bims-musmir 2026-04-26 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–04–26
sixteen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Vitamin B12 improves skeletal muscle mitochondrial biology in aged mice.
Separating food intake-dependent and -independent effects in cancer cachexia.
A skeletal muscle atlas shows neuromuscular junction adaptations to growth and atrophy.
Lysophosphatidic acid mediates skeletal muscle fibrosis in denervation via activation of YAP/TAZ.
Cancer IDO1-Mediated Tryptophan-Kynurenine Metabolic Reprogramming to Drive Skeletal Muscle Atrophy and Cachexia Acceleration.
Evaluating skeletal muscle dysfunction and recovery in a zymosan model of critical illness in mice.
The unfolded protein response and its activation by insulin in muscle are not altered by obesity or type 2 diabetes.
Depletion of TECPR2 leads to mitochondrial failure associated with neurodegeneration.
Integrated miRNA-mRNA Analysis Reveals Obesity-Driven Regulatory Networks in Human Visceral Adipose Tissue With and Without Type 2 Diabetes.
10-Gingerol induces ferroptosis via TFEB-mediated NRF2 lysosomal degradation in NSCLC.
Exosomes secreted by ADMSCs preserve cartilage integrity in knee osteoarthritis via AMPK-mediated mitochondrial dynamics and apoptosis.
MITOCHONDRIAL METABOLISM AS A DETERMINANT OF HETEROGENEOUS PLATELET FUNCTIONAL PHENOTYPES: IMPLICATIONS FOR ANTIPLATELET RESISTANCE.
Subcellular mRNA localization patterns across tissues resolved with spatial transcriptomics.
miR-329-3p derived from mast cells-exosomes exacerbates intestinal ischemia-reperfusion injury by targeting ATG10 to regulate autophagy.
Glutamine metabolic stress induces SLC25A6-dependent mitofission via MIC60-MIC19 complex disassembly in colorectal cancer.
Lysosomal accumulation of Masitinib alters autophagy via pH-dependent trapping.

Geroscience. 2026 Apr 24.

Vitamin B12 improves skeletal muscle mitochondrial biology in aged mice.

Abigail R Williamson, Angad Yadav, Wenxia Ma, Susan Schmitt, Shelby Rorrer, Lauren E Odom, Luisa F Castillo, Chloe T Purello, Olga V Malysheva, James Mobley, Martha Field, Anna E Thalacker-Mercer.

  Age-related skeletal muscle deterioration is a commonly reported disability among older adults, attributed to several factors including mitochondrial dysfunction, a major hallmark of aging. Therapies to attenuate or reverse mitochondrial decline are limited. Despite identified positive relationships between vitamin B12 (B12) and mitochondrial biology, the impact of B12 supplementation on skeletal muscle mitochondria, in advanced age, has not been examined. Thus, the impact of B12 supplementation on skeletal muscle mitochondrial biology was examined in aged female mice, given 12 weeks of B12 supplementation (SUPP) or vehicle control. In the mouse model, mitochondrial DNA and content were measured with PCR and citrate synthase activity, respectively; mitochondrial morphology was examined using transmission electron microscopy; mitochondrial function was examined using extracellular metabolic flux analysis; and proteins and pathway enrichment was identified with proteomics. The results demonstrated that SUPP in aged mice increased muscle mitochondrial content and improved morphology. Further, differentially expressed proteins were enriched in TCA cycle, OXPHOS, and oxidative stress pathways. This is the first study, to our knowledge, examining the impact of B12 supplementation on skeletal muscle mitochondrial biology in aged female mice. Results suggest that B12 supplementation improves mitochondrial biology in aged female mice.

Keywords:  Aging; Mitochondria; Sarcopenia; Skeletal muscle; Vitamin B12

DOI:  https://doi.org/10.1007/s11357-026-02264-1
iScience. 2026 May 15. 29(5): 115525

Separating food intake-dependent and -independent effects in cancer cachexia.

Yanshan Liang, Young-Yon Kwon, Sheng Hui.

  Cancer cachexia is characterized by involuntary weight loss and wasting of fat and muscle, with diminished food intake commonly cited as a cause. However, the extent to which reduced food intake drives these symptoms, and other phenotypes such as physical weakness, remains unclear. Using the colon carcinoma 26 (C26) mouse model, we assessed the role of food intake in key cachexia phenotypes. We found that reduced food intake was the predominant driver of body weight loss and tissue wasting, suggesting no additional causal mechanisms. In contrast, food intake reduction did not affect physical performance, indicating food intake-independent factors in causing weakness. Thus, depending on the model or patient group, reduced food intake may primarily drive some cachectic phenotypes while having no role in others. Discriminating between food intake-mediated effects and those independent of it is critical for guiding research focus and unraveling the causal pathways of cancer cachexia.

