bims-ripira 2026-02-15 papers

bims-ripira

Biomed News

on RRM2B MDMD in Adults

Issue of 2026–02–15
fourteen papers selected by
Martín Lopo

Cognate amino acid therapies provide preclinical benefit in 19 C. elegans models of ARS2 deficiency.
Short telomeres in mitochondrial DNA depletion disorders.
Rhabdomyolysis due to mtDNA pathogenic variants: Report of a subject with a novel MT-CO3 variant and review of the literature.
Molecular Bases of Myopathies and Their Impact on Clinical Practice: Advances and Future Perspectives.
Mitochondrial DNA: a molecular switch driving sterile neuroinflammation.
Mechanisms and disease relevance of mitochondrial translation in humans.
Remodeling of Mitochondrial Networks: Cellular Adaptation and Microenvironmental Reprogramming in Hematologic Malignancies.
Progression of peripheral blood mononuclear cell mitochondrial function during the early phase of sepsis in intensive care unit patients.
Single-cell mitochondrial lineage tracing: Opportunities and challenges.
Myopathy and ataxia related to impaired mitochondrial function in mevalonate kinase deficiency.
GDF15 orchestrates mitochondrial-immune crosstalk via SMAD7-HIF-1α-PKM2 cascade to attenuate septic liver injury.
Oculomotor abnormalities in patients with cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) reflect midline cerebellar impairment.
Mitochondria-targeted delivery strategies for age-related diseases.
Iron dysregulation and mitochondrial dysfunction in aging: A longitudinal study on mobility decline in low- and high-functioning older adults.

bioRxiv. 2026 Feb 05. pii: 2026.02.03.703549. [Epub ahead of print]

Cognate amino acid therapies provide preclinical benefit in 19 C. elegans models of ARS2 deficiency.

Cristina Remes, Kelsey Keith, Rui Xiao, Vernon E Anderson, Donna M Iadarola, Eiko Nakamaru-Ogiso, Neal D Mathew, Marni J Falk.

Mitochondrial aminoacyl-tRNA synthetases (mt-ARS) are essential mitochondrial translation machinery components that catalyze mitochondrial transfer RNAs (tRNAs) charging with their cognate amino acid. Although mt-ARS have a common biochemical function, patients with mt-ARS pathogenic variants commonly develop neurological disorders with varying phenotypes, severity spectrum, and age of onset. Cognate amino acid supplementation has shown reported benefits in select cases of both mt-ARS ( ARS2 ) and cytosolic ( ARS1 ) deficiencies, although the safety and potential benefits of this candidate therapy approach across the full spectrum of mt-ARS disorders remain unclear. Here, C. elegans models were systematically generated for all 19 mitochondrial mt-ARS genes by feeding RNAi knockdown for one or two generations. mt-ARS deficient animals at baseline and upon cognate amino acid treatment were studied at the level of linear growth, neuromuscular activity, lifespan, mitochondrial physiology, and fertility. Results demonstrated that cognate amino acid treatment in a dose-dependent fashion consistently improved worm linear growth and neuromuscular activity, and reduced mitochondrial unfolded protein response stress, in all 19 knockdown models. It further rescued impaired fertility of hars-1 and fars-2 knockdown strains. Collectively, these preclinical studies provide compelling evidence to warrant future cognate amino acid treatment study in rigorous clinical trials spanning all human mt-ARS deficiencies.

DOI: https://doi.org/10.64898/2026.02.03.703549
Mitochondrion. 2026 Feb 10. pii: S1567-7249(26)00021-8. [Epub ahead of print]88 102131

Short telomeres in mitochondrial DNA depletion disorders.

Yumi Dille, Emmanouil Rampakakis, Geraldine Aubert, Christelle Dassi, William Mannherz, Saoussen Berrahmoune, Myriam Srour, Daniela Buhas, Suneet Agarwal, Kenneth A Myers.

  Mitochondrial DNA (mtDNA) depletion disorders (MDDs) are rare, genetically diverse conditions marked by a significant reduction in mtDNA, primarily affecting energy-demanding tissues such as muscle, liver, and brain, sometimes leading to catastrophic multisystem failure. In a cohort of patients with MDDs, we measured telomere length in lymphocytes, granulocytes, T cells, and B cells, and compared to healthy controls. Telomere length was shorter overall in patients with MDDs, with the most significant differences observed in granulocytes. The observation that mtDNA depletion is associated with shorter telomeres may provide insight into MDD pathophysiology. Telomere length may have potential as a biomarker in mitochondrial disease, but further study is needed.

