bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2025–04–13
sixteen papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture.
  2. TMEM65 joins the mitochondrial Ca2+ club.
  3. A decisive technical leap forward for personalized medicine to treat mitochondrial diseases.
  4. Metabolite tunes MDV pathway to maintain mitochondrial fitness.
  5. Small molecules restore mutant mitochondrial DNA polymerase activity.
  6. Knockdown of POLG Mimics the Neuronal Pathology of Polymerase-γ Spectrum Disorders in Human Neurons.
  7. Mitochondria and cell death signalling.
  8. Cells are swapping their mitochondria. What does this mean for our health?
  9. Epigenetics and Mitochondrial Biogenesis: The Role of Sirtuins in HIV Neuropathogenesis.
  10. Novel in vivo models of autosomal optic atrophy reveal conserved pathological changes in neuronal mitochondrial structure and function.
  11. The mitochondrial unfolded protein response inhibits pluripotency acquisition and mesenchymal-to-epithelial transition in somatic cell reprogramming.
  12. The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT.
  13. HRI protein kinase in cytoplasmic heme sensing and mitochondrial stress response: relevance to hematological and mitochondrial diseases.
  14. The Role of Autophagy in Excitotoxicity, Synaptic Mitochondrial Stress and Neurodegeneration.
  15. TMEM65 regulates and is required for NCLX-dependent mitochondrial calcium efflux.
  16. Multipotent neural stem cells originating from neuroepithelium exist outside the mouse central nervous system.
  1. EMBO Mol Med. 2025 Apr 09.
    Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture.
    Pavel A Nash, Keira M Turner, Christopher A Powell, Lindsey Van Haute, Pedro Silva-Pinheiro, Felix Bubeck, Ellen Wiedtke, Eloïse Marques, Dylan G Ryan, Dirk Grimm, Payam A Gammage, Michal Minczuk.
      Mutations in the mitochondrial genome (mtDNA) often lead to clinical pathologies. Mitochondrially-targeted zinc finger nucleases (mtZFNs) have been successful in reducing the levels of mutation-bearing mtDNA both in vivo and in vitro, resulting in a shift in the genetic makeup of affected mitochondria and subsequently to phenotypic rescue. Given the uneven distribution in the mtDNA mutation load across tissues in patients, and a great diversity in pathogenic mutations, it is of interest to develop mutation-specific, selective gene therapies that could be delivered to particular tissues. This study demonstrates the effectiveness of in vivo mitochondrial gene therapy using a novel mtZFN architecture on skeletal muscle using adeno-associated viral (AAV) platforms in a murine model harboring a pathogenic mtDNA mutation. We observed effective reduction in mutation load of cardiac and skeletal muscle, which was accompanied by molecular phenotypic rescue. The gene therapy treatment was shown to be safe when markers of immunity and inflammation were assessed. These results highlight the potential of curative approaches for mitochondrial diseases, paving the way for targeted and effective treatments.
    Keywords:  Adeno-Associated Viruses (AAV); Gene Therapy; Skeletal Muscle; Zinc Finger Nuclease (mtZFN); mtDNA Heteroplasmy Modification
    DOI:  https://doi.org/10.1038/s44321-025-00231-5
  2. Nat Metab. 2025 Apr 08.
    TMEM65 joins the mitochondrial Ca2+ club.
    Yasemin Sancak.
      
    DOI:  https://doi.org/10.1038/s42255-025-01271-4
  3. EMBO Mol Med. 2025 Apr 09.
    A decisive technical leap forward for personalized medicine to treat mitochondrial diseases.
    Abi S Ghifari, Martin Ott.
      
    DOI:  https://doi.org/10.1038/s44321-025-00232-4
  4. Mol Cell. 2025 Apr 03. pii: S1097-2765(25)00189-3. [Epub ahead of print]85(7): 1253-1255
    Metabolite tunes MDV pathway to maintain mitochondrial fitness.
    Shiori Sekine, Yusuke Sekine.
      In this issue of Molecular Cell, Tang et al.1 demonstrate that the ketone body β-hydroxybutyrate (BHB) promotes the biogenesis of mitochondrial-derived vesicles (MDVs) via lysine β-hydroxybutyrylation (Kbhb) on SNX9, revealing a way to fine-tune the mitochondrial quality control pathway with metabolites.
    DOI:  https://doi.org/10.1016/j.molcel.2025.02.027
  5. Nature. 2025 Apr 09.
    Small molecules restore mutant mitochondrial DNA polymerase activity.