Keywords:  Cancer; Nutrition; Physiology

DOI:  https://doi.org/10.1016/j.isci.2026.115525
Dev Cell. 2026 Apr 21. pii: S1534-5807(26)00122-X. [Epub ahead of print]

A skeletal muscle atlas shows neuromuscular junction adaptations to growth and atrophy.

Silvia Campanario, Mercedes Grima-Terrén, Megan Rommelfanger, Stefania Dell' Orso, Xuesong Feng, Andrés Cisneros, Ignacio Ramírez-Pardo, Aina Calls-Cobos, Benjamin A Yang, Kyung Dae Ko, Esther García-Domínguez, Laura Pena-Couso, Grace Chou, Yuewen Zheng, Nasun Hah, Davide Randazzo, Alberto Pérez-Garcia, Tovah E Markowitz, Jose Milisenda, Iago Pinal-Fernandez, Andrew Mammen, Mari Carmen Gómez-Cabrera, Antonio L Serrano, Eusebio Perdiguero, Vittorio Sartorelli, Joan Isern, Pura Muñoz-Cánoves.

  The molecular basis underlying muscle atrophy, as it occurs during disuse or aging, and activity-induced hypertrophy remain poorly understood. A major challenge has been defining the diverse cellular and niche environments within skeletal muscle, which is mostly composed of multinucleated myofibers. Here, we present a single-nucleus and single-cell transcriptomic atlas, coupled with spatial profiling, of mouse limb skeletal muscle under resting conditions and during experimentally induced atrophy or hypertrophy. We identify condition-dependent shifts in muscle-resident cell populations and fiber-type-specific transcriptional responses. We also uncover extensive remodeling of the neuromuscular junction (NMJ), including the emergence of specialized synaptic myonuclei (SynM) and terminal Schwann cells (tSCs) associated with atrophic or hypertrophic states. High-resolution 3D imaging and spatial transcriptomics confirm these changes at the tissue level. Similar NMJ alterations are observed in denervated and exercised human muscle, supporting the translational relevance of this atlas for studying muscle plasticity and identifying therapeutic targets in muscle-related diseases.

Keywords:  Schwann cell; atrophy; cell atlas; hypertrophy; neuromuscular junction; skeletal muscle

DOI:  https://doi.org/10.1016/j.devcel.2026.03.010
JCI Insight. 2026 Apr 22. pii: e198388. [Epub ahead of print]11(8):

Lysophosphatidic acid mediates skeletal muscle fibrosis in denervation via activation of YAP/TAZ.

Meilyn Cruz-Soca, Adriana Córdova-Casanova, Jennifer Faundez-Contreras, Nicolás W Martínez, Francesca Vaccaro-Rivera, Sebastián Bazaes-Astorga, Cristian Gutiérrez-Rojas, Felipe S Gallardo, Daniela L Rebolledo, Felipe A Court, Jerold Chun, Carlos P Vio, Soledad Matus, Juan Carlos Casar, Enrique Brandan.

  Lysophosphatidic acid (LPA) is a bioactive lipid that signals through G protein-coupled receptors (LPA1-6) and regulates multiple cellular processes, including fibrosis. Although LPA signaling has been implicated in fibrotic diseases in several organs, its role in skeletal muscle remains unclear. Here, we show that LPA/LPA1 signaling promotes fibrogenesis after sciatic nerve transection. Denervation induces differential expression of LPA signaling axis components and a transient early increase in intramuscular LPA levels. Pharmacological inhibition of LPA1/3 with Ki16425, or genetic deletion of LPA1, reduces extracellular matrix accumulation and expansion of fibro/adipogenic progenitors (FAPs) in denervated muscle. Although LPA blockade suppresses atrophy-related gene expression, it does not fully preserve myofiber size. Mechanistically, denervation increases YAP/TAZ expression, nuclear localization in FAPs, and transcriptional activity, effects that are attenuated by LPA axis inhibition. Furthermore, pharmacological inhibition of YAP/TAZ with verteporfin reduces fibrosis after denervation, supporting their role as critical downstream mediators. Finally, transient denervation activates the LPA axis, promotes muscle fibrosis, reduces axonal density in the sciatic nerve, and increases neuromuscular junction instability, effects reversed by Ki16425. Together, these findings identify the LPA/LPA1/YAP/TAZ pathway as a key driver of denervation-induced muscle fibrosis and a potential therapeutic target in neuromuscular disorders.