Keywords:  C10orf2; DGUOK; Mitochondrial DNA depletion disorders; POLG; RRM2B; SUCLA2; SUCLG1; TK2; TYMP; Telomere length; Telomeres

DOI:  https://doi.org/10.1016/j.mito.2026.102131
Mol Genet Metab. 2026 Feb 08. pii: S1096-7192(26)00050-8. [Epub ahead of print]147(3): 109767

Rhabdomyolysis due to mtDNA pathogenic variants: Report of a subject with a novel MT-CO3 variant and review of the literature.

Emanuele Barca, Nuri Jacoby, Ali Naini, Michael L Miller, Valentina Emmanuele, Christopher J Winfree, Saba Tadesse, Kurenai Tanji, Michio Hirano.

  Rhabdomyolysis can be due to mitochondrial myopathy, but mitochondrial DNA (mtDNA) pathogenic variants are often overlooked in standard genetic panels. We report a 41-year-old woman with recurrent rhabdomyolysis due to a novel MT-CO3 variant. Muscle biopsy showed cytochrome c oxidase-negative fibers that segregated with high heteroplasmic load on single-fiber. We additionally review previously reported mtDNA variants associated with rhabdomyolysis, highlighting the diagnostic relevance of mtDNA analysis and tissue-specific testing in unexplained rhabdomyolysis.

Keywords:  COX stain; Mitochondrial DNA; Rhabdomyolysis; Single-fiber analysis; mtDNA pathogenic variant

DOI:  https://doi.org/10.1016/j.ymgme.2026.109767
Int J Mol Sci. 2026 Jan 30. pii: 1392. [Epub ahead of print]27(3):

Molecular Bases of Myopathies and Their Impact on Clinical Practice: Advances and Future Perspectives.

Martín Campuzano-Donoso, Claudia Reytor-González, Melannie Toral-Noristz, Yamilia González, Daniel Simancas-Racines.

  Myopathies represent a highly heterogeneous group of primary muscle disorders, traditionally classified based on clinical presentation and histopathological findings. Recent breakthroughs in molecular genetics, immunology, and pathophysiology have revolutionized the understanding, diagnosis, and management of these conditions. Both inherited and acquired forms of myopathy, including structural, metabolic, inflammatory, endocrine, and mitochondrial subtypes, are now recognized to arise from diverse pathogenic mechanisms such as impaired calcium handling, mitochondrial dysfunction, chronic inflammation, altered metabolism, and defective muscle regeneration. The advent of next-generation sequencing technologies has enabled more precise diagnosis of genetic forms, while the discovery of novel molecular biomarkers and immunological signatures offers promising avenues for disease monitoring and stratification across the broader spectrum. Importantly, molecular and mechanistic insights have redefined clinical classifications, allowing for better prognostic predictions and patient-tailored therapeutic approaches. Innovative treatments, including gene therapy, antisense oligonucleotide therapies, immune-modulating agents, metabolic support strategies, and targeted pharmacological interventions, are progressively translating molecular knowledge into clinical applications. However, technical limitations, biological variability, and ethical considerations continue to pose significant challenges to the implementation of precision medicine in myopathies. In this narrative review, we comprehensively discuss the latest molecular findings, their integration into clinical practice, and the emerging therapeutic strategies based on these discoveries. We also highlight current limitations and propose future research directions aimed at bridging the gap between molecular insights and effective, equitable patient care.

Keywords:  molecular genetics; myopathies; next-generation sequencing; precision medicine; therapeutic strategies

DOI:  https://doi.org/10.3390/ijms27031392
Transl Neurodegener. 2026 Feb 13. 15(1): 5

Mitochondrial DNA: a molecular switch driving sterile neuroinflammation.

Abhishek Jauhari, Tanisha Singh, Diane L Carlisle, Robert M Friedlander.