    Sebastian Valenzuela, Xuefeng Zhu, Bertil Macao, Mattias Stamgren, Carol Geukens, Paul S Charifson, Gunther Kern, Emily Hoberg, Louise Jenninger, Anja V Gruszczyk, Seoeun Lee, Katarina A S Johansson, Javier Miralles Fusté, Yonghong Shi, S Jordan Kerns, Laleh Arabanian, Gabriel Martinez Botella, Sofie Ekström, Jeremy Green, Andrew M Griffin, Carlos Pardo-Hernández, Thomas A Keating, Barbara Küppers-Munther, Nils-Göran Larsson, Cindy Phan, Viktor Posse, Juli E Jones, Xie Xie, Simon Giroux, Claes M Gustafsson, Maria Falkenberg.
      Mammalian mitochondrial DNA (mtDNA) is replicated by DNA polymerase γ (POLγ), a heterotrimeric complex consisting of a catalytic POLγA subunit and two accessory POLγB subunits1. More than 300 mutations in POLG, the gene encoding the catalytic subunit, have been linked to severe, progressive conditions with high rates of morbidity and mortality, for which no treatment exists2. Here we report on the discovery and characterization of PZL-A, a first-in-class small-molecule activator of mtDNA synthesis that is capable of restoring function to the most common mutant variants of POLγ. PZL-A binds to an allosteric site at the interface between the catalytic POLγA subunit and the proximal POLγB subunit, a region that is unaffected by nearly all disease-causing mutations. The compound restores wild-type-like activity to mutant forms of POLγ in vitro and activates mtDNA synthesis in cells from paediatric patients with lethal POLG disease, thereby enhancing biogenesis of the oxidative phosphorylation machinery and cellular respiration. Our work demonstrates that a small molecule can restore function to mutant DNA polymerases, offering a promising avenue for treating POLG disorders and other severe conditions linked to depletion of mtDNA.
    DOI:  https://doi.org/10.1038/s41586-025-08856-9
  6. Cells. 2025 Mar 22. pii: 480. [Epub ahead of print]14(7):
    Knockdown of POLG Mimics the Neuronal Pathology of Polymerase-γ Spectrum Disorders in Human Neurons.
    Çağla Çakmak Durmaz, Felix Langerscheidt, Imra Mantey, Xinyu Xia, Hans Zempel.
      Impaired function of Polymerase-γ (Pol-γ) results in impaired replication of the mitochondrial genome (mtDNA). Pathogenic mutations in the POLG gene cause dysfunctional Pol-γ and dysfunctional mitochondria and are associated with a spectrum of neurogenetic disorders referred to as POLG spectrum disorders (POLG-SDs), which are characterized by neurologic dysfunction and premature death. Pathomechanistic studies and human cell models of these diseases are scarce. SH-SY5Y cells (SHC) are an easy-to-handle and low-cost human-derived neuronal cell model commonly used in neuroscientific research. Here, we aimed to study the effect of reduced Pol-γ function using stable lentivirus-based shRNA-mediated knockdown of POLG in SHC, in both the proliferating cells and SHC-derived neurons. POLG knockdown resulted in approximately 50% reductions in POLG mRNA and protein levels in naïve SHC, mimicking the residual Pol-γ activity observed in patients with common pathogenic POLG mutations. Knockdown cells exhibited decreased mtDNA content, reduced levels of mitochondrial-encoded proteins, and altered mitochondrial morphology and distribution. Notably, while chemical induction of mtDNA depletion via ddC could be rescued by the mitochondrial biosynthesis stimulators AICAR, cilostazol and resveratrol (but not MitoQ and formoterol) in control cells, POLG-knockdown cells were resistant to mitochondrial biosynthesis-mediated induction of mtDNA increase, highlighting the specificity of the model, and pathomechanistically hinting towards inefficiency of mitochondrial stimulation without sufficient Pol-γ activity. In differentiated SHC-derived human neurons, POLG-knockdown cells showed impaired neuronal differentiation capacity, disrupted cytoskeletal organization, and abnormal perinuclear clustering of mitochondria. In sum, our model not only recapitulates key features of POLG-SDs such as impaired mtDNA content, which cannot be rescued by mitochondrial biosynthesis stimulation, but also reduced ATP production, perinuclear clustering of mitochondria and impaired neuronal differentiation. It also offers a simple, cost-effective and human (and, as such, disease-relevant) platform for investigating disease mechanisms, one with screening potential for therapeutic approaches for POLG-related mitochondrial dysfunction in human neurons.