Keywords:  Cell biology; Fibrosis; Muscle biology; Signal transduction; Skeletal muscle

DOI:  https://doi.org/10.1172/jci.insight.198388
J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70295

Cancer IDO1-Mediated Tryptophan-Kynurenine Metabolic Reprogramming to Drive Skeletal Muscle Atrophy and Cachexia Acceleration.

Leng Han, Lingjie Jing, Xinting Zhu, Ciqin Li, Lu Bai, Yang Fang, Yuxuan Zhou, Dingyuan Bai, Jin Lu, Yonglong Han, Cheng Guo, Shumin Zhou, Quanjun Yang.

   BACKGROUND: Cancer cachexia is a debilitating syndrome characterized by severe skeletal muscle wasting, which significantly impairs patient quality of life and survival. Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in tryptophan (Trp) metabolism, is often upregulated in cancers, but its specific role in driving lung cancer-associated cachexia remains inadequately defined. This study investigated the mechanistic role of Ido1 in cancer cachexia and evaluated the therapeutic potential of its inhibition.
METHODS: We established Lewis lung carcinoma (LLC) models in C57BL/6 mice using wild-type, Ido1-overexpressing (Ido1-OE) and Ido1-knockout (Ido1-KO) cells. Muscle mass, tumour growth and metabolic changes were assessed in vivo. Transcriptomic and targeted metabolomic analyses were performed on muscle and serum samples. In vitro, we examined the effects of tumour-conditioned media, the Trp metabolite kynurenine (Kyn) and Trp supplementation on C2C12 myotube atrophy. In vivo experiments verified the efficacy of the Ido1 inhibitor palmatine hydrochloride (PAL). Molecular pathways were analysed via western blot and qPCR.
RESULTS: Compared to LLC mouse models, Ido1-OE significantly exacerbated tumour growth and cachexia, leading to a significant decrease in lean body weight, gastrocnemius and tibialis anterior muscle weights (p < 0.01, p < 0.0001, p < 0.001). Gastrocnemius muscle fibre cross-sectional area significantly decreased in the Ido1-OE group (p < 0.0001). Transcriptomic analysis revealed that Ido1-OE activated pro-inflammatory and protein degradation pathways (upregulating MuRF1/Atrogin1, p < 0.05) while suppressing anabolic signalling pathways (oestrogen pathways, p < 0.01). Metabolomics analysis revealed unique metabolic signatures in Ido1-OE mice: Trp depletion and Kyn accumulation. In vitro experiments demonstrated that Ido1-OE enhanced LLC cell proliferation and migration capabilities (p < 0.0001, p < 0.0001). Tumour-conditioned medium (TCM) derived from Ido1-OE tumours significantly induced C2C12 myotube atrophy (p < 0.01). Similarly, direct treatment with Kyn led to dose-dependent muscle fibre shrinkage, with significant atrophy observed at 30 μM (p < 0.01) and 100 μM (p < 0.0001). Notably, the myotube atrophy induced by Kyn was significantly reversed by the addition of supplemental Trp (p < 0.0001). Compared with the Ido1-OE group, PAL treatment reduced gastrocnemius and tibialis anterior atrophy (p < 0.01; p < 0.05). Mechanistically, PAL inhibited the mRNA expression levels of MuRF1/Atrogin1 (p < 0.0001, p < 0.001), as well as their corresponding protein levels (p < 0.0001, p < 0.0001). Furthermore, PAL restored the phosphorylation level of mTOR (p < 0.001), as well as the mRNA expression of myosin heavy chain (p < 0.01).
CONCLUSIONS: Our findings demonstrate that Ido1 accelerates muscle atrophy and cancer cachexia by driving a metabolic reprogramming centred on the Trp-Kyn pathway. Pharmacological inhibition of Ido1 with PAL effectively mitigates these effects, positioning Ido1 as a promising therapeutic target for treating cancer cachexia.

Keywords:  cancer cachexia; indoleamine 2,3‐dioxygenase 1; kynurenine; metabolic reprogramming; muscle atrophy; tryptophan

DOI:  https://doi.org/10.1002/jcsm.70295
Dis Model Mech. 2026 Apr 24. pii: dmm.052712. [Epub ahead of print]

Evaluating skeletal muscle dysfunction and recovery in a zymosan model of critical illness in mice.

