bims-mitmed 2026-02-01 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2026–02–01
fourteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.
ALKB-1-dependent tRNA methylation is required for efficient paternal mitochondrial elimination.
Sensitivity of primary mitochondrial disease fibroblasts to ferroptosis: The role of intracellular iron.
Mitochondrial DNA Instability and Neuroinflammation: Connecting the Dots Between Base Excision Repair and Neurodegenerative Disease.
Transmitophagy in the heart: An overview of molecular mechanisms and implications for pathophysiology.
Mitochondrial Dysfunction Combined with Elevated CoQ10 Levels Specifically in Placental Cytotrophoblasts Suggests a Role for Mitophagy in Preeclampsia.
Outcomes of kidney transplantation in three patients with single large-scale mitochondrial DNA deletion syndromes.
Myo-Inositol modulates AKT signalling, mitochondrial protein expression and intracellular Ca²⁺dynamics in human dermal fibroblasts.
Cryo-EM structures of human ClpXP reveal mechanisms of assembly and proteolytic activation.
Biallelic Truncating DNAH14 Variant in Siblings with Neurodevelopmental Disorder and Predominant Ataxia: Clinical Report and Literature Review.
Hereditary Ataxias: From Pathogenesis and Clinical Features to Neuroimaging, Fluid, and Digital Biomarkers-A Scoping Review.
Mitochondrial DAMPs as a critical driver in the development of acute graft versus host disease and emerging mitochondria targeted therapeutic strategies.
Mitochondria as sources and targets of cellular signaling.
Impaired stem cell migration and divisions in Duchenne muscular dystrophy revealed by live imaging.

J Cell Biol. 2026 Apr 06. pii: e202501023. [Epub ahead of print]225(4):

Energy stress activates AMPK to arrest mitochondria via phosphorylation of TRAK1.

Jill E Falk, Tobias Henke, Sindhuja Gowrisankaran, Simone Wanderoy, Himanish Basu, Sinead Greally, Judith Steen, Thomas L Schwarz.

Neuronal signaling requires large amounts of ATP, making neurons particularly sensitive to defects in energy homeostasis. Mitochondrial movement and energy production are therefore regulated to align local demands with mitochondrial output. Here, we report a pathway that arrests mitochondria in response to decreases in the ATP-to-AMP ratio, an indication that ATP consumption exceeds supply. In neurons and cell lines, low concentrations of the electron transport chain inhibitor antimycin A decrease the production of ATP and concomitantly arrest mitochondrial movement without triggering mitophagy. This arrest is accompanied by the accumulation of actin fibers adjacent to the mitochondria, which serve as an anchor that resists the associated motors. This arrest is mediated by activation of the energy-sensing kinase AMPK, which phosphorylates TRAK1. This mechanism likely helps maintain cellular energy homeostasis by anchoring energy-producing mitochondria in places where they are most needed.

DOI: https://doi.org/10.1083/jcb.202501023
Nat Commun. 2026 Jan 29.

ALKB-1-dependent tRNA methylation is required for efficient paternal mitochondrial elimination.

Zhenhuan Luo, Yimin Li, Chenyang He, Dan Wu, Wenyu Dai, Liubing Hu, Jing Yang, Brian L Harry, Zhenyu Ju, Nektarios Tavernarakis, Hao Wang, Qin-Li Wan, Qinghua Zhou.

Maternal mitochondrial inheritance is secured by mechanisms that exclude paternal mitochondrial DNA (mtDNA). While, epigenetic modifications are vital for spermatogenesis and embryo development, their roles in the paternal mitochondrial elimination (PME) remain poorly understood. Here, we identify ALKB-1, a DNA/RNA demethylase, as a pivotal factor for efficient PME in Caenorhabditis elegans (C. elegans), acting through ALKB-1-dependent modulation of tRNA m1A methylation. Mechanistically, ALKB-1 inactivation leads to m1A hypermethylation of tRNA, which subsequently disrupts protein translation, impairs mitochondrial proteostasis, and increases ROS levels. This cascade activates the oxidative stress response factor SKN-1/Nrf2 and initiates the mitochondrial unfolded protein response (UPRmt) through ATFS-1, causing accumulation of mitochondria and mtDNA in sperm, which ultimately impedes efficient paternal mitochondrial removal and negatively impacts male fertility and embryonic development. Our findings describe a mechanism whereby ALKB-1-mediated tRNA m1A epitranscriptomic modifications are necessary for maintaining mitochondrial quality control, thereby influencing PME efficiency, underscoring the importance of this epitranscriptomic stress checkpoint in upholding proper mitochondrial inheritance during reproduction.