    Keywords:  Polymerase-γ; SH-SY5Y; mitochondria; mtDNA; neurogenetics; neuronal differentiation
    DOI:  https://doi.org/10.3390/cells14070480
  7. Curr Opin Cell Biol. 2025 Apr 10. pii: S0955-0674(25)00048-1. [Epub ahead of print]94 102510
    Mitochondria and cell death signalling.
    Ella Hall-Younger, Stephen Wg Tait.
      Mitochondria are essential organelles in the life and death of a cell. During apoptosis, mitochondrial outer membrane permeabilisation (MOMP) engages caspase activation and cell death. Under nonlethal apoptotic stress, some mitochondria undergo permeabilisation, termed minority MOMP. Nonlethal apoptotic signalling impacts processes including genome stability, senescence and innate immunity. Recent studies have shown that upon MOMP, mitochondria and consequent signalling can trigger inflammation. We discuss how this occurs, and how mitochondrial inflammation might be targeted to increase tumour immunogenicity. Finally, we highlight how mitochondria contribute to other types of cell death including pyroptosis and ferroptosis. Collectively, these studies reveal critical new insights into how mitochondria regulate cell death, highlighting that mitochondrial signals engaged under nonlethal apoptotic stress have wide-ranging biological functions.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102510
  8. Nature. 2025 Apr;640(8058): 302-304
    Cells are swapping their mitochondria. What does this mean for our health?
    Gemma Conroy.
      
    Keywords:  Cancer; Cell biology; Diseases
    DOI:  https://doi.org/10.1038/d41586-025-01064-5
  9. Mol Neurobiol. 2025 Apr 08.
    Epigenetics and Mitochondrial Biogenesis: The Role of Sirtuins in HIV Neuropathogenesis.
    James Haorah, Hemavathi Iyappan, Malaroviyam Samikkannu, Karthick Chennakesavan, Jay P McLaughlin, Thangavel Samikkannu.
      Mitochondrial energy deficits play a central role in HIV-associated neurocognitive disorder (HAND). HIV disrupts cellular functions, including epigenetic modifications such as class III histone deacetylation mediated by sirtuins (SIRTs). However, the role of SIRTs in HAND pathogenesis remains unclear. We hypothesize that HIV alters mitochondrial biogenesis and energy homeostasis by modifying SIRT family members 1-7, contributing to HAND progression. To test this hypothesis, we examined postmortem frontal lobe brain tissue from people with HIV (PWH) and HIV-negative controls, focusing on epigenetic alterations in SIRTs 1-7, the energy sensor adenosine monophosphate-activated protein kinase (AMPK), the mitochondrial master regulator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and transcription factors such as mitochondrial transcription factor A (TFAM), nuclear respiratory factors 1 and 2 (NRF-1/2), and factors associated with oxidative phosphorylation (OXPHOS). Our analysis revealed a significant increase in AMPK, OXPHOS, and PGC-1α levels, alongside a decrease in TFAM levels in PWH brains compared to uninfected controls. NRF-1 was upregulated in mitochondria but downregulated in the cytoplasm, while NRF-2 exhibited the opposite trend in PWH compared to HIV-negative controls. The epigenetic signatures of SIRTs 1, 2, 3, 4, 6, and 7 were upregulated in PWH, while SIRT5 was downregulated compared to uninfected brain tissues. We exposed primary human astrocyte and microglial cultures to the HIV-1 transactivator of transcription (Tat) protein to identify the cell types involved. These studies confirmed that HIV-induced epigenetic modifications of SIRTs and mitochondrial impairments occurred in both astrocytes and microglia, highlighting the crucial role of SIRTs in HAND pathogenesis.
    Keywords:  Epigenetic modification; HAND; HIV; Mitochondrial biogenesis; Sirtuins
    DOI:  https://doi.org/10.1007/s12035-025-04885-7
  10. FASEB J. 2025 Apr 15. 39(7): e70497
    Novel in vivo models of autosomal optic atrophy reveal conserved pathological changes in neuronal mitochondrial structure and function.
    Elin L Strachan, Eugene T Dillon, Mairéad Sullivan, Jeffrey C Glennon, Amandine Peyrel, Jérôme Sarniguet, Kevin Dubois, Benjamin Delprat, Breandán N Kennedy, Niamh C O'Sullivan.