Amy J Bongetti, Annabel Chee, John H V Nguyen, Jin D Chung, Wenlan Li, Kristy Swiderski, Yasmine Ali Abdelhamid, Olav E Rooyackers, Marissa K Caldow, Gordon S Lynch.

  Muscle wasting and weakness are common complications associated with critical illness and admission to the Intensive Care Unit (ICU), that contribute to increased mortality and health deficits post-discharge. The mechanisms underlying ICU-acquired muscle weakness (ICU-AW) are incompletely understood and small animal models can help address this shortfall and provide experimental platforms for devising therapeutic strategies. We used a zymosan model to induce wasting, and weakness in C57BL/6J mice and evaluated recovery of hindlimb muscles and diaphragm at 4, 7, 14, and 28 days (D) after induction of critical illness, through extensive physiological and immunohistological analyses. Tibialis anterior (TA) muscles from zymosan treated mice exhibited atrophy and functional impairment at D4 and D7 with recovery at D14. In contrast, the DIA exhibited a delay in wasting and recovery from critical illness, with muscle fibre atrophy at D28 despite inflammatory cell infiltration from D4 and transient impairments in respiratory function. The zymosan mouse model provides important insights into mechanisms underlying the recovery from wasting and weakness after critical illness to better understand and treat ICU-AW.

Keywords:  Animal models; Critical illness; Inflammation; Intensive care; Muscle wasting; Muscle weakness; Sepsis; Skeletal muscle

DOI:  https://doi.org/10.1242/dmm.052712
Clin Sci (Lond). 2026 Apr 22. pii: CS20250639. [Epub ahead of print]

The unfolded protein response and its activation by insulin in muscle are not altered by obesity or type 2 diabetes.

Rikke Kruse, Jonas Møller Kristensen, Birgitte Falbe Vind, Stine Juhl, Jacob Volmer Stidsen, Rugivan Sabaratnam, Kurt Højlund.

  Insulin resistance in obesity and type 2 diabetes (T2D) is characterized by reduced insulin-stimulated glucose uptake, accumulation of triacylglycerol, mitochondrial dysfunction, and altered protein metabolism in skeletal muscle. This may involve disturbed endoplasmic reticulum (ER) homeostasis, leading to alterations in the unfolded protein response (UPR), and hence the protein folding capacity. Here, we investigated if markers of UPR activity are elevated in skeletal muscle in obesity and T2D, and to what extent insulin regulates these UPR markers. In a case-control design, we determined mRNA expression, protein abundance, and phosphorylation of key UPR markers in skeletal muscle biopsies obtained from patients with T2D, matched to glucose-tolerant individuals with obesity and lean individuals, before and after 4-h insulin infusion during a hyperinsulinemic-euglycemic clamp. The mRNA expression or protein abundance of GRP78, the canonical ER stress sensors (ATF6, PERK, and IRE-1α), several downstream UPR markers, and related markers of mitochondrial dynamics did not differ between groups. Insulin increased the mRNA expression of ATF6, ERN1 (encoding IRE-1α), XBP1, DDIT3 (encoding CHOP), and a marker of mitochondrial fission DNM1l (encoding DRP1), as well as eIF2α Ser51 phosphorylation in skeletal muscle in all groups (all p<0.05), with no between-group differences. Our results demonstrate that markers of UPR activity are not elevated in skeletal muscle in obesity or T2D. Interestingly, insulin increases the expression of UPR markers and activates eIF2α, which is necessary for increasing the protein folding capacity of ER in muscle, and these responses are intact in obesity and T2D.

Keywords:  ER stress; Insulin; Obesity; Skeletal muscle; Unfolded protein response; type 2 diabetes

DOI:  https://doi.org/10.1042/CS20250639
Autophagy. 2026 Apr 23. 1-15

Depletion of TECPR2 leads to mitochondrial failure associated with neurodegeneration.

Madhuri Chaurasia, Milana Fraiberg, Nemanja Subic, Oren Shatz, Kamilya Kokabi, Olee Gogoi, Olena Trofimyuk, Bat Chen Tamim-Yecheskel, Saskia Freud, Alik Demishtein, Ekaterina Kopitman, Inna Goliand, Sabita Chourasia, Yoav Peleg, Elena Ainbinder, Nili Dezorella, Zvulun Elazar.