DOI: https://doi.org/10.1038/s41467-026-68813-6
Mitochondrion. 2026 Jan 23. pii: S1567-7249(26)00002-4. [Epub ahead of print]87 102112

Sensitivity of primary mitochondrial disease fibroblasts to ferroptosis: The role of intracellular iron.

Svetlana Pecheritsyna, Melisa Emel Ermert, Emina Podhumljak, Bas Pennings, Ruth Zondag, Eligio F Iannetti, Herma Renkema, Jan Smeitink.

  Primary mitochondrial diseases (PMDs) are directly linked to oxidative phosphorylation (OXPHOS) dysfunction. Here, we investigated the selective sensitivity of PMD patient fibroblasts compared to healthy control primary human skin fibroblasts (PHSF) to ferroptosis, and the role of iron in this cell death mechanism. To address this, we investigated sensitivity to ferroptosis inducers, the effects of iron supplementation, and intracellular iron pools. The selectivity of PMD fibroblasts ferroptotic cell death was found to be more pronounced with class 1 ferroptosis inducers (FINs) that deplete GSH than upon direct GPX4 inhibitors. Notably, exogenous iron discriminatory triggered ferroptosis in patient fibroblasts and enhanced BSO-induced cell death in both patient and control cells. Further study revealed elevated basal levels of labile iron in patient fibroblasts, but mRNA analysis of iron-regulating genes did not reveal major expression differences. These findings suggest that increased labile iron predisposes PMD fibroblasts to ferroptosis. Complementation of defective OXPHOS restored ferroptosis sensitivity and LIP levels in a cell line with an NDUFS7 mutation, indicating a functional relationship caused by OXPHOS deficiency. Further understanding this interplay may provide insights into therapeutic strategies targeting iron homeostasis to mitigate ferroptotic cell death in PMDs.

Keywords:  Ferroptosis; Labile iron pool; Primary mitochondrial disease

DOI:  https://doi.org/10.1016/j.mito.2026.102112
Genes (Basel). 2026 Jan 13. pii: 82. [Epub ahead of print]17(1):

Mitochondrial DNA Instability and Neuroinflammation: Connecting the Dots Between Base Excision Repair and Neurodegenerative Disease.

Magan N Pittman, Mary Beth Nelsen, Marlo K Thompson, Aishwarya Prakash.

  Neurons have exceptionally high energy demands, sustained by thousands to millions of mitochondria per cell. Each mitochondrion depends on the integrity of its mitochondrial DNA (mtDNA), which encodes essential electron transport chain (ETC) subunits required for oxidative phosphorylation (OXPHOS). The continuous, high-level ATP production by OXPHOS generates reactive oxygen species (ROS) that pose a significant threat to the nearby mtDNA. To counter these insults, neurons rely on base excision repair (BER), the principal mechanism for removing oxidative and other small, non-bulky base lesions in nuclear and mtDNA. BER involves a coordinated enzymatic pathway that excises damaged bases and restores DNA integrity, helping maintain mitochondrial genome stability, which is vital for neuronal bioenergetics and survival. When mitochondrial BER is impaired, mtDNA becomes unstable, leading to ETC dysfunction and a self-perpetuating cycle of bioenergetic failure, elevated ROS levels, and continued mtDNA damage. Damaged mtDNA fragments can escape into the cytosol or extracellular space, where they act as damage-associated molecular patterns (DAMPs) that activate innate immune pathways and inflammasome complexes. Chronic activation of these pathways drives sustained neuroinflammation, exacerbating mitochondrial dysfunction and neuronal loss, and functionally links genome instability to innate immune signaling in neurodegenerative diseases. This review summarizes recent advancements in understanding how BER preserves mitochondrial genome stability, affects neuronal health when dysfunctional, and contributes to damage-driven neuroinflammation and neurodegenerative disease progression. We also explore emerging therapeutic strategies to enhance mtDNA repair, optimize its mitochondrial environment, and modulate neuroimmune pathways to counteract neurodegeneration.

Keywords:  base excision repair; damage associated molecular patterns; mitochondrial DNA; neurodegeneration; neuroinflammation

DOI:  https://doi.org/10.3390/genes17010082
Acta Pharm Sin B. 2026 Jan;16(1): 1-12

Transmitophagy in the heart: An overview of molecular mechanisms and implications for pathophysiology.

