bims-musmir 2026-04-12 papers

bims-musmir

Biomed News

on microRNAs in muscle

Issue of 2026–04–12
seventeen papers selected by
Katarzyna Agnieszka Goljanek-Whysall, University of Galway

Associations of Elevated Red Cell Distribution Width (RDW) with Decreased Physical and Cognitive Function in Older Adults, and The Potential Mediation by Mitochondrial Energetics: The Study of Muscle, Mobility and Aging (SOMMA).
Vitamin D binding protein induces skeletal muscle atrophy and contributes to cancer-associated muscle wasting independently of vitamin D status in preclinical models.
Adrβ2 in skeletal muscle cells is required for exercise-induced Pgc1α but not for metabolic benefits of exercise on diet-induced obesity.
Skeletal and cardiac muscle longitudinal associations in the Baltimore Longitudinal Study of Aging (BLSA).
Rab12 is a regulator of mitophagy and mitochondrial homeostasis.
A Distinct Population of Mitochondrial miRNA in Human Male Skeletal Muscle Assessed Before and After Exercise.
Metabolite biomarkers present in urine predict alterations in skeletal muscle associated with sarcopenia.
ADT-OH promotes mitophagy and suppresses the cytosolic mtDNA-cGAS-STING inflammatory cascade in microglia.
The Diagnostic Potential of Axon Excitability Is Consistent Across Hand Muscles in Amyotrophic Lateral Sclerosis.
Lysosomal Control of Aging through Transcriptional and Epigenetic Regulation.
Stress-Induced PTBP1 Reprograms Neuronal Function and Activates Cellular Senescence.
Systematic profiling of cytosolic membraneless organelles reveals enrichment of oncogenic mRNA upon oxidative stress.
Cabozantinib activates TFEB-mediated autophagy to exert anti-tumor effects in hepatocellular carcinoma.
Exercise induces sex-specific assembly of mitochondrial supercomplexes.
Lysosome-related organelles orchestrate guanine crystal formation in pigment cells.
Nanomedicine novel strategies: deciphering the EV-metabolic axis as a natural nanocarrier network in lung cancer progression and cachexia.
Functional Analysis of Late-Onset Alzheimer's Disease Risk Genes in Caenorhabditis elegans Identifies Regulators of Neuronal Aging.

Aging Dis. 2025 Apr 22. 17(3): 1654-1663

Associations of Elevated Red Cell Distribution Width (RDW) with Decreased Physical and Cognitive Function in Older Adults, and The Potential Mediation by Mitochondrial Energetics: The Study of Muscle, Mobility and Aging (SOMMA).

Kyoung Min Kim, Li-Yung Lui, Theresa Mau, Paul M Coen, Steven R Cummings.

We analyzed the association between RDW and skeletal muscle mitochondrial energetics and how skeletal muscle mitochondrial energetics may mediate the associations of RDW with physical and cognitive performance. The study analyzed cross-sectional baseline data from the Study of Muscle, Mobility and Aging (SOMMA) that enrolled 864 participants aged 70 and older (mean=76.3 years). RDW, clinical and demographic parameters were assessed. Comprehensive evaluations were conducted for both physical and cognitive function using objective and subjective measures. Elevated RDW values were significantly correlated with decreased physical performance, evidenced by reduced cardiorespiratory fitness (VO2peak) and longer time to 400 m Walk, alongside impaired cognitive performance. Higher RDW values also demonstrated robust negative associations with various measurements of mitochondrial energetics, including maximal ATP production and oxidative phosphorylation. Mediation analysis revealed that impaired mitochondrial function partly mediated the associations between RDW values and VO2peak, and other physical and cognitive performance. These findings suggest that higher RDW is associated with declines in various physical and cognitive performance, with skeletal muscle mitochondrial energetics serving as a potential mediating factor. Causal inferences about potential mediation are limited by the cross-sectional design of the study. Nevertheless, the findings highlight the value of RDW as a potential biomarker for age-related declines in physical and cognitive function partly mediated by mitochondrial energetics.

DOI: https://doi.org/10.14336/AD.2024.1724
Nat Commun. 2026 Apr 10.

Vitamin D binding protein induces skeletal muscle atrophy and contributes to cancer-associated muscle wasting independently of vitamin D status in preclinical models.

Tommaso Raiteri, Simone Reano, Andrea Scircoli, Ivan Zaggia, Alessandro Antonioli, Stefania Faletti, Francesco Favero, Marcello Manfredi, Giuliana Pelicci, Davide Corà, Lorenza Scotti, Richard R Kew, Flavia Prodam, Paolo E Porporato, Nicoletta Filigheddu.