  Mitochondrial DNA (mtDNA) plays a pivotal role in the regulation of neuroinflammation, acting as a potent trigger of innate immune responses when released into the cytoplasm or extracellular space. mtDNA is structurally similar to bacterial DNA, containing unmethylated CpG motifs that are readily recognized by immune sensors. Under conditions of cellular stress, injury, or mitochondrial dysfunction, mtDNA can escape into the cytoplasm, where it activates the cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) signaling pathway, or it can be detected extracellularly by Toll-like receptors on immune cells. These signaling events lead to the production of pro-inflammatory cytokines and type I interferons, amplifying neuroinflammatory responses. In the central nervous system, this process contributes to the pathogenesis of various neurodegenerative and inflammatory conditions, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), etc.. The dual role of mtDNA as both a damage-associated molecular pattern and a signaling molecule underscores its importance as a therapeutic target for modulating neuroinflammation and protecting against progressive neuronal damage. In this review, we will discuss the implications of mtDNA-mediated neuroinflammation in neurodegenerative diseases, including AD, PD, and HD, highlighting its potential as a diagnostic biomarker and therapeutic target.

Keywords:  Mitochondria; Mitochondrial DNA; Neurodegeneration; Neuroinflammation

DOI:  https://doi.org/10.1186/s40035-026-00540-w
Nat Rev Mol Cell Biol. 2026 Feb 13.

Mechanisms and disease relevance of mitochondrial translation in humans.

Ricarda Richter-Dennerlein, Xaquin Castro Dopico, Joanna Rorbach.

Human mitochondrial ribosomes (mitoribosomes) synthesize the 13 mitochondrial-encoded proteins of the oxidative phosphorylation machinery in a coordinated manner, ensuring proper folding of nascent peptides into the inner mitochondrial membrane and their dynamic assembly with nuclear-encoded oxidative phosphorylation components. Our understanding of mitochondrial translation is rapidly advancing, and in this Review, we discuss recent studies that reveal the intricate regulation of mitochondrial translation initiation, elongation and termination, ribosome biogenesis, redox sensing, mitochondrial mRNA maturation, and quality control mechanisms such as mitoribosome rescue. High-resolution structural studies, mitoribosome profiling and other innovative methodologies provide comprehensive insights into these regulatory networks. We also discuss pathological consequences of mitochondrial translation dysfunction, particularly antibiotic-induced ribosome stalling, which can have severe side effects in some individuals and therapeutic benefits in others. Relatedly, we discuss the emerging roles and clinical relevance of mitochondrial protein synthesis in cancer and immunity. Finally, we outline future directions in the field, including in vitro reconstitution of mitochondrial translation, gene editing in mitochondrial DNA and therapeutic applications.

DOI: https://doi.org/10.1038/s41580-026-00948-2
Blood Cancer Discov. 2026 Feb 10. OF1-OF13

Remodeling of Mitochondrial Networks: Cellular Adaptation and Microenvironmental Reprogramming in Hematologic Malignancies.

Yutang Li, Xinting Hu, Xiangxiang Zhou.

Mitochondria regulate critical cellular processes beyond energy production, including organelle quality control, programmed cell death, and intercellular and interorganellar communication. In hematologic malignancies, mitochondria undergo adaptations through mechanisms including genetic mutations, metabolic reprogramming, mitochondrial transfer, fusion, and mitophagy. These alterations create heterogeneity, contribute to therapeutic resistance, and can also reshape the tumor microenvironment to promote progression. Collectively, these findings suggest that mitochondria represent a promising frontier in next-generation therapeutics, with emerging strategies such as mitochondrial-targeted small molecules and mitochondrial transplantation holding significant therapeutic potential.
SIGNIFICANCE: In this review, we summarize the functions of mitochondria beyond energy production and highlight the heterogeneity of mitochondrial functional adaptations in hematologic malignancies, as well as the vital role of mitochondrial alterations in reshaping the tumor microenvironment. Understanding these changes is critical to deciphering the pathophysiology of hematologic malignancies.

DOI: https://doi.org/10.1158/2643-3230.BCD-25-0338
Sci Rep. 2026 Feb 13.

Progression of peripheral blood mononuclear cell mitochondrial function during the early phase of sepsis in intensive care unit patients.

Hanneke P F X Moonen, Rianne Slingerland-Boot, Jelle C B C de Jong, Anaïs M T Y Wiech, Arie G Nieuwenhuizen, Sander Grefte, Arthur R H van Zanten.