Joshua Kramer, Eric Rohwer, Palaniappan Sethu, Min Xie, Timmy Lee, Victor Darley-Usmar, Jianhua Zhang.

  Mitochondria are essential for meeting cardiac metabolic demands and their dysfunction is associated with heart failure and is a key mediator of cardiac ischemia-reperfusion injury. Cardiomyocytes engage integrated mechanisms to maintain mitochondrial function; however, chronic stress or disease can overwhelm this capacity. The removal of damaged mitochondria is mediated by a process known as mitophagy, which, together with mitochondrial biogenesis, plays a key role in maintaining mitochondrial quality control. Maintenance of mitochondrial quality control was initially thought to be autonomously regulated within each cellular population with little exchange between cells. However, recently the phenomenon of transmitophagy has been identified in which damaged mitochondria are transferred to neighboring cells for degradation. This review discusses the current understanding of transmitophagy in the context of heart injury, aging and disease, with particular emphasis on exophers, migrasomes, and tunneling nanotubes as pathways mediating cell-cell communication between cardiomyocytes, macrophages and fibroblasts. We further discuss the potential of targeting transmitophagy for cardioprotection and highlight key unanswered questions and challenges. Addressing these gaps may reveal novel strategies to preserve mitochondrial homeostasis and improve the outcomes of patients with cardiovascular disease.

Keywords:  Cardiomyocytes; Exophers; Fibroblasts; Macrophages; Migrasomes; Mitophagy; TNTs; Transmitophagy

DOI:  https://doi.org/10.1016/j.apsb.2025.11.030
Biology (Basel). 2026 Jan 13. pii: 139. [Epub ahead of print]15(2):

Mitochondrial Dysfunction Combined with Elevated CoQ10 Levels Specifically in Placental Cytotrophoblasts Suggests a Role for Mitophagy in Preeclampsia.

Jessica Ábalos-Martínez, Francisco Visiedo, María Victoria Cascajo-Almenara, Celeste Santos-Rosendo, Victoria Melero-Jiménez, Carlos Santos-Ocaña, Luis Vázquez-Fonseca, Fernando Bugatto.

  Preeclampsia is a serious pregnancy disorder of unknown etiology. One of its cellular hallmarks is increased mitochondrial dysfunction in placental tissue. Further investigation into this aspect may help elucidate the molecular basis of preeclampsia. A total of 24 pregnant women who delivered by cesarean section participated in the study: n = 13 controls and n = 11 diagnosed with preeclampsia. Maternal blood samples were collected to assess the biochemical profile, and demographic and clinical data were recorded. Placental trophoblast samples were processed to isolate mitochondria and perform molecular biology assays. Women with preeclampsia exhibited the characteristic clinical features of the disease, along with biochemical alterations consistent with an inflammatory process. A significant decrease (73%) in mitochondrial DNA (mtDNA) copy number in trophoblastic tissue and a reduction in citrate synthase (CS) activity (-51%) in cytotrophoblast mitochondria-enriched fractions were observed in preeclampsia, indicating mitochondrial dysfunction accompanied by a loss of functional mitochondrial mass. In addition, we detected a marked decrease in MnSOD levels (-32%), together with an increase in the LC3II/LC3I ratio (47%) in cytotrophoblast mitochondria-enriched fractions, supporting the presence of mitochondrial alterations and suggesting the possible activation of mitophagy specifically in this cell type. Moreover, coenzyme Q10 (CoQ10) levels were elevated by 31% in trophoblastic villi. A pronounced 2.5-fold increase in CoQ10 normalized to CS activity (CoQ10/CS) was detected specifically in cytotrophoblasts from preeclamptic placentas. Importantly, we did not observe these alterations in the syncytiotrophoblast. In conclusion, preeclampsia is associated with mitochondrial dysfunction and increased CoQ10 levels normalized to CS activity, specifically in cytotrophoblast mitochondria, with findings being consistent with a possible involvement of mitophagy in this cell type. These findings suggest that cytotrophoblast mitochondrial metabolism may be more affected in preeclampsia compared with syncytiotrophoblasts, and that CoQ10 accumulation together with the possible activation of mitophagy may represent cellular defense mechanisms. Due to the limitations of the study, it should be considered exploratory and hypothesis-generating, and its results should be regarded as preliminary.

