bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2025–11–02
twenty-two papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Super mitochondria-enriched extracellular vesicles enable enhanced mitochondria transfer.
  2. The evolving landscape of mitochondrial base editing: advances in precision, modeling, and therapeutic potential.
  3. Siblings of FBXL4-related mitochondrial DNA depletion syndrome, leading to fatal fulminant pneumonia.
  4. Cytosine methylase and hydroxymethylase activity in mammalian mitochondria.
  5. A special latch in yeast mitofusin guarantees mitochondrial fusion by stabilizing self-assembly.
  6. A case of POLG-related mitochondrial DNA maintenance defect.
  7. Light-evoked activity and BDNF regulate mitochondrial dynamics and mitochondrial localized translation in CNS axons.
  8. Modeling Mitochondrial Disease Using Brain Organoids: A Focus on Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes.
  9. Accumulation of complex I assembly intermediates in a novel presentation of RTN4IP1-related disorder with developmental delay, ataxia and dyskinesia.
  10. Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration.
  11. Improved specificity and efficiency of in vivo adenine base editing therapies with hybrid guide RNAs.
  12. Mitochondrial organization in the developing proximal tubule is controlled by LRRK2.
  13. Brain organoid models of Huntington's disease shift the focus towards neurodevelopment.
  14. mTORC1-dependent suppression of autophagic activity in somatic cell nuclear transfer mouse embryos.
  15. Mitochondrial dysfunction in adipocyte differentiation: implications for obesity and metabolic syndrome intervention.
  16. VDAC1 inhibitor DIDS uncouples respiration in isolated tissue mitochondria and induces mitochondrial hyperfusion in mammalian cells.
  17. Loss of Ezrin triggers mitochondrial dysfunction and oxidative stress, associated with neuronal cell death.
  18. Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle.
  19. Marf- and Opa1-Dependent Formation of Mitochondrial Network Structure Is Required for Cell Growth and Subsequent Meiosis in Drosophila Males.
  20. Personalized gene editing helped one baby: can it be rolled out widely?
  21. Targeted cell interconversions reveal inner hair cell control of organ of Corti cytoarchitecture.
  22. Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial.
  1. Nat Commun. 2025 Oct 27. 16(1): 9448
    Super mitochondria-enriched extracellular vesicles enable enhanced mitochondria transfer.
    Yi Wang, Hao-Yuan Yu, Zi-Juan Yi, Lian-Yu Qi, Jing-Song Yang, Hai-Xin Xie, Min Zhao, Na-Hui Liu, Jia-Qi Chen, Tian-Jiao Zhou, Lei Xing, Xian-Wu Cheng, Hu-Lin Jiang.
      Mitochondria transfer is a spontaneous process that releases functional mitochondria to damaged cells via different mechanisms including extracellular vesicle containing mitochondria (EV-Mito) to restore mitochondrial functions. However, the limited EV-Mito yield makes it challenging to supply a sufficient quantity of functional mitochondria to damaged cells, hindering their application in mitochondrial diseases. Here, we show that the release of EV-Mito from mesenchymal stem cells (MSCs) is regulated by a calcium-dependent mechanism involving CD38 and IP3R signaling (CD38/IP3R/Ca2+ pathway). Activating this pathway through our non-viral gene engineering approach generates super donor MSCs which produce Super-EV-Mito with a threefold increase in yield compared to Ctrl-EV-Mito from normal MSCs. Leber's hereditary optic neuropathy (LHON), a classic mitochondrial disease caused by mtDNA mutations, is used as a proof-of-concept model. Super-EV-Mito rescues mtDNA defects and alleviates LHON-associated symptoms in LHON male mice. This strategy offers a promising avenue for enhancing mitochondria transfer efficiency and advancing its clinical application in mitochondrial disorders.
    DOI:  https://doi.org/10.1038/s41467-025-64486-9
  2. Mitochondrion. 2025 Oct 29. pii: S1567-7249(25)00090-X. [Epub ahead of print] 102093
    The evolving landscape of mitochondrial base editing: advances in precision, modeling, and therapeutic potential.