  HSAN9 is a rare progressive neurodegenerative disease in children linked to bi-allelic loss-of-function mutations in the TECPR2 gene. TECPR2 is a multi-domain protein harboring N-terminal WD repeats and C-terminal TECPR repeats, followed by a functional LIR motif that serves in phagophore targeting. Here, we demonstrate that the absence of TECPR2 results in impaired mitophagy, which can be restored by expressing its C-terminal domain. Accordingly, we uncover severe mitochondrial dysfunction and accumulation of mitochondrial content in primary fibroblasts derived from an HSAN9 patient, as well as in embryonic fibroblasts and dorsal root ganglia derived from an HSAN9 mouse model. Notably, these mitochondrial defects are mediated by mitochondrial stress through the activation of the integrated stress response (ISR), whereas mitochondrial function is restored by pharmaceutical or genetic suppression of ISR. Our findings establish a new connection between mitophagy and ISR in maintaining mitochondrial homeostasis during neurodegeneration.Abbreviations: Baf. A1: bafilomycin A1; CYCS: cytochrome c, somatic; HSAN9: hereditary sensory and autonomic neuropathy IX; ISR: integrated stress response; OA: oligomycin + antimycin A; ROS: reactive oxygen species; TECPR2: tectonin beta-propeller repeat containing 2.

Keywords:  HSAN9; TECPR2; integrated stress response; mitophagy; neurodegeneration; unfolded protein response

DOI:  https://doi.org/10.1080/15548627.2026.2660850
Diabetes Obes Metab. 2026 Apr 23.

Integrated miRNA-mRNA Analysis Reveals Obesity-Driven Regulatory Networks in Human Visceral Adipose Tissue With and Without Type 2 Diabetes.

Elsa Villa-Fernández, Ana Victoria García, Laura Gallardo-Nuell, Miguel García-Villarino, Judit Fernández-García, Aldara Martin Alonso, Claudia Lozano-Aida, Lorena Suárez Gutiérrez, Pedro Pujante, Jessica Ares, Tomás González-Vidal, Raquel Rodríguez Uría, Sandra Sanz Navarro, María Moreno Gijón, Lourdes María Sanz Álvarez, Estrella Olga Turienzo Santos, José Manuel Fernández-Real, Mario Fernández Fraga, Elías Delgado, Carmen Lambert.

   AIMS: Obesity is characterised by pathological alterations in visceral white adipose tissue (vWAT) that may contribute to the development of type 2 diabetes (T2D). While microRNAs (miRNAs) are key post-transcriptional regulators, comprehensive human vWAT profiling across metabolic states remains limited. This study characterised vWAT miRNA expression in lean, obese and obese+T2D individuals to identify obesity-driven regulatory networks associated with metabolic dysfunction.
METHODS: Deep miRNA sequencing was performed on vWAT samples from a discovery cohort comprising lean controls and individuals with obesity (with and without T2D). Findings were validated via RT-qPCR in an independent replication cohort. Differentially expressed miRNAs were bioinformatically integrated with matched mRNA transcriptomic data to construct putative functional regulatory associations and identify enriched pathways underlying metabolic impairment.
RESULTS: The dominant transcriptomic signal was driven by obesity rather than T2D status, with substantial overlap between obese subgroups in principal component analyses. miR-141-3p, miR-200b-3p, miR-12 136 and miR-585-3p showed consistent differential expression associated with obesity. miR-141-3p and miR-200b-3p were upregulated and inversely associated with metabolic stress-related genes, including TF and FBXO32. Integrated miRNA-mRNA analyses revealed putative regulatory associations involving inflammation, lipid metabolism, insulin signalling and iron homeostasis. These associations were robust across progressive covariate adjustment models for age and sex.
CONCLUSIONS: This study provides a comprehensive characterisation of the vWAT miRNA landscape predominantly shaped by obesity, with T2D contributing comparatively subtle additional variation. We identified putative miRNA-mRNA regulatory associations that may contribute to pathological adipose tissue dysfunction. These findings highlight candidate molecular regulators worthy of further functional investigation in the context of obesity and T2D.

Keywords:  gene regulatory networks; metabolic dysfunction; miRNAs; obesity; type 2 diabetes; visceral adipose tissue

DOI:  https://doi.org/10.1111/dom.70787
Toxicol Appl Pharmacol. 2026 Apr 19. pii: S0041-008X(26)00124-9. [Epub ahead of print]511 117828

10-Gingerol induces ferroptosis via TFEB-mediated NRF2 lysosomal degradation in NSCLC.

Siying Li, Kaihua Shi, Lei Huang, Ziqing Li, Zhuo Qin, Yanan Sun, Caifang Qin, Chunmei Wang, He Li, Jinghui Sun, Wei Liu, Jiping Wu, Zhihong Zhang.