Keywords:  coenzyme Q10; cytotrophoblast; mitochondria; mitophagy; preeclampsia

DOI:  https://doi.org/10.3390/biology15020139
Mol Genet Metab. 2026 Jan 07. pii: S1096-7192(26)00014-4. [Epub ahead of print]147(3): 109731

Outcomes of kidney transplantation in three patients with single large-scale mitochondrial DNA deletion syndromes.

Steven H Lang, Naiga Cottingham, Colleen Donnelly, Sarah Risen, Rossana Malatesta Muncher, Eileen D Brewer, Jeffery M Saland, Corrine Benchimol, Fernando Scaglia, Jaya Ganesh.

  Single large-scale mitochondrial DNA deletion syndromes (SLSMDS) are a clinical continuum of three classic discrete clinical syndromes: Pearson marrow-pancreas syndrome, Kearns-Sayre syndrome, and chronic progressive ophthalmoplegia. Kidney manifestations, including chronic kidney disease with progression kidney failure has emerged as significant cause of morbidity and mortality in SLSMDS. Despite this recognition, reports of kidney transplantation in this population are limited. Here, we describe outcomes of kidney transplantation in three patients with SLSMDS and kidney failure over a 1-2.5-year follow-up period. All three patients had multisystem involvement at the time of transplantation. In all three patients, surgery was uncomplicated without evidence of acute metabolic decompensation in the perioperative period and standard immunosuppressive protocols were well tolerated. One patient developed post-transplant lymphoproliferative disease at 9 months status-post transplant which was ultimately fatal. The two surviving patients remain with stable graft function and functional quality of life at 1- and 3.5-years post-transplant.

Keywords:  CKD (chronic kidney disease); Kearns-Sayre syndrome (KSS); Kidney transplant; Mitochondrial disease; Pearson marrow-pancreas syndrome (PMP); Progressive external ophthalmoplegia (PEO); Single large scale mitochondrial DNA deletion syndromes (SLSMDS)

DOI:  https://doi.org/10.1016/j.ymgme.2026.109731
Sci Rep. 2026 Jan 28.

Myo-Inositol modulates AKT signalling, mitochondrial protein expression and intracellular Ca²⁺dynamics in human dermal fibroblasts.

Paola Zanfardino, Alessandro Amati, Domenico Iacobellis, Matilde Colella, Vittoria Petruzzella.



Keywords:  AKT; Calcium; Mitochondria; Myoinositol; Oxidative phosphorylation; Phosphoinositides

DOI:  https://doi.org/10.1038/s41598-026-37423-z
Nat Commun. 2026 Jan 27. 17(1): 1064

Cryo-EM structures of human ClpXP reveal mechanisms of assembly and proteolytic activation.

Wenqian Chen, Gabriel C Lander, Jie Yang.

The human ClpXP complex (hClpXP) orchestrates mitochondrial protein quality control through targeted degradation of misfolded and unnecessary proteins. While bacterial ClpXP systems are well characterized, the assembly and regulation of human ClpXP remain poorly understood. In this study, we elucidate the complete assembly pathway of hClpXP through high-resolution cryo-electron microscopy (cryo-EM) structures. Our findings confirm that hClpP exists as a single-ring heptamer in isolation and reveal a previously undocumented initial assembly complex in which hexameric hClpX first engages with heptameric hClpP. We further demonstrate how this interaction drives substantial conformational rearrangements that facilitate the formation of tetradecameric hClpP within the fully assembled complex. Notably, we characterize a unique eukaryotic sequence in hClpX, termed the E-loop, which plays a critical role in stabilizing hexamer assembly and maintaining ATPase activity. Additionally, we show that peptide binding at the hClpP active site triggers further structural changes essential for achieving full proteolytic competence. Together, these structures provide unprecedented mechanistic insights into the stepwise assembly and activation of hClpXP, significantly advancing our understanding of this essential mitochondrial protein degradation machinery.

DOI: https://doi.org/10.1038/s41467-025-67010-1
Int J Mol Sci. 2026 Jan 06. pii: 575. [Epub ahead of print]27(2):

Biallelic Truncating DNAH14 Variant in Siblings with Neurodevelopmental Disorder and Predominant Ataxia: Clinical Report and Literature Review.

Savas Baris, Mustafa Dogan, Kerem Terali, Alper Gezdirici, Recep Eroz, Peren Perk Yucel, Huseyin Kilic, Cuneyd Yavas, Gizem Yildirim, Ibrahim Baris.