The maintenance of skeletal muscle is of pivotal importance, as its loss is often associated with progressive pathologies, generally worsening the prognosis. Increased levels of vitamin D binding protein (VDBP) were reported in diseases susceptible to muscle wasting, including several tumors. We hypothesized that VDBP might participate in muscle wasting and investigated its direct effects on skeletal muscle homeostasis. Here, we demonstrate that VDBP induces atrophy independently of vitamin D. In C2C12 myotubes, we identified intracellular actin dynamics perturbation and subsequent mitochondrial fragmentation as the main molecular mechanisms of VDBP-induced atrophy. Coherently, the ectopic introduction of VDBP in mice lacking the protein (Gc-knockout mice) induced muscle atrophy and decreased strength. Finally, we present proof-of-concept evidence that VDBP contributes to cancer-associated muscle wasting in Lewis lung carcinoma (LLC)-bearing male mice. Altogether, these findings provide novel insights into the biological function of VDBP as a pro-atrophic hormone with potential implications for the treatment of muscle wasting.

DOI: https://doi.org/10.1038/s41467-026-71530-9
bioRxiv. 2026 Mar 31. pii: 2026.03.27.714812. [Epub ahead of print]

Adrβ2 in skeletal muscle cells is required for exercise-induced Pgc1α but not for metabolic benefits of exercise on diet-induced obesity.

Marco Galvan, Mina Fujitani, Jasmine Dushime, Safia Baset, Bandy Chen, Shreya Thomas, Carlos M Castorena, Joel K Elmquist, Teppei Fujikawa.

β2-Adrenergic receptor ( Adrβ2 ) is the most abundant form of adrenergic receptors in skeletal muscle. Our previous studies have shown that the ventromedial hypothalamic nucleus (VMH) regulates metabolic benefits of exercise, potentially by skeletal muscle Adrβ2 . Although a large body of literature has shown the importance of Adrβ2 on skeletal muscle physiology, it remains unexplored whether skeletal muscle Adrβ2 contributes to metabolic benefits of exercise, such as prevention of diet-induced obesity (DIO). Here, we generated mice lacking Adrβ2 in skeletal muscle cells (SKM Adrβ2 ) and tested whether SKM Adrβ2 is required for metabolic benefits of exercise on DIO. Deletion of SKM Adrβ2 completely abolished the induction of peroxisome proliferator-activated receptor gamma coactivator 1-alpha ( Pgc-1α ) in skeletal muscle by β2-agonist, which is a potent activator of Pgc-1α . Exercise upregulates Pgc-1α, which regulates a broad range of skeletal muscle physiology, including hypertrophy and mitochondrial function. Deletion of SKM Adrβ2 hampers augmented Pgc-1α in skeletal muscle by a single bout of exercise. Intriguingly, we found that deletion of SKM Adrβ2 increased endurance capacity. Further, our data showed that body weight in DIO mice lacking SKM Adrβ2 is comparable to that of control DIO mice during exercise training, suggesting that deletion of SKM Adrβ2 did not affect the metabolic benefits of exercise in DIO. Collectively, our data indicate that SKM Adrβ2 contributes to exercise-induced transcriptional changes and endurance capacity, however, it is not required for exercise benefits on bodyweight in DIO mice.

DOI: https://doi.org/10.64898/2026.03.27.714812
BMC Med. 2026 Apr 06.

Skeletal and cardiac muscle longitudinal associations in the Baltimore Longitudinal Study of Aging (BLSA).

Jie Jun Wong, Fei Gao, Edward G Lakatta, Eleanor Simonsick, Luigi Ferrucci, Ru-San Tan, Majd AlGhatrif, Angela S Koh.