  Sepsis is associated with high rates of multiorgan failure and mortality. Altered mitochondrial function is an essential component of the early sepsis syndrome. However, its progression over time in peripheral blood mononuclear cells (PBMCs) is thus far unclear. Our purpose was to investigate this in the early phase of sepsis in ICU patients. A single-centre prospective observational cohort study was conducted in sepsis patients and compared with age- and sex-matched controls. Mitochondrial function was measured in PBMCs thrice during the first ICU week. RT-qPCR was used for semi-quantitative analysis of expression of genes involved in oxidative phosphorylation. Secondary endpoints included associations between mitochondrial function and (I) sepsis severity and (II) clinical outcomes, including 3-month mortality. Basal, ATP-linked, maximal and proton leak associated respiration were increased in sepsis patients (n = 25) compared to matched controls (n = 24) at all time points. This was associated with increased expression of SDBH (complex II) and ATP5F1A (complex V). Increased basal respiration was associated with 3-month mortality (HR 3.794, 95% CI 1.018-14.149, p = 0.047). No differences were observed in other secondary outcomes. PBMC mitochondria were shown to have an increased respiratory rate during the first week of sepsis. Moreover, a progressive increase was negatively associated with 3-month survival.

Keywords:  Critical illness; Immunoparalysis; Metabolism; PBMC; Respiration

DOI:  https://doi.org/10.1038/s41598-026-39202-2
Quant Biol. 2026 Mar;14(1): e70018

Single-cell mitochondrial lineage tracing: Opportunities and challenges.

Siqi Li, Kun Wang, Xin Wang, Zheng Hu.

  Lineage tracing using endogenous mitochondrial DNA (mtDNA) variants holds great promise for reconstructing the lineage histories of individual cells, with broad applications in oncology, developmental biology, and regenerative medicine. Unlike synthetic DNA barcoding techniques, mitochondrial lineage tracing does not require genetic engineering of exogenous genetic markers, and thus is particularly suitable for human clinical samples. Various experimental and computational methods have been developed to profile mtDNA variants from single-cell genomic, transcriptomic, and epigenomic sequencing data. Despite the technical advances, several challenges still limit the robustness of single-cell mitochondrial lineage tracing, such as random genetic drift, genetic bottlenecks, informative variant identification, and low mtDNA coverage. In this review, we systematically examine current experimental and computational approaches for analyzing mtDNA variants in single cells and discuss current challenges and future technical developments aimed at enhancing the robustness and applicability of single-cell mitochondrial lineage tracing.

Keywords:  lineage tracing; mtDNA variants; phylogenetic reconstruction; single‐cell genomics

DOI:  https://doi.org/10.1002/qub2.70018
Orphanet J Rare Dis. 2026 Feb 12.

Myopathy and ataxia related to impaired mitochondrial function in mevalonate kinase deficiency.

Alessia Pugliese, Christina von Landenberg, Romina Gallizzi, Alba Migliorato, Sabata Pierno, Carmelo Rodolico, Cornelia Kornblum, Ignazio Giuseppe Arena, Wolfram S Kunz, Jens Reimann, Antonio Toscano, Olimpia Musumeci.



Keywords:  Ataxia; Coenzyme Q10; Metabolic myopathy; Mevalonate kinase deficiency; Mevalonic aciduria; Mitochondrial dysfunction; hyperCKemia

DOI:  https://doi.org/10.1186/s13023-026-04248-y
Front Immunol. 2025 ;16 1712741

GDF15 orchestrates mitochondrial-immune crosstalk via SMAD7-HIF-1α-PKM2 cascade to attenuate septic liver injury.

Xiandong Kuang, Zhili Niu, Wenqiang Liu, Zhaoyang Huang, Shuo Li, Ye Zhang, Li Wang, Xin Cai, Faxi Wang, Pingan Zhang.