      Autosomal optic atrophy (AOA) is a form of hereditary optic neuropathy characterized by the irreversible and progressive degermation of the retinal ganglion cells. Most cases of AOA are associated with a single dominant mutation in OPA1, which encodes a protein required for fusion of the inner mitochondrial membrane. It is unclear how loss of OPA1 leads to neuronal death, and despite ubiquitous expression appears to disproportionately affect the RGCs. This study introduces two novel in vivo models of OPA1-mediated AOA, including the first developmentally viable vertebrate Opa1 knockout (KO). These models allow for the study of Opa1 loss in neurons, specifically RGCs. Though survival is significantly reduced in Opa1 deficient zebrafish and Drosophila, both models permit the study of viable larvae. Moreover, zebrafish Opa1 KO larvae show impaired visual function but unchanged locomotor function, indicating that retinal neurons are particularly sensitive to Opa1 loss. Proteomic profiling of both models reveals marked disruption in protein expression associated with mitochondrial function, consistent with an observed decrease in mitochondrial respiratory function. Similarly, mitochondrial fragmentation and disordered cristae organization were observed in neuronal axons in both models highlighting Opa1's highly conserved role in regulating mitochondrial morphology and function in neuronal axons. Importantly, in Opa1 deficient zebrafish, mitochondrial disruption and visual impairment precede degeneration of RGCs. These novel models mimic key features of AOA and provide valuable tools for therapeutic screening. Our findings suggest that therapies enhancing mitochondrial function may offer a potential treatment strategy for AOA.
    Keywords:   Drosophila ; mitochondria; optic atrophy; visual impairment; zebrafish
    DOI:  https://doi.org/10.1096/fj.202403271R
  11. Nat Metab. 2025 Apr 09.
    The mitochondrial unfolded protein response inhibits pluripotency acquisition and mesenchymal-to-epithelial transition in somatic cell reprogramming.
    Zhongfu Ying, Yanmin Xin, Zihuang Liu, Tianxin Tan, Yile Huang, Yingzhe Ding, Xuejun Hong, Qiuzhi Li, Chong Li, Jingyi Guo, Gaoshen Liu, Qi Meng, Shihe Zhou, Wenxin Li, Yao Yao, Ge Xiang, Linpeng Li, Yi Wu, Yang Liu, Miaohui Mu, Zifeng Ruan, Wenxi Liang, Junwei Wang, Yaofeng Wang, Baojian Liao, Yang Liu, Wuming Wang, Gang Lu, Dajiang Qin, Duanqing Pei, Wai-Yee Chan, Xingguo Liu.
      The mitochondrial unfolded protein response (UPRmt), a mitochondria-to-nucleus retrograde pathway that promotes the maintenance of mitochondrial function in response to stress, plays an important role in promoting lifespan extension in Caenorhabditis elegans1,2. However, its role in mammals, including its contributions to development or cell fate decisions, remains largely unexplored. Here, we show that transient UPRmt activation occurs during somatic reprogramming in mouse embryonic fibroblasts. We observe a c-Myc-dependent, transient decrease in mitochondrial proteolysis, accompanied by UPRmt activation at the early phase of pluripotency acquisition. UPRmt impedes the mesenchymal-to-epithelial transition (MET) through c-Jun, thereby inhibiting pluripotency acquisition. Mechanistically, c-Jun enhances the expression of acetyl-CoA metabolic enzymes and reduces acetyl-CoA levels, thereby affecting levels of H3K9Ac, linking mitochondrial signalling to the epigenetic state of the cell and cell fate decisions. c-Jun also decreases the occupancy of H3K9Ac at MET genes, further inhibiting MET. Our findings reveal the crucial role of mitochondrial UPR-modulated MET in pluripotent stem cell plasticity. Additionally, we demonstrate that the UPRmt promotes cancer cell migration and invasion by enhancing epithelial-to-mesenchymal transition (EMT). Given the crucial role of EMT in tumour metastasis3,4, our findings on the connection between the UPRmt and EMT have important pathological implications and reveal potential targets for tumour treatment.
    DOI:  https://doi.org/10.1038/s42255-025-01261-6
  12. Nat Commun. 2025 Apr 04. 16(1): 3221
    The Futile Creatine Cycle powers UCP1-independent thermogenesis in classical BAT.
    Jakub Bunk, Mohammed F Hussain, Maria Delgado-Martin, Bozena Samborska, Mina Ersin, Abhirup Shaw, Janane F Rahbani, Lawrence Kazak.