   BACKGROUND: Sarcopenia, the age-related loss of skeletal muscle mass and function, has been linked to adverse health outcomes. Cross-sectional associations have been observed between skeletal and cardiac muscle mass and function in healthy, community-dwelling older adults during normative aging. Further longitudinal studies on the skeletal muscle-cardiac axis during aging are needed to inform the temporal patterns and impact of these associations.
METHODS: We analyzed data from participants from the Baltimore Longitudinal Study of Aging. Individual longitudinal rates of change (random slopes) of echocardiography-derived cardiac function, appendicular lean mass (ALM), and maximal handgrip strength (HGS) were estimated with linear mixed-effects models. The associations between baseline measurements and rates of change (Change) were examined using Pearson correlation and multiple linear regression. Continuous variables are expressed as mean ± standard deviation (SD).
RESULTS: Among 1025 participants (66.6 ± 13.1 years, 47.8% male), the baseline mean HGS was 33.1 ± 11.0 kg, and ALM was 20.8 ± 5.3 kg; the mean left ventricular ejection fraction was 67.5 ± 9.7%, and LV mass (LVM) was 145.6 ± 50.4 g. With aging, HGS decreased by 0.36 kg/year (95% CI: -0.41, -0.31), ALM decreased by 25.1 g/year (95% CI: -34.7, -15.5), and LVM decreased by 0.730 g/year (95% CI: -0.998, -0.460). Both ALMChange and HGSChange were inversely correlated with advancing age ([r = -0.159 p < 0.001] and [r = -0.172 p < 0.001], respectively), while LVMChange was not (p = 0.178). Adjusting for baseline, ALMChange was significantly associated with LVMChange independently of age, sex, and LVM (β = 0.287, p < 0.001, adj. R2 = 0.663); the association persisted after adjustment for pulse pressure, mean arterial pressure, and body mass index. The interaction term sex*baseline-adjusted ALMChange was statistically significant (p < 0.050). ALMChange was also correlated with LVEFChange (r = 0.102, p = 0.001), while HGSChange was not significantly correlated with LVMChange (p = 0.642).
CONCLUSIONS: Among community-dwelling normative aging adults, age-associated decline in skeletal muscle mass correlated with reductions in LVM and function, independently of age, sex, and hemodynamic loading conditions. Our findings suggest a skeletal muscle-cardiac axis characterized by parallel declines beginning in early aging, preceding cardiovascular disease. Further studies exploring cardiac and skeletal muscle aging-related declines may direct interventions to halt these adverse processes concurrently.

Keywords:  Cardiac aging; Lean body mass; Sarcopenia; Skeletal muscle

DOI:  https://doi.org/10.1186/s12916-026-04829-5
bioRxiv. 2026 Mar 31. pii: 2026.03.29.715103. [Epub ahead of print]

Rab12 is a regulator of mitophagy and mitochondrial homeostasis.

Tara Richbourg, Alex George, Anas Bitar, Ian T Ryde, Casey Farrell, Tuyana Malankhanova, Jennifer Liu, Silas A Buck, Ivana Barraza, So Young Kim, Xiaoyan Nie, Andrew B West, Joel N Meyer, Laurie H Sanders.

Rab GTPases orchestrate vesicular trafficking, but their contributions to mitochondrial quality control are not fully defined, despite links to multiple mitochondria-related human diseases. We conducted a family-wide siRNA-based screen using mt-mKeima/YFP-Parkin HeLa cells to identify regulators of depolarization-induced mitophagy. The screen identified several candidate Rabs, and follow-up studies validated Rab12 as a negative regulator of mitophagy. Rab12 knockdown or knockout augments clearance of damaged mitochondria basally and/or after FCCP-induced depolarization, with findings reproduced across distinct cell types. Rab12 depletion increased mitochondrial content, lowered mitochondrial membrane potential, and reduced mitochondrial DNA damage, without detectable changes in overall cellular bioenergetic capacity. Together, these results indicate that Rab12 restrains mitophagic engagement and its loss permits accumulation of lower-functioning mitochondria that are hypersensitive to mitophagy-inducing stress. Rab12 thus emerges as a novel effector linking vesicular trafficking machinery and mitochondrial homeostasis, with potential implications for neurodegenerative disorders and other Rab-associated diseases.

DOI: https://doi.org/10.64898/2026.03.29.715103
FASEB J. 2026 Apr 30. 40(8): e71764

A Distinct Population of Mitochondrial miRNA in Human Male Skeletal Muscle Assessed Before and After Exercise.

Jessica L Silver, Danielle Hiam, Stella Loke, Larry Croft, Megan Soria, Adam J Trewin, Søren Nielsen, Séverine Lamon, Glenn D Wadley.

  Initially thought to localize at the cytosol and nucleus only, emerging evidence indicates that miRNAs also localize within mitochondria where they could regulate diverse pathological and physiological processes. Therefore, the aim of the current study was to profile the population of miRNAs in isolated mitochondria and whole-tissue from human skeletal muscle at rest and in response to acute endurance exercise. Twelve healthy males (age 26 ± 4 years, mean ± SD) cycled for 60 min at 70% VO2peak and muscle biopsies were collected at rest, immediately after and 3 h after exercise. The mitochondria were isolated by immunoprecipitation, enzymatically purified, then the resident RNA was sequenced to assess the mitochondrial transcriptome. Small RNA sequencing revealed that mitochondria isolated from male skeletal muscle tissue contain a distinct population of miRNAs. Of the approximately 127 mature miRNAs detected in skeletal muscle mitochondria at each time point, the canonical muscle-specific miRs (myo-miRs) miR-1, miR-133 and miR-206 families constituted on average 45% of total mitochondria miRNA reads. However, none of these canonical myo-miRs were differentially expressed in mitochondria following endurance exercise. One miRNA, hsa-miR-146b-5p, was differentially expressed 3 h after exercise when compared to pre-exercise in both mitochondria (log2 fold-change = 5.4, p = 0.003, FDR = 0.82) and whole muscle tissue (log2 fold-change = 2.3, p < 0.0001, FDR = 0.060) but not when adjusted for multiple testing. Future research is now required to investigate miRNA-mRNA interactions in the mitochondria of skeletal muscle tissue.

