morgane Boone, Pascal F Egea, Lingjie He, Nimit Jain, D John Lee, Yuwei Liu, Lucas C Reineke, Kazuki Saito, Nathaniel Talledge, Hannah Toutkoushian, Maxence Le Vasseur, Francesca Zappa, Raoul J de Groot, Diego Acosta-Alvear, Christopher P Arthur, Jodi Nunnari, Susan Marqusee, Rosalie E Lawrence, Mauro Costa-Mattioli, James J Crawford, Frank J M van Kuppeveld, Tristan I Croll, Peter Walter, Adam Frost.

The ternary complex, composed of eIF2, GTP and initiator methionyl-tRNA, delivers the first amino acid to the ribosome to initiate protein synthesis. Eukaryotic initiation factor 2B (eIF2B) catalyzes GDP to GTP exchange on eIF2, thereby setting the ternary complex level. Stress-induced phosphorylation converts eIF2 from the substrate of eIF2B into an inhibitor (eIF2-P). This conversion reduces ternary complex levels and induces the integrated stress response (ISR). Here we chart an allosteric axis running through eIF2B, revealing the importance of an α-helix in its β-subunit, the 'latch-helix', that hooks onto the α-subunit to induce eIF2B activity. eIF2-P binding promotes latch-helix unhooking, opening eIF2B, which inhibits its activity. Convergently evolved viral proteins stabilize this latch-helix-binding active state of eIF2B. Using these insights, we generated ISR-activating compounds that stabilize eIF2B in its inhibited, unlatched state. Our study thus highlights how long-range eIF2B allostery can be pharmacologically manipulated to sustain or attenuate the ISR.

DOI: https://doi.org/10.1038/s41589-026-02256-4
Orphanet J Rare Dis. 2026 Jun 30.

Mitochondrial stress markers associate with phenotypic variability in Fabry disease.

Lucia Lavalle, Hibba Kurdi, David Moreno Martinez, Vincent Muczynski, Simon Heales, Derralynn Hughes.

   BACKGROUND: Fabry disease (FD) exhibits marked clinical heterogeneity that cannot be fully explained by residual α-galactosidase A activity. Mitochondrial dysfunction has been reported in FD, but the role of mitochondrial stress remains unexplored.
OBJECTIVE: To investigate whether mitochondrial unfolded protein response (mtUPR) related markers associate with phenotypic variability and correlates with disease severity.
METHODS: We measured intracellular heat-shock protein 60 (Hsp60) expression by western blotting in fibroblasts and peripheral blood mononuclear cells (PBMCs). In the clinical cohort, intracellular Hsp60 was measured in PBMC whole-cell lysates from 27 FD patients (14 males, 13 females). Serum fibroblast growth-factor-21 and growth differentiation-factor-15 were measured in 35 patients. Clinical outcomes included Mainz Severity Score Index, Age-Adjusting Severity Score, estimated glomerular filtration rate, and left-ventricular mass index (LVMI).
RESULTS: Hsp60 showed variability, with sex-specific associations. In males, higher Hsp60 correlated with lower LVMI (r2 = -0.82, p = 0.01) and preserved renal function in late-onset patients (r2 = 0.89, p = 0.006). In females, higher Hsp60 associated with higher LVMI (r2 = 0.66, p = 0.045) and greater clinical severity. Male patients had elevated growth differentiation-factor-15 vs controls (935 vs 559 pg/ml, p = 0.002). Both mitokines correlated with age and disease severity.
CONCLUSIONS: mtUPR related markers exhibit sex- and genotype-specific patterns associated with disease severity, suggesting that mitochondrial stress contributes to phenotypic heterogeneity and support further longitudinal evaluation of Hsp60, FGF-21 and GDF-15 as candidate biomarkers of disease burden and treatment response.

Keywords:  Fabry disease; Hsp60; Mitochondrial unfolded protein response; Mitokines (FGF-21, GDF-15); Phenotypic heterogeneity

DOI:  https://doi.org/10.1186/s13023-026-04461-9