   Background: Sepsis-induced multi-organ failure involves pathological crosstalk between mitochondrial dysfunction and hyperinflammation, yet endogenous protective mechanisms remain incompletely defined. This study investigates Growth Differentiation Factor 15 (GDF15) as a potential regulator of sepsis tolerance.
Methods: Using LPS-challenged mouse endotoxemia and a murine macrophage (RAW264.7) cell line model, we assessed GDF15's functional role through: (1) recombinant Adeno-Associated Virus serotype 8 (rAAV8)-mediated tissue-specific overexpression, (2) siRNA knockdown, (3) pharmacological modulation (BAY 87-2243/Hypoxia-Inducible Factor 1-alpha (HIF-1α) inhibitor, Shikonin/PKM2 inhibitor, Asiaticoside/SMAD7 activator), and (4) comprehensive metabolic-inflammatory phenotyping including mitochondrial complex integrity (assessed via UQCRC1, Ubiquinol-Cytochrome c Reductase Core Protein 1), cytokine dynamics (TNF-α, IL-6) and lactate metabolism.
Results: LPS challenge induced time-dependent mitochondrial dysfunction concurrent with cytokine storms and compensatory GDF15 upregulation in both liver and macrophages. Hepatocyte-specific GDF15 overexpression attenuated injury through restored mitochondrial integrity, diminished macrophage infiltration, and reduced systemic inflammation, as evidenced by significantly lower levels of circulating TNF-α and IL-6. Mechanistically, GDF15 preserved mitochondrial homeostasis by inducing SMAD7 expression while suppressing HIF-1α accumulation and PKM2 nuclear translocation. Pharmacological HIF-1α/PKM2 inhibition recapitulated GDF15's protective effects, restoring mitochondrial function and reducing inflammation even in GDF15-deficient models. Clinical analysis of a sepsis patient cohort (n=119) confirmed a significant elevation of circulating GDF15, with its levels strongly correlating with disease severity scores. Critically, SMAD7 activation attenuated HIF-1α accumulation and rescued mitochondrial failure independently of GDF15 status.
Conclusion: GDF15 orchestrates sepsis tolerance through the SMAD7-HIF-1α axis, preserving mitochondrial integrity while resolving metabolic-inflammatory dysregulation, notably by suppressing the release of pro-inflammatory cytokines such as TNF-α and IL-6. This study identifies GDF15 as a central guardian of mitochondrial-immune homeostasis in sepsis, positioning it as both a robust severity biomarker and a promising therapeutic target for mitochondrial resuscitation.

Keywords:  GDF15; SMAD7-HIF-1 α axis; metabolic-inflammatory dysregulation; mitochondrial dysfunction; mitochondrial resuscitation; sepsis

DOI:  https://doi.org/10.3389/fimmu.2025.1712741
J Neurol. 2026 Feb 14. 273(2): 143

Oculomotor abnormalities in patients with cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) reflect midline cerebellar impairment.

Renana Storm, Bente Lübbers, Max Borsche, Emmelie Weiss, Astrid Nümann, Christos Ganos, Norbert Brüggemann, Christoph Helmchen, Andreas Sprenger.

   BACKGROUND: Biallelic intronic repeat expansions in the RFC1 gene are associated with the cerebellar ataxia, neuropathy, and vestibular areflexia (bilateral vestibulopathy) syndrome (CANVAS). Oculomotor abnormalities may serve as a state marker exclusively reflecting the midline cerebellar involvement in CANVAS, i.e., independent of the combined disorders affecting the patient's postural control stance and gait.
METHODS: Slow and fast eye movements of 15 CANVAS patients and 14 healthy subjects were compared using a high-resolution video-based eye tracker allowing to record visually-guided saccades, gaze-holding function and smooth pursuit paradigms. Scores of cognitive impairment were related to oculomotor performance.
RESULTS: Saccades (latency, metria, velocity) were normal. Small amplitude omnidirectional gaze-holding deficit was found in 70% of patients, with downbeat nystagmus (60%) being more common than upbeat nystagmus (13%). Latency of initial acceleration of smooth pursuit was prolonged and there was severe impairment of smooth pursuit eye movements. Montreal Cognitive Assessment (MoCA) scores were lower in patients and correlated with saccade and pursuit latency and initial acceleration. Disease duration and vestibulopathy correlated with no oculomotor abnormalities.
CONCLUSION: Cerebellar oculomotor dysfunction affected mainly smooth pursuit and gaze holding function at eccentric gaze positions, but it did neither comprise spontaneous nystagmus nor saccade abnormalities. Prolonged latencies in initial pursuit acceleration might be related to the patient's cognitive decline, but normal saccade latencies point to cerebellar oculomotor neurodegeneration. Smooth pursuit impairment was not related to disease duration and vestibulopathy, contrariwise pursuit impairment became worse with larger functional impairment. Oculomotor abnormalities in CANVAS are in line with midline cerebellar impairment without evidence for extracerebellar (brainstem) brain involvement.