Keywords:  exercise; mitochondria; non‐coding RNA; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202500435R
Front Aging. 2026 ;7 1736916

Metabolite biomarkers present in urine predict alterations in skeletal muscle associated with sarcopenia.

Rafaela Andrade-Vieira, Hirad A Feridooni, Alyne Teixeira, Dylan Deska-Gauthier, Xingjian Chang, Tobias Karakach, Rebecca Moyer, John P Frampton.

   Introduction: Sarcopenia, characterized by the progressive loss of skeletal muscle mass and strength with age, is associated with adverse health outcomes and reduced health span in aging populations. Early detection is critical for implementing preventive strategies; however, current diagnostic methods are often costly, specialized, and not suitable for routine screening. This study aimed to identify metabolite biomarkers associated with early alterations in muscle metabolism that may support accessible screening approaches.
Methods: In this cross-sectional observational study, serum samples from 200 individuals aged 550-70 years from the general population were analyzed. Participants completed the International Physical Activity Questionnaire (IPAQ). In a subset of 60 participants, urine samples were also collected, and participants underwent additional assessments including the Short Physical Performance Battery (SPPB), dual-energy X-ray absorptiometry (DXA), IPAQ, and a supplementary health questionnaire. Targeted metabolomic analyses were performed to identify metabolites associated with early sarcopenia-related metabolic changes.
Results: A panel of metabolites in serum-L-glutamic acid, xanthine, taurine, succinate, and L-carnitine-was associated with early alterations in muscle metabolism. These metabolites were also detectable in urine samples. Importantly, predictive performance for sarcopenia-related changes was observed when the metabolites were analyzed as a combined panel rather than as individual biomarkers.
Conclusion: Our findings identify a metabolite panel detectable in urine that reflect early metabolic alterations associated with sarcopenia. This panel provide a foundation for developing accessible screening tools to support early detection and preventive strategies for muscle health decline in aging populations.

Keywords:  aging; metabolomic and musculoskeletal health; metabolomics; musculoskeletal health; sarcopenia; urinary biomakers

DOI:  https://doi.org/10.3389/fragi.2026.1736916
Acta Pharmacol Sin. 2026 Apr 09.

ADT-OH promotes mitophagy and suppresses the cytosolic mtDNA-cGAS-STING inflammatory cascade in microglia.

Xiao-Ou Hou, Miao Wang, Rong Deng, Yi-Fan Lu, Jin-Ru Zhang, Li Ren, Jing Chen, Chun-Feng Liu, Ya-Ping Yang, Li-Fang Hu.

  Mitochondrial dysfunction, driven by genetic susceptibility or environmental insults, contributes to the pathogenesis of neurodegenerative disorders, including Parkinson's disease (PD). Mitophagy is a selective pathway that eliminates dysfunctional mitochondria, and mitophagy inducers hold therapeutic promise for neurodegeneration. However, the arsenal of specific, clinically viable inducers remains limited. ADT-OH, a slow-release H2S compound, was recently reported to induce mitochondrial uncoupling through sulfide-quinone oxidoreductase (SQR)-mediated oxidation of H2S. In this study, we report that ADT-OH elicits mitophagic flux in microglia. This is evidenced by the reduced steady-state levels of mitochondrial marker proteins (TOM20, COXIV, and HSP60), enhanced mitochondrial fission dynamics, and mitochondrial translocation into lysosomes, as visualized by the mt-Keima probe. Mechanistically, its mitophagy-promoting effect is dependent on SQR-mediated mitochondrial uncoupling and subsequent activation of PINK1-PARKIN signaling. Importantly, ADT-OH abrogates the accumulation of dysfunctional mitochondria and the subsequent cytosolic release of mitochondrial DNA in α-synuclein preformed fibrils (α-Syn PFF)-challenged microglia, thereby blunting the activation of the cGAS-STING pathway and the downstream production of inflammatory mediators. Furthermore, systemic administration of ADT-OH dampened microglial activation and cGAS expression in α-Syn-overexpressing PD mice, thereby mitigating the loss of midbrain dopaminergic neurons and ameliorating motor coordination deficits. Collectively, our findings demonstrate that ADT-OH exerts robust neuroprotective effects in PD models, both in vitro and in vivo, by enhancing mitophagy and inhibiting microglia-mediated neuroinflammation.