      Classical brown adipose tissue (BAT) is traditionally viewed as relying exclusively on uncoupling protein 1 (UCP1) for thermogenesis via inducible proton leak. However, the physiological significance of UCP1-independent mechanisms linking substrate oxidation to ATP turnover in classical BAT has remained unclear. Here, we identify the Futile Creatine Cycle (FCC), a mitochondrial-localized energy-wasting pathway involving creatine phosphorylation by creatine kinase b (CKB) and phosphocreatine hydrolysis by tissue-nonspecific alkaline phosphatase (TNAP), as a key UCP1-independent thermogenic mechanism in classical BAT. Reintroducing mitochondrial-targeted CKB exclusively into interscapular brown adipocytes in vivo restores thermogenesis and cold tolerance in mice lacking native UCP1 and CKB, in a TNAP-dependent manner. Furthermore, mice with inducible adipocyte-specific co-deletion of TNAP and UCP1 exhibit severe cold-intolerance. These findings challenge the view that BAT thermogenesis depends solely on UCP1 because of insufficient ATP synthase activity and establishes the FCC as a physiologically relevant thermogenic pathway in classical BAT.
    DOI:  https://doi.org/10.1038/s41467-025-58294-4
  13. J Biol Chem. 2025 Apr 08. pii: S0021-9258(25)00343-6. [Epub ahead of print] 108494
    HRI protein kinase in cytoplasmic heme sensing and mitochondrial stress response: relevance to hematological and mitochondrial diseases.
    Jane-Jane Chen.
      Most iron in humans is bound in heme used as a prosthetic group for hemoglobin. Heme-regulated inhibitor (HRI) is responsible for coordinating heme availability and protein synthesis. Originally characterized in rabbit reticulocyte lysates, HRI was shown in 1976 to phosphorylate the α-subunit of eIF2, revealing a new molecular mechanism for regulating protein synthesis. Since then, HRI research has mostly been focused on the biochemistry of heme inhibition through direct binding, and heme sensing in balancing heme and globin synthesis to prevent proteotoxicity in erythroid cells. Beyond inhibiting translation of highly translated mRNAs, eIF2α phosphorylation also selectively increases translation of certain poorly translated mRNAs, notably ATF4 mRNA, for reprogramming of gene expression to mitigate stress, known as the integrated stress response (ISR). In recent years, there have been novel mechanistic insights of HRI-ISR in oxidative stress, mitochondrial function and erythroid differentiation during heme deficiency. Furthermore, HRI-ISR is activated upon mitochondrial stress in several cell types, establishing the bifunctional nature of HRI protein. The role of HRI and ISR in cancer development and vulnerability is also emerging. Excitingly, the UBR4 ubiquitin ligase complex has been demonstrated to silence the HRI-ISR by degradation of activated HRI proteins, suggesting additional regulatory processes. Together, these recent advancements indicate that the HRI-ISR mechanistic axis is a target for new therapies for hematological and mitochondrial diseases, as well as oncology. This review covers the historical overview of HRI biology, the biochemical mechanisms of regulating HRI, and the biological impacts of the HRI-ISR pathway in human diseases.
    Keywords:  ATF4; E3 ubiquitin ligase; Erythropoiesis; Heme; Mitochondrial stress; Protein kinase; Protein synthesis; Proteostasis; Stress response; eIF2
    DOI:  https://doi.org/10.1016/j.jbc.2025.108494
  14. Autophagy Rep. 2025 ;pii: 2464376. [Epub ahead of print]4(1):
    The Role of Autophagy in Excitotoxicity, Synaptic Mitochondrial Stress and Neurodegeneration.
    Charleen T Chu.
      Brain and nervous system functions depend upon maintaining the integrity of synaptic structures over the lifetime. Autophagy, a key homeostatic quality control system, plays a central role not only in neuronal development and survival/cell death, but also in regulating synaptic activity and plasticity. Glutamate is the major excitatory neurotransmitter that activates downstream targets, with a key role in learning and memory. However, an excess of glutamatergic stimulation is pathological in stroke, epilepsy and neurodegeneration, triggering excitotoxic cell death or a sublethal process of excitatory mitochondrial calcium toxicity (EMT) that triggers dendritic retraction. Markers of autophagy and mitophagy are often elevated following excitatory neuronal injuries, with the potential to influence cell death or neurodegenerative outcomes of these injuries. Interestingly, leucine-rich repeat kinase 2 (LRRK2) and PTEN-induced kinase 1 (PINK1), two kinases linked to autophagy, mitophagy and Parkinson disease, play important roles in regulating mitochondrial calcium handling, synaptic density and function, and maturation of dendritic spines. Mutations in LRRK2, PINK1, or proteins linked to Alzheimer's disease perturb mitochondrial calcium handling to sensitize neurons to excitatory injury. While autophagy and mitophagy can play both protective and harmful roles, studies in various excitotoxicity and stroke models often implicate autophagy in a pathogenic role. Understanding the role of autophagic degradation in regulating synaptic loss and cell death following excitatory neuronal injuries has important therapeutic implications for both acute and chronic neurological disorders.