  Neurodevelopmental disorders (NDDs) with ataxia are genetically heterogeneous and remain a diagnostic challenge. Recent advances in genomic technologies have facilitated the identification of rare, potentially causative variants in genes not traditionally associated with classic NDD phenotypes. The DNAH14 gene, encoding a dynein axonemal heavy chain involved in ciliary motility, has recently emerged as a novel candidate in neurological syndromes. Here, we report two Turkish siblings presenting with late-onset balance disorder, progressive ataxia, and cognitive impairment. Initial genetic analysis revealed that both siblings also harbor FXN GAA repeat expansions consistent with pathogenic Friedreich's ataxia (FRDA). To elucidate the molecular basis of the patients' cognitive impairment, whole-exome sequencing was performed. This analysis identified a novel homozygous frameshift variant in the DNAH14 gene, located within the conserved linker domain upstream of the motor core, which is critical for ATP hydrolysis and microtubule interactions. The variant is absent from population databases, predicted to be deleterious by multiple in silico algorithms, and segregates in the family in a manner consistent with autosomal recessive inheritance. The coexistence of FRDA expansions and a truncating DNAH14 variant suggests a potential dual genetic contribution to the observed phenotype, in which FRDA-associated pathology likely underlies the ataxia, while DNAH14 disruption may contribute to additional neurodevelopmental features. This is the first report describing the co-occurrence of FRDA and a homozygous truncating DNAH14 variant in the same individuals, broadening our understanding of overlapping neurogenetic mechanisms. Our findings expand the phenotypic spectrum of DNAH14-related disorders and highlight the importance of considering multilocus pathogenic variants in patients with complex or atypical ataxia presentations.

Keywords:  DNAH14; ataxia; bioinformatic; genetic disease; neurodevelopment; variant

DOI:  https://doi.org/10.3390/ijms27020575
Int J Mol Sci. 2026 Jan 15. pii: 881. [Epub ahead of print]27(2):

Hereditary Ataxias: From Pathogenesis and Clinical Features to Neuroimaging, Fluid, and Digital Biomarkers-A Scoping Review.

Eugenio Bernardi, Óscar López-Lombardía, Gonzalo Olmedo-Saura, Javier Pagonabarraga, Jaime Kulisevsky, Jesús Pérez-Pérez.

  Hereditary ataxias are a heterogeneous group of disorders with overlapping clinical presentations but diverse genetic and molecular etiologies. Biomarkers are increasingly essential to improve diagnosis, refine prognosis, and accelerate the development of targeted therapies. Following PRISMA-ScR guidelines, we conducted a scoping review of PubMed and complementary sources (2010-2025) to map and describe the current landscape of genetic, imaging, fluid, electrophysiological, and digital biomarkers across the most prevalent hereditary ataxias, including SCA1, SCA2, SCA3, SCA6, SCA7, SCA17, SCA27B, dentatorubral-pallidoluysian atrophy (DRPLA), Friedreich's ataxia (FRDA), RFC1-related ataxia (CANVAS), SPG7, and fragile X-associated tremor/ataxia syndrome (FXTAS). Eligible evidence encompassed observational cohorts, clinical trials, case series, and case reports providing primary biomarker data, with the objective of characterizing evidence breadth and identifying knowledge gaps rather than assessing comparative effectiveness. Across modalities, converging evidence highlights subtype-specific biomarker signatures. MRI volumetry, DTI, and FDG-PET map characteristic neurodegeneration patterns. Fluid biomarkers such as neurofilament light chain are informative across several SCAs and FRDA, while frataxin levels constitute robust endpoints in FRDA trials. Pathology-specific biomarkers such as ataxin-3 are advancing as tools for target engagement and may generalize to future gene-lowering strategies. Electrophysiological and oculographic measures show sensitivity for early disease detection, and wearable technologies are emerging as scalable tools for longitudinal monitoring. This scoping review synthesizes the heterogeneous evidence on hereditary ataxia biomarkers, highlighting multimodal frameworks that link molecular mechanisms with clinical endpoints. Mapping current approaches also reveals substantial variability and gaps across diseases and modalities, underscoring the need for harmonized validation in international multicenter cohorts and systematic integration into future clinical trials to advance precision medicine in hereditary ataxias.

Keywords:  CANVAS; FDG-PET; FXTAS; Friedreich’s ataxia; MRI biomarker; biomarker; cerebellar ataxia; genetic ataxia; hereditary ataxia; neurofilament light chain; spinocerebellar ataxia

DOI:  https://doi.org/10.3390/ijms27020881
Front Immunol. 2025 ;16 1740433

Mitochondrial DAMPs as a critical driver in the development of acute graft versus host disease and emerging mitochondria targeted therapeutic strategies.