Keywords:  ADT-OH; Parkinson’s disease; cGAS-STING; microglia; mitochondrial DNA; mitophagy

DOI:  https://doi.org/10.1038/s41401-026-01789-7
Muscle Nerve. 2026 Apr 11.

The Diagnostic Potential of Axon Excitability Is Consistent Across Hand Muscles in Amyotrophic Lateral Sclerosis.

Alana K O Hodgson, Christopher J McDermott, Pamela J Shaw, James J P Alix.

   INTRODUCTION/AIMS: Recent work suggests that nerve excitability testing has diagnostic potential in amyotrophic lateral sclerosis (ALS). The diagnostic performance of nerve excitability across hand muscles is currently unknown. This study aimed to assess if muscles of the so-called split hand (abductor pollicis brevis [APB], first dorsal interosseous [FDI], and abductor digiti minimi [ADM]) manifest differences in diagnostic performance.
METHODS: We prospectively recruited 60 consecutive patients investigated for ALS. Nerve excitability, motor unit number and size (MScanFit), needle electromyography (EMG), and standard clinical data were collected. ALS and non-ALS groups were compared using t tests, area under receiver operating characteristic curves (AUROC), and multivariate modeling.
RESULTS: Forty-eight patients completed testing of all three muscles, 25 were diagnosed with ALS. The most prominent nerve excitability changes were in superexcitability (APB p = 0.001, FDI p = 0.0001, ADM p = 0.002). Diagnostic performance with superexcitability was similar across the three muscles (p > 0.05). Reductions in motor unit number were observed in ALS patients. Changes in excitability were evident without loss of motor units, most frequently in APB (40% of recordings). Improvements to the AUROC were obtained using combined excitability/motor unit parameters from APB/FDI (AUROC 0.97, p = 0.01 vs. FDI superexcitability alone). Combined excitability and motor unit modeling outperformed detection of EMG abnormalities.
DISCUSSION: Disturbances to nerve excitability are similar across the split hand muscles at the time of ALS diagnosis. These occurred prior to motor unit loss and traditional EMG changes. Combining excitability and motor unit parameters in the lateral hand can identify early pathology and potentially lead to earlier diagnosis.

Keywords:  amyotrophic lateral sclerosis; diagnosis; motor unit number; nerve excitability

DOI:  https://doi.org/10.1002/mus.70239
Ageing Res Rev. 2026 Apr 08. pii: S1568-1637(26)00126-1. [Epub ahead of print] 103134

Lysosomal Control of Aging through Transcriptional and Epigenetic Regulation.

Yikai Bai, Yu Luo, Yuyuan Wang, Jiayi Qiu, Dan Li.

  Despite the well-known role as degradative organelles, lysosomes have been identified as a central signaling hub in maintaining cellular homeostasis. Lysosomal dysfunction is a well-established driver of cellular senescence and age-related pathologies. However, the precise molecular mechanisms through which lysosomes actively regulate aging remain unclear. Excitingly, latest studies show that lysosomes are not merely passive in aging but may actively govern longevity. In this review we summarize two significant discoveries about lysosome and senescence. Li et al. discovered the lysosomal surveillance response (LySR) and Zhang et al. uncovered transgenerational lysosomal signaling. These pathways substantially contribute to enhanced organismal longevity. We further discuss the transcription factor EB (TFEB) as a central regulator linking lysosomal activity to senescence and tissue homeostasis. Together, these findings reposition lysosomes as dynamic regulators that integrate stress and metabolic cues to modulate aging programs. Therefore, targeting lysosomal signaling emerges as a promising strategy for extending healthspan and mitigating age-related disorders.

Keywords:  Aging; Lysosome; Senescence; Transcription, TFEB

DOI:  https://doi.org/10.1016/j.arr.2026.103134
bioRxiv. 2026 Apr 04. pii: 2026.04.03.711742. [Epub ahead of print]

Stress-Induced PTBP1 Reprograms Neuronal Function and Activates Cellular Senescence.

Priyanka Priyanka, Amir Gamliel, Havilah Taylor, Kenneth Ohgi, Michael G Rosenfeld.