  10-Gingerol (10-G) exhibits antitumor activity, yet its mechanism in non-small cell lung cancer (NSCLC) remains unclear. Ferroptosis, a mode of programmed cell death resulting from lipid peroxidation, is regulated by abnormalities in the antioxidant system and iron metabolism. This study investigated the antitumor mechanism of 10-G in NSCLC, emphasizing its dual role in activating lysosomes and inducing ferroptosis. In this study, we found 10-G induced ferroptosis in NSCLC by increasing iron accumulation, lipid peroxidation, intracellular ROS levels, and malondialdehyde (MDA) production, while depleting glutathione (GSH) and rising Fe2+ levels. Mechanistically, 10-G induced the dephosphorylation of Transcription Factor EB (TFEB) and TFEB dissociation from the 14-3-3 protein, thereby promoting the nuclear translocation of TFEB and the activation of lysosomal gene expression. Subsequently, the activation of lysosomes promoted the degradation of Nuclear factor erythroid 2-related factor 2 (NRF2), thereby affecting the expression levels of downstream targets Glutathione Peroxidase 4 (GPX4) and cystine/glutamate antiporter SLC7A11 (xCT), ultimately leading to ferroptosis. In vivo, 10-G suppressed tumor growth by inhibiting the TFEB-mediated NRF2/xCT/GPX4 axis and promoting ferroptosis. These findings demonstrated that 10-G suppressed the progression of NSCLC by promoting TFEB-mediated lysosomal degradation of NRF2, thereby inducing ferroptosis, which provides a rationale for a novel potential therapeutic strategy.

Keywords:  10-Gingerol; Ferroptosis; NRF2; NSCLC; TFEB

DOI:  https://doi.org/10.1016/j.taap.2026.117828
Stem Cells. 2026 Apr 22. pii: sxag021. [Epub ahead of print]

Exosomes secreted by ADMSCs preserve cartilage integrity in knee osteoarthritis via AMPK-mediated mitochondrial dynamics and apoptosis.

Jinliang He, Yang Liu, Lu Zhang, Nan Nan, Te Ba, Yanfang Gao, Junfeng Kang, Huiqin Hao.

  Adipose-derived mesenchymal stem cell (ADMSC) exosomes have emerged as promising therapeutic agents for degenerative joint diseases, yet their molecular actions in knee osteoarthritis (KOA) remain inadequately defined. In this study, exosomes were isolated from ADMSCs under both physiological and IL-1β-induced inflammatory conditions and comprehensively characterized by NTA, TEM, and exosome marker expression. Both types of exosomes were efficiently internalized by chondrocytes, with uptake reaching saturation after 12 hours regardless of inflammatory status. Functional assays revealed that while exosomes from healthy ADMSCs (EXOs) significantly enhanced levels of mitochondrial fusion proteins and decreased fission marker in IL-1β-induced chondrocytes after 24 hours, these beneficial effects were absent in exosomes derived from inflamed ADMSCs (IL-1β EXOs). Notably, EXO treatment reduced intracellular ROS accumulation, boosted SOD2 levels, and diminished apoptotic cell rates in chondrocytes. In vivo, administration of EXOs to rats with ACLT-induced KOA markedly alleviated cartilage degeneration, restoration of mitochondrial dynamics, and suppression of inflammatory and matrix-degrading mediators. Transcriptomic analysis showed that EXOs activated gene expression programs related to fatty acid metabolism, oxidative phosphorylation, and AMPK signaling, while IL-1β EXOs enriched inflammatory and apoptotic pathways. Importantly, both genetic knockdown and pharmacological inhibition of AMPK abolished the restorative effects of EXOs on mitochondrial dynamics and on the reduction of apoptotic markers both ex vivo and in vivo. These findings demonstrate that exosomes secreted by ADMSCs preserve cartilage integrity in KOA via AMPK-mediated mitochondrial dynamics. This work supports AMPK-targeted modulation of mitochondrial dynamics by stem cell exosomes as a promising disease-modifying strategy for KOA.

Keywords:  AMPK; DRP; MFN; OPA; adipose-derived mesenchymal stem cells; exosomes; knee osteoarthritis; mitochondrial dynamics

DOI:  https://doi.org/10.1093/stmcls/sxag021
Free Radic Biol Med. 2026 Apr 22. pii: S0891-5849(26)00445-4. [Epub ahead of print]

MITOCHONDRIAL METABOLISM AS A DETERMINANT OF HETEROGENEOUS PLATELET FUNCTIONAL PHENOTYPES: IMPLICATIONS FOR ANTIPLATELET RESISTANCE.