Vasantharaja Raguraman, Yogamaya Divakar Prabhu, Gopal Viswanathan Velmurugan, Gerhard C Hildebrandt, Senthilnathan Palaniyandi.

  Mitochondrial fusion and fission regulate mitochondrial morphology and homeostasis, both of which are essential for maintaining cellular health. Free mitochondria and mitochondrial-containing extracellular vesicles have emerged as key mediators of pathological processes. Conditioning regimens for allogeneic hematopoietic cell transplantation (HCT) damage and lead to impaired mitochondrial function, including biogenesis and respiration, as well as elevated reactive oxygen species (ROS), which contribute to the development of inflammatory conditions as well as activation of antigen presenting cells, the latter being key players in acute graft versus host pathophysiology (GVHD). This leads to increased T-cell activation and proliferation, which increases alloreactivity and drives GVHD. Dysregulated mitochondrial dynamics lead to the release of mitochondrial DNA and formylated peptides, which act as Damage-Associated Molecular Patterns (DAMPs) and trigger cellular homeostatic imbalances, ultimately leading to more inflammation. The understanding that mitochondrial dysfunction contributes to GVHD offers novel therapeutic strategies, including blocking DAMP signaling and modulating immune cell metabolism to restore mitochondrial health. This review aims to understand mitochondrial homeostasis in both recipient and donor cells. This is crucial for understanding GVHD pathophysiology and developing mitochondria-targeted therapies or mitochondrial transfer strategies as potential therapeutic interventions for GVHD.

Keywords:  DAMP (Damage Associated Molecular Pattern); Graft versus host disease (GVHD); hematopoietic cell transplantation (HCT); mitochondria transfer; mitochondrial DNA

DOI:  https://doi.org/10.3389/fimmu.2025.1740433
Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00028-6. [Epub ahead of print]

Mitochondria as sources and targets of cellular signaling.

Anna Meichsner, Verian Bader, Konstanze F Winklhofer.

  Mitochondria are multifunctional organelles that, in addition to providing energy, coordinate various signaling pathways essential for maintaining cellular homeostasis. Their suitability as signaling organelles arises from a unique combination of structural and functional plasticity, allowing them to sense, integrate, and respond to a wide variety of cellular cues. Mitochondria are highly dynamic-they can fuse and divide, pinch off vesicles, and move around, facilitating interorganellar communication. Moreover, their ultrastructural peculiarities enable tight regulation of fluxes across the inner and outer mitochondrial membranes. As organelles of proteobacterial origin, mitochondria harbor danger signals and require protection from the consequences of membrane damage by efficient quality control mechanisms. However, mitochondria have also been co-opted by eukaryotic cells to react to cellular damage and promote effective immune responses. In this review, we provide an overview of our current knowledge of mitochondria as both sources and targets of cellular signaling.

Keywords:  ISR; MAVS; NEMO; NF-κB; UPRmt; cGAS/STING; cardiolipin; inflammation; innate immune signaling; membrane contact sites; mitochondria; mtDNA; mtRNA; signaling

DOI:  https://doi.org/10.1016/j.molcel.2026.01.008
Nat Commun. 2026 Jan 28.

Impaired stem cell migration and divisions in Duchenne muscular dystrophy revealed by live imaging.

Liza Sarde, Gaëlle Letort, Hugo Varet, Vincent Laville, Julien Fernandes, Shahragim Tajbakhsh, Brendan Evano.

Dysregulation of stem cell properties is a hallmark of many pathologies, but the dynamic behaviour of stem cells in their microenvironment during disease progression remains poorly understood. Using the mdx mouse model of Duchenne Muscular Dystrophy, we developed innovative live imaging of muscle stem cells (MuSCs) in vivo, and ex vivo on isolated myofibres. We show that mdx MuSCs have impaired migration and precocious differentiation through unbalanced symmetric divisions, driven by p38 and PI3K signalling pathways, in contrast to the p38-only dependence of healthy MuSCs. Cross-grafting shows that MuSC fate decisions are governed by fibre-independent cues, whereas their migration behaviour is determined by the myofibre niche. This study provides the first dynamic analysis of dystrophic MuSC properties in vivo, reconciling conflicting reports on their function. Our findings establish DMD as a MuSC disease with niche dysfunctions, offering strategies to restore stem cell functions for improved muscle regeneration.

DOI: https://doi.org/10.1038/s41467-026-68474-5