Chronic oxidative stress is a major contributor to neuronal aging. Due to the lack of homologous recombination (HR) DNA damage repair, high oxygen consumption in neurons causes DNA damage accumulation with age, resulting in a decline in neuronal function, senescence-like phenotypes and onset of neurodegenerative diseases. Here, we identify increased PTBP1 as a stress-inducible negative regulator of neuronal gene expression and senescence-protectant genes. Oxidative stress robustly increases PTBP1 expression in ShSY-5Y differentiated neurons and primary mouse cortical neurons, coinciding with the loss of neuronal genes, including neuronal PTBP2 , and activation of stress-responsive genes. Knockdown of PTBP1 in fibroblasts reduces the expression of key senescence genes. Transcriptomic analyses revealed that PTBP1 overexpression results in coordinated shift in gene expression characterized by repression of neuronal commitment genes and activation of stress and senescence genes. Mechanistically, PTBP1 induction is regulated by stress induced CTCF binding at the PTBP1 promoter. Together, our findings suggest that alteration in levels of PTBP1 acts as a molecular switch between neuronal function and survival, providing insight into transcriptional adaptations associated with aging.
SUMMARY: Loss of PTBP1 in fibroblasts acts as a senescence protective gene xidative stress induces expression of PTBP1 , reducing neuronal function gene expression and activating stress and cell cycle genes Ectopic PTBP1 expression reprograms neuronal transcription, down-regulating cell fate commitment genes and activating a cell senescence program xidative stress induces PTBP1 and suppresses neuronal specific PTBP2 expression in primary cortical neurons.

DOI: https://doi.org/10.64898/2026.04.03.711742
Cell Rep. 2026 Apr 04. pii: S2211-1247(26)00281-0. [Epub ahead of print]45(4): 117203

Systematic profiling of cytosolic membraneless organelles reveals enrichment of oncogenic mRNA upon oxidative stress.

Savannah O'Connell, Helen E King, Peter Kjer-Hansen, Karina Pazaky, Gabriela Santos Rodriguez, Daisy Kavanagh, Helaine Graziele S Vieira, Javier Fernandez-Chamorro, Robert J Weatheritt.

  Cytosolic mRNA regulation during and after stress is driven by distinct membraneless organelles. However, their compositional and functional dynamics throughout the stress response remain unclear. We combine APEX2-mediated proximity labeling, RNA sequencing, and high-content imaging to map the human P-body and stress granule transcriptomes during oxidative stress and recovery. Our findings reveal that P-bodies undergo extensive compositional remodeling during stress and that these changes persist during stress recovery. P-body-associated mRNAs during stress exhibit increased AU-rich elements and oncogenic content relative to the cytosol. In contrast, stress granule-associated mRNAs closely resemble the cytosol. These results uncover critical differences between P-bodies and stress granules, shedding light on their functional specialization. Our study provides a valuable resource of cytosolic membraneless organelle-associated transcripts and suggests a specialized role for P-bodies in stress adaptation and recovery.

Keywords:  APEX-sequencing; CP: cell biology; CP: molecular biology; P-bodies; bioinformatics; membraneless organelles; stress granules; stress response

DOI:  https://doi.org/10.1016/j.celrep.2026.117203
In Vitro Cell Dev Biol Anim. 2026 Apr 08.

Cabozantinib activates TFEB-mediated autophagy to exert anti-tumor effects in hepatocellular carcinoma.

Cheng Chen, Yongjie Hu, Chenggang Zhang, Xiaocui Zhou.

  Autophagy signaling plays a crucial yet complex role in hepatocellular carcinoma (HCC), influencing tumor progression and treatment response. Cabozantinib is an orally administered multi-kinase inhibitor used in the treatment of various advanced cancers, including renal cell carcinoma and HCC. However, its precise mechanisms of action in HCC require further elucidation. Our study first revealed elevated levels of phosphorylated TFEB (p-TFEB, Ser142) in human HCC tissues and cell lines, indicating impaired TFEB-mediated autophagic flux in hepatocellular carcinoma. Treatment with Cabozantinib induced dose-dependent cytotoxicity, oxidative stress (increased ROS and decreased GSH), and mitochondrial dysfunction (reduced Complex IV activity and ATP production). Furthermore, Cabozantinib promoted autophagy activation, as evidenced by increased autophagosome formation, elevated LC3-II/I conversion and Beclin1 expression, and decreased p62 levels. Mechanistically, Cabozantinib inhibited TFEB phosphorylation at Ser142 and enhanced its nuclear translocation. Critically, TFEB knockdown abolished Cabozantinib-induced autophagy, confirming that the pro-autophagic effects are TFEB-dependent. These findings demonstrate that Cabozantinib exerts its anti-tumor activity in HCC through activating TFEB-mediated autophagy pathway by inducing oxidative stress and mitochondrial damage.

Keywords:  Autophagy; Cabozantinib; Hepatocellular carcinoma; TFEB

DOI:  https://doi.org/10.1007/s11626-026-01161-3
Cell Rep. 2026 Apr 03. pii: S2211-1247(26)00295-0. [Epub ahead of print]45(4): 117217

Exercise induces sex-specific assembly of mitochondrial supercomplexes.