Camila Velandia Franco, Ramiro Araya-Maturana, Eduardo Fuentes.

  Platelets are increasingly recognized as a heterogeneous circulating cell population whose functional behavior cannot be fully explained by receptor-agonist signaling alone; instead, their bioenergetic state emerges as a molecular determinant that shapes both physiological hemostasis and disease-associated hyperreactivity. This review synthesizes evidence supporting energetic specialization in platelets, where glycolytic ATP predominantly supports rapid responses such as shape changes and aggregation; mitochondrial oxidative phosphorylation (OXPHOS) instead is critical for high-demand functions, particularly sustained granule secretion and thrombus amplification. Building on this framework, we propose that mitochondria act as a molecular "switch" that sets the threshold between an aggregatory phenotype and procoagulant fate, for which mitochondrial membrane potential (ΔΨm) instability and sustained opening of the mitochondrial permeability transition pore (mPTP) drive commitment to a procoagulant crisis. Mitochondrial quality-control pathways, including fission/fusion dynamics and mitophagy, emerge as a key regulator that preserve this threshold; their impairment increases susceptibility to stress and predisposes platelets to pathological activation. In cardiometabolic disorders (e.g., type 2 diabetes and obesity), mitochondrial remodeling, oxidative stress, and a shift toward a more glycolytic profile are associated with intrinsically heightened reactivity and pharmacodynamic failure manifesting as high on-treatment platelet reactivity (HTPR), underscoring the need for functional stratification. Collectively, these findings support a bioenergetically informed framework in which mitochondrial function defines platelet functional heterogeneity and contributes to thrombotic risk. Integrating platelet mitochondrial biology into translational research may enable improved risk stratification and the development of precision antithrombotic strategies that preserve essential hemostatic function.

Keywords:  antiplatelet; metabolism; mitochondria; phenotypes; platelet

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.04.145
Nat Commun. 2026 Apr 20.

Subcellular mRNA localization patterns across tissues resolved with spatial transcriptomics.

Roy Novoselsky, Ofra Golani, Tal Barkai, Merav Kedmi, Inna Goliand, Michal Fine, Ilan Kent, Ido Nachmany, Shalev Itzkovitz.

Subcellular RNA localization, including nuclear retention and apical-basal compartmentalization in polarized epithelia plays a central role in post-transcriptional regulation. However, methods for high-throughput mapping of mRNA localization within intact tissue sections remain limited. Here, we apply high-resolution spatial transcriptomics to systematically resolve intracellular mRNA localization across diverse mammalian tissues. We introduce a computational approach that leverages image-derived features to extract subcellular information from spatial data and quantifies transcript localization patterns. Using this framework, we map apical-basal mRNA localization and nuclear retention in gastrointestinal epithelia and in liver hepatocytes. Our analyses reveal conserved and tissue-specific localization signatures. This approach broadens the scope of spatial transcriptomics by enabling routine investigation of intracellular RNA distributions in both healthy and diseased tissues.

DOI: https://doi.org/10.1038/s41467-026-72156-7
Int J Biol Macromol. 2026 Apr 19. pii: S0141-8130(26)02017-9. [Epub ahead of print] 152091

miR-329-3p derived from mast cells-exosomes exacerbates intestinal ischemia-reperfusion injury by targeting ATG10 to regulate autophagy.

Yanqiu Liang, Ruxiang Sheng, Huan Deng, Dingbang Huang, Kexin Xu, Ying Wang, Dezhao Liu.

  Activation and degranulation of intestinal mucosal mast cells (IMMCs) play a critical role in intestinal ischemia-reperfusion (IIR) injury. Exosomes can regulate various physiological and pathological processes by mediating intercellular communication. However, whether activated mast cells modulate IIR injury via exosome secretion remains unclear. In this study, exosomes were isolated from IMMCs of sham-operated and IIR model mice, followed by microRNA (miRNA) high-throughput sequencing to identify significantly altered miRNA, particularly miR-329-3p. First, the impact of oxygen-glucose deprivation/reperfusion (OGD/R)-treated human mast cell (HMC-1)-derived exosomes (OGD/R-HMC-exo) on OGD/R-induced injury in Caco-2 cells was investigated in vitro. Subsequently, the role of miR-329-3p in IIR injury via targeting ATG10 was explored through bioinformatics analysis, cellular experiments, and animal studies. Mechanistic investigations were performed using 5-ethynyl-2-deoxyuridine (EdU) assay, Western blot, reverse transcription quantitative polymerase chain reaction (RT-qPCR), small interfering RNA (siRNA), dual-luciferase reporter assay, and flow cytometry. The research results show that exosomal OGD/R inhibited autophagy, thereby promoting apoptosis and ultimately exacerbating OGD/R injury in Caco-2 cells. After IIR injury, miR-329-3p levels were significantly elevated in exosomes secreted by IMMCs. Upregulation of miR-329-3p downregulated ATG10 expression, suppressed autophagy, impaired autophagic flux, and subsequently aggravated apoptosis, compromised intestinal mucosal barrier integrity, and ultimately exacerbated IIR injury as well as OGD/R injury in Caco-2 cells. These findings provide a novel potential therapeutic target and theoretical basis for the prevention and treatment of IIR injury.