    Keywords:  Alzheimer disease; Epilepsy; Glutamate toxicity; Leucine-rich repeat kinase 2; Mitochondrial Na+/Ca2+ exchanger; Mitochondrial calcium uniporter; PTEN-induced kinase 1; Parkinson disease; hypoxia-ischemia; post-synaptic calcium
    DOI:  https://doi.org/10.1080/27694127.2025.2464376
  15. Nat Metab. 2025 Apr 08.
    TMEM65 regulates and is required for NCLX-dependent mitochondrial calcium efflux.
    Joanne F Garbincius, Oniel Salik, Henry M Cohen, Carmen Choya-Foces, Adam S Mangold, Angelina D Makhoul, Anna E Schmidt, Dima Y Khalil, Joshua J Doolittle, Anya S Wilkinson, Emma K Murray, Michael P Lazaropoulos, Alycia N Hildebrand, Dhanendra Tomar, John W Elrod.
      The balance between mitochondrial calcium (mCa2+) uptake and efflux is essential for ATP production and cellular homeostasis. The mitochondrial sodium-calcium exchanger, NCLX, is a critical route of mCa2+ efflux in excitable tissues, such as the heart and brain, and animal models support NCLX as a promising therapeutic target to limit pathogenic mCa2+ overload. However, the mechanisms that regulate NCLX activity are largely unknown. Using proximity biotinylation proteomic screening, we identify the mitochondrial inner membrane protein TMEM65 as an NCLX binding partner that enhances sodium (Na+)-dependent mCa2+ efflux. Mechanistically, acute pharmacological NCLX inhibition or genetic deletion of NCLX ablates the TMEM65-dependent increase in mCa2+ efflux, and loss-of-function studies show that TMEM65 is required for Na+-dependent mCa2+ efflux. In line with these findings, knockdown of Tmem65 in mice promotes mCa2+ overload in the heart and skeletal muscle and impairs both cardiac and neuromuscular function. Collectively, our results show that loss of TMEM65 function in excitable tissue disrupts NCLX-dependent mCa2+ efflux, causing pathogenic mCa2+ overload, cell death, and organ-level dysfunction. These findings demonstrate the essential role of TMEM65 in regulating NCLX-dependent mCa2+ efflux and suggest modulation of TMEM65 as a therapeutic strategy for a variety of diseases.
    DOI:  https://doi.org/10.1038/s42255-025-01250-9
  16. Nat Cell Biol. 2025 Apr;27(4): 605-618
    Multipotent neural stem cells originating from neuroepithelium exist outside the mouse central nervous system.
    Dong Han, Wan Xu, Hyun-Woo Jeong, Hongryeol Park, Kathrin Weyer, Yaroslav Tsytsyura, Martin Stehling, Guangming Wu, Guocheng Lan, Kee-Pyo Kim, Henrik Renner, Dong Wook Han, Yicong Chen, Daniela Gerovska, Marcos J Araúzo-Bravo, Jürgen Klingauf, Jens Christian Schwamborn, Ralf H Adams, Pentao Liu, Hans R Schöler.
      Conventional understanding dictates that mammalian neural stem cells (NSCs) exist only in the central nervous system. Here, we report that peripheral NSCs (pNSCs) exist outside the central nervous system and can be isolated from mouse embryonic limb, postnatal lung, tail, dorsal root ganglia and adult lung tissues. Derived pNSCs are distinct from neural crest stem cells, express multiple NSC-specific markers and exhibit cell morphology, self-renewing and differentiation capacity, genome-wide transcriptional profile and epigenetic features similar to control brain NSCs. pNSCs are composed of Sox1+ cells originating from neuroepithelial cells. pNSCs in situ have similar molecular features to NSCs in the brain. Furthermore, many pNSCs that migrate out of the neural tube can differentiate into mature neurons and limited glial cells during embryonic and postnatal development. Our discovery of pNSCs provides previously unidentified insight into the mammalian nervous system development and presents an alternative potential strategy for neural regenerative therapy.
    DOI:  https://doi.org/10.1038/s41556-025-01641-w
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