Jesús R Huertas, Jerónimo Aragón-Vela, Andreas Breenfeldt Andersen, Jacob Bejder, Lars Nybo, Nikolai B Nordsborg, Andrea Rodríguez-Carrillo, José A Enriquez, Sara Cogliati, Rafael A Casuso.

  The mitochondrial respiratory complexes of the electron transport chain (ETC) form supramolecular structures known as supercomplexes (SCs) whose functions remain partially understood. An increase in carbohydrate oxidation, such as that induced by high-intensity contractions within skeletal muscle (SKM), has been proposed to promote the assembly of high molecular weight SCs (HMWSCs). Here, healthy, active young subjects (7 females and 9 males) performed a moderate- followed by a high-intensity exercise bout. We found that males increased the assembly of complex III (CIII) into SCs, particularly HMWSCs, in an intensity-dependent manner within SKM. Females showed a stable content of both HMWSCs and I+III2 SCs during exercise. In contrast, the assembly of CIV into SCs was not promoted by exercise in either sex. These findings indicate that the ETC complex organization can be modulated by exercise, and the mitochondrial supercomplex assembly in human SKM appears to be regulated in a sex-specific manner.

Keywords:  CP: metabolism; CP: molecular biology; electron transport chain; electron transport chain remodeling; high-intensity exercise; human muscle bioenergetics; lactate; mitochondrial complexes; sex-specific mitochondrial adaptation; sexual dimorphism; skeletal muscle; skeletal muscle metabolism

DOI:  https://doi.org/10.1016/j.celrep.2026.117217
Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2524305123

Lysosome-related organelles orchestrate guanine crystal formation in pigment cells.

Anna Gorelick-Ashkenazi, Yuval Barzilay, Tali Lerer-Goldshtein, Tsviya Olender, Zohar Eyal, May Glaser, Yonatan Broder, Nadav Mishol, Rachael Deis, Merav Kedmi, Dvir Gur.

  Iridosomes, the guanine crystal-forming organelles of pigment-producing iridophores, are among the most versatile, visually striking yet mechanistically uncharacterized organelles in vertebrate biology. Lysosome-related organelles (LROs) support cell type-specific functions by adapting endolysosomal pathways for specialized roles. Here, we show that iridosomes represent a subtype of LROs. Using transcriptomic profiling of zebrafish iridophores, CRISPR-Cas9-mediated gene disruption, and cryogenic transmission electron microscopy, we define the molecular program underlying iridosome biogenesis. Iridosomes have evolved unique adaptations for crystal growth while retaining core features of other LROs. Key regulators, including Rab32a, Ap3m2, and Hps5, are essential for crystal formation, with gene knockouts causing reduced crystal number, altered morphology, and distinct maturation defects. We further identify hallmark LRO features in iridosomes, including intraluminal vesicles and pH-regulated developmental transitions. Cross-species transcriptomic analysis confirms that iridosomes share an LRO signature across vertebrates, including teleost fish and reptiles, suggesting ancient evolutionary origins. These findings establish iridosomes as crystalline LROs and as a model for investigating how cells construct structurally specialized organelles through coordinated trafficking and crystallization, with implications for LRO evolution and human disease.

Keywords:  crystals; guanine; iridosome; lysosome related organelle; zebrafish

DOI:  https://doi.org/10.1073/pnas.2524305123
J Nanobiotechnology. 2026 Apr 09.

Nanomedicine novel strategies: deciphering the EV-metabolic axis as a natural nanocarrier network in lung cancer progression and cachexia.

Xinxin Zhao, Dongmei Lv, Min Wang, Qinyu Guo, Yidi Gao, Wenxiang Fang, Wenlong Zhang, Peipei Wu.