Keywords:  ATG10; Autophagy; Exosomes; Intestinal ischemia-reperfusion injury; Mast cells; miR-329-3p

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152091
Cell Death Dis. 2026 Apr 23.

Glutamine metabolic stress induces SLC25A6-dependent mitofission via MIC60-MIC19 complex disassembly in colorectal cancer.

Yinong Wang, Bingzhi Wang, Yu Liu, Cheng Zhou, Junhu Yuan, Fanyu Zhang, Ling Ma, Yiming Ma, Hongying Wang.

Glutamine addiction is a key metabolic vulnerability in cancer. However, the mechanisms governing the limited efficacy of glutamine metabolism inhibitor (GMI) monotherapy require further investigation. Via single-cell monitoring using a caspase-3 activity indicator, we identified SLC25A6 as a key mediator of GMI-induced apoptosis in colorectal cancer cells. SLC25A6 overexpression enhanced apoptosis both in vitro and in vivo. SLC25A6 promoted mitochondrial fragmentation and dysfunction and upregulated the expression of mitochondrial fission markers. Notably, mitofission inhibitors largely abolished SLC25A6-related mitochondrial dysfunction and intrinsic apoptosis. Mechanistically, SLC25A6 directly interacted with MIC60, competitively inhibiting MIC19 binding; both MIC60 and MIC19 are key components of the mitochondrial contact site and cristae organizing system (MICOS). The SLC25A6 T126A mutant failed to bind MIC60 and lost its ability to destabilize the MICOS complex and facilitate mitofission. Upregulation of SLC25A6 expression induced by the glutaminase inhibitor CB-839 sensitized cancer cells to the Bcl-2 inhibitor ABT-199. Combined CB-839 and ABT-199 treatment showed strong synergistic antitumor effects in colorectal cancer xenograft models. Our findings reveal a novel function of SLC25A6 that links metabolic stress to mitochondrial apoptosis via disruption of the MICOS complex. Combination treatments with mitochondrial apoptotic inducers represent a promising avenue for maximizing the efficacy of GMIs in cancer treatment.

DOI: https://doi.org/10.1038/s41419-026-08754-6
Eur J Pharmacol. 2026 Apr 18. pii: S0014-2999(26)00354-7. [Epub ahead of print] 178872

Lysosomal accumulation of Masitinib alters autophagy via pH-dependent trapping.

Abdulrahman El Sayed, Monika Kluzek, Remigiusz Serwa, Abdelhalim Azzi.

  Small-molecule kinase inhibitors often exhibit complex cellular behaviors that cannot be explained solely by target inhibition. Masitinib is a clinically investigated tyrosine kinase inhibitor with reported anti-inflammatory and neuroprotective effects, yet its intracellular mechanism of action remains poorly defined. Here, we show that masitinib undergoes pH-dependent lysosomal sequestration that dominates its cellular activity. Across multiple cell lines, masitinib suppresses mTORC1 signaling while paradoxically inducing AKT phosphorylation through a VPS34 and rapamycin-sensitive pathway independent of class I PI3K. Thermal proteome profiling identifies lysosomal proteins as the primary off-target signature of masitinib. Using defined membrane model systems that recapitulate lysosomal lipid composition and acidity, we demonstrate that masitinib preferentially accumulates and intercalates into acidic, negatively charged membranes. This lysosomal accumulation impairs lysosomal acidification and disrupts autophagic flux, providing a mechanistic link between the physicochemical properties of masitinib and its downstream signaling effects. Together, our findings highlight lysosomal sequestration as a key determinant of kinase inhibitor behavior and underlie the importance of subcellular drug distribution in modulating cellular responses.

Keywords:  GUVs; LUVs; Masitinib; autophagy; lysosome trapping

DOI:  https://doi.org/10.1016/j.ejphar.2026.178872