Keywords:   RFC1 ; CANVAS; Nystagmus; Oculomotor; Saccades

DOI:  https://doi.org/10.1007/s00415-026-13678-4
Int J Pharm X. 2026 Jun;11 100494

Mitochondria-targeted delivery strategies for age-related diseases.

Zefan Liu, Pei Yang, Guilin Cheng, Xin Kang, Lian Li, Yucheng Xiang.

  Aging is a complex progress accompanied with the progressive deterioration of physiological functions and a marked elevation in mortality risk. Among prominent aging theories, the free radical theory and the mitochondrial dysfunction hypothesis have gained significant attention. Thus, targeted delivery of therapeutic drug to mitochondria might be able to alleviate the mitochondrial dysfunction induced by reactive oxygen species. This review summarizes the possible molecular mechanisms between mitochondrial dysfunction and aging progression. Especially, the recent breakthroughs of mitochondrial-targeted delivery platforms for therapeutics against aging progress. Innovative strategies, including small molecular modification, mitochondrial targeting functional peptide guided delivery and some other strategies are discussed. Their translational potential in anti-aging interventions is evaluated. We anticipate that mitochondria-targeted anti-aging therapeutics will soon enter clinical translation, offering potential solutions to address current age-related challenges.

Keywords:  Age-Related Diseases; Mitochondrial Dysfunction; Mitochondrial-Targeted Delivery

DOI:  https://doi.org/10.1016/j.ijpx.2026.100494
Exp Gerontol. 2026 Feb 09. pii: S0531-5565(26)00040-9. [Epub ahead of print] 113062

Iron dysregulation and mitochondrial dysfunction in aging: A longitudinal study on mobility decline in low- and high-functioning older adults.

Nevena Stanojevic, Stephanie Wohlgemuth, Rola S Zeidan, XiangYang Lou, Javier A Tamargo, Bella Bravo, Jennifer Newman, Anna Picca, Emanuele Marzetti, Kevin Wu, Christian McLaren, Robert Mankowski, Bhanuprasad Sandesara, Aditya Shirali, Todd Manini, Christiaan Leeuwenburgh, Stephen Anton.

   BACKGROUND: Mobility loss in older adults reduces quality of life and increases risks of falls, hospitalizations, and mortality. Low-functioning (LF) older adults experience faster mobility decline than their high-functioning (HF) peers, but the underlying biological mechanisms remain unclear. Although iron accumulation in aging muscle mitochondria has recently been linked to lower physical function, its longitudinal impact on physical function remains understudied.
METHODS: Muscle Iron Flow is a prospective, observational study which enrolled LF and HF older adults (N = 114; age 75.8 ± 3.2 years, 64.9% female) to examine links between iron dysregulation, mitochondrial function, and physical performance. Assessments include blood biomarkers, physical function tests, and behavioral measures (diet, activity, sleep, medication use), collected at baseline and annually, and muscle biopsies obtained at baseline and year three. This manuscript reports baseline characteristics and measurement procedures only; longitudinal portion is ongoing.
RESULTS: At baseline, HF older adults demonstrated significantly better physical performance than LF adults across all functional tests, including Short Physical Performance Battery (SPPB), 6-minute walk distance, handgrip strength, and knee extensor torque (ps < 0.05). LF participants also had lower hemoglobin levels and higher red cell distribution width (RDW; ps < 0.05).
DISCUSSION: This study is among the first to investigate how biomarkers of iron dysregulation, mitochondrial function, and related ferroptosis and senescence pathways may contribute to changes in physical function in LF and HF older adults. By integrating molecular and functional assessments, the study will inform how disrupted iron handling and mitochondrial health influence mobility trajectories in aging populations.

Keywords:  Aging; Ferritin; Inflammation; Mitochondrial dysfunction; Muscle strength; Physical function; iron regulation

DOI:  https://doi.org/10.1016/j.exger.2026.113062