  The systemic progression of lung cancer involves a complex interplay between local tumor microenvironment (TME) dynamics and host-level metabolic decline, culminating in cachexia. Extracellular vesicles (EVs), have emerged as critical mediators in this process. This review constructs a comprehensive model of the "EV-metabolic axis" in lung cancer, framing EVs as natural nanocarriers within a systemic communication network that orchestrates a dual pathological process. Locally, EVs remodel the TME to support tumor growth, metastasis, and therapeutic resistance by transferringdiverse metabolic cargoes. Systemically, they transmit catabolic signals to distant adipose and muscle tissues, driving the severe tissue wasting characteristic of cachexia. This integrated perspective reveals the EV-metabolic axis as a central, targetable node in lung cancer pathology. From a nanomedicine perspective, targeting EV biogenesis, cargo loading, or uptake offers a novel, multifaceted therapeutic strategy to simultaneously inhibit tumor growth and mitigate cachexia, heralding a paradigm shift in future lung cancer treatment Scheme 1. This schematic illustrates the tripartite "EV-Metabolic Axis" framework linking local tumor metabolism, systemic EV trafficking, and cachexia development in lung cancer. In the Local Metabolic Axis, primary tumors and stromal cells (CAFs, TAMs, BMSCs) secrete extracellular vesicles (EVs) that reprogram glucose, lipid, and amino acid metabolism via cargoes such as miRNAs, metabolic enzymes, and cytokines - promoting glycolysis, glutamine addiction, ferroptosis resistance, and epithelial-mesenchymal transition (EMT). In the Circulatory System EV Transport Axis, EVs (40-150 nm exosomes, 50-1000 nm ectosomes) traverse biological barriers via membrane fusion, receptor-mediated endocytosis, or ligand-receptor binding, acting as natural nano-carriers. In the Systemic Cachexia Axis, circulating EVs deliver catabolic signals (e.g., miR-21, IL-6, HSP70/90, TGF-β, PTHrP) to distant organs - triggering adipose tissue browning, lipolysis, myofibrillar atrophy, and mitochondrial dysfunction - culminating in cancer-associated cachexia. This integrated axis positions EVs as both biomarkers and therapeutic targets across the nano-bio interface.

Keywords:  Extracellular vesicles; Lung cancer cachexia; Metabolic remodeling; Nanomedicine; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12951-026-04367-5
bioRxiv. 2026 Mar 30. pii: 2026.03.26.714531. [Epub ahead of print]

Functional Analysis of Late-Onset Alzheimer's Disease Risk Genes in Caenorhabditis elegans Identifies Regulators of Neuronal Aging.

Swapnil G Waghmare, Meera M Krishna, Emily C Maccoux, Ariel L Franitza, Brian A Link, Lezi E.

Background: Genome-wide studies in late-onset Alzheimer's disease (LOAD) have uncovered many risk loci, yet identifying the causal genes and clarifying how these genetic signals connect to molecular and cellular mechanisms relevant to AD pathogenesis in vivo remains challenging.
Methods: Using Caenorhabditis elegans as a model to identify LOAD-associated genes that drive neurodegenerative processes, we focused on 14 understudied genes and their homologs: ABI3/abi-1 , B4GALT3/bre-4 , CCDC6/T09B9.4 , CLPTM1 (two homologs C36B7.6 and R166.2 ), CNN2/cpn-2 , DMWD/wdr-20 , ECHDC3/ech-2 , MADD/aex-3 , NCK2/nck-1 , RABEP1/rabn-5 , RIN3/rin-1 , SLC39A13/zipt-13 , TRAM1/tram-1 , and USP6NL/tbc-17 . We knocked down these genes by RNAi and quantified lifespan, aging-associated degeneration of two neuron classes, PVD and PLM, and associative learning and short-term memory.
Results: Lifespan was unaffected by most knockdowns, and only nck-1 and tbc-17 shortened lifespan. Across neuronal assays, multiple homologs modulated aging with clear neuron-class selectivity. Knockdown of aex-3 , C36B7.6 , cpn-2 , ech-2 , rabn-5 , rin-1 , T09B9.4 , and zipt-13 attenuated late-life PVD degeneration, whereas R166.2 and tram-1 accelerated early PVD aging. Only two genes affected PLM aging: R166.2 knockdown exacerbated degeneration, while tbc-17 knockdown attenuated it despite its lifespan-shortening effect. In PLM neurons, tbc-17 knockdown, targeting a Rab GTPase-activating protein, also preserved mitochondrial architecture during early aging and shifted heat stress-induced mitochondrial remodeling toward a pattern consistent with improved quality control. In behavioral assays, ech-2 knockdown, targeting an enoyl-CoA-hydratase, enhanced short-term memory during early stages of aging. To further assess how LOAD-linked genes interact with Aβ-driven neurodegeneration, we developed a model that combines the PVD aging assay with a background expressing human Aβ 1-42 panneuronally. In this model, Aβ expression accelerated age-dependent PVD degeneration, whereas ech-2 knockdown abolished this Aβ-induced effect.
Conclusions: Our findings show that conserved homologs of several understudied LOAD risk genes causally modulate neuronal aging in vivo in a neuron-class-selective manner, often dissociable from organismal longevity. This C. elegans framework translates human genetic associations into quantitative, aging-linked neuronal phenotypes, and our results further emphasize early endosomal and lipid-related processes as key pathways that warrant functional testing in neuronal aging. This study also provides a tractable platform to prioritize targets for cross-species validation and to test synergy with established LOAD risk genes.

DOI: https://doi.org/10.64898/2026.03.26.714531