    Prathamesh Shelke, Sharon Tribhuvan, Ashish Kumar Agrahari, Reshu Saxena.
      The recent development of mitochondrial base editors (mitoBEs) has ushered in a transformational time that has overcome some long-standing limitations in the field of mitochondrial genetics. By closely tracing mitoBE development from the earliest tool mitochondria targeted TALENs to the most recent base editing systems that can precisely convert C•G → T•A and A•T → G•C, we review mitoBEs. We describe the development of recent advancements in mitoBEs including the generation of second generation mitoBEs (mitoBEs v2), which have evidence to identify over 70 mouse mtDNA mutations comparable to human pathogenic variants. Notably, in order to incorporate circular RNA (circRNA) as a delivery vector the editing efficiency has been increased by over 82 %, without experimental evidence of off-target effects. Taking advantage of these gains in technology, these mouse models of mitochondrial diseases, including those associated with Leigh syndrome and LHN, are highly faithful. These models have also confirmed that these specific mtDNA variants have pathological phenotypic evaluations, and have compared to previous editing strategies, mitoBEs v2 have demonstrated improved specificity, stability and safety. We finally discuss the future of mitochondrial base editing and outline the ways it will move forward towards therapeutic potentials in the treatment of the mitochondrial disorders and also in precision medicine.
    Keywords:  ABE; CBE; Mitochondrial diseases; TALED; circRNA; mitoBEs; mtDNA
    DOI:  https://doi.org/10.1016/j.mito.2025.102093
  3. Mol Genet Metab Rep. 2025 Dec;45 101266
    Siblings of FBXL4-related mitochondrial DNA depletion syndrome, leading to fatal fulminant pneumonia.
    Takato Akiba, Shino Shimada, Shimpei Matsuda, Shoji Ishida, Yosuke Baba, Atsushi Yamashita, Hiromichi Shoji, Yasushi Okazaki, Kei Murayama.
      The F-box and leucine-rich repeat protein 4 (FBXL4) is a nuclear encoded mitochondrial protein essential for mitochondrial DNA (mtDNA) maintenance. Biallelic variants in FBXL4 cause FBXL4-related mitochondrial DNA depletion syndrome (FBXL4-MTDPS), characterized by lactic acidosis and developmental delay. We report two siblings diagnosed with FBXL4-MTDPS who died of fulminant pneumonia in infancy; autopsy revealed extensive pulmonary inflammation consistent with severe bacterial infection. FBXL4-MTDPS may involve intrinsic defects in pulmonary infection defense, increasing susceptibility to fatal infection such as pneumonia.
    Keywords:  Encephalomyopathic mitochondrial DNA depletion syndrome; F-box and leucine-rich repeat protein 4; Fatal fulminant pneumonia; Lactic acidosis; Mitophagy
    DOI:  https://doi.org/10.1016/j.ymgmr.2025.101266
  4. Front Cell Dev Biol. 2025 ;13 1677402
    Cytosine methylase and hydroxymethylase activity in mammalian mitochondria.
    Lisa S Shock, Prashant V Thakkar, Jason M Robinson, Shirley M Taylor.
       Introduction: Mitochondria are integral components of eukaryotic cells, functioning as energy powerhouses and key mediators of diverse metabolic and signaling cascades. As endosymbiotic remnants, these unique organelles retain and express their own DNA. Mitochondrial DNA (mtDNA) is packaged into DNA-protein complexes called nucleoids, and is also subject to epigenetic modification. We identified a mitochondrial isoform of DNA methyltransferase 1 (mtDNMT1) that binds to mtDNA in critical control regions; however, its enzymatic activity remained unexplored.
    Results: Here, we show that endogenously-tagged mtDNMT1 purified from mitochondria exhibits time- and concentration-dependent CpG-specific DNA methyltransferase activity, but it is not working alone: DNMT3b cooperates with mtDNMT1 to methylate mtDNA and regulate mitochondrial transcription. In addition, we detect ten-eleven translocase (TET)-like hydroxymethylase activity in mitochondria, demonstrating that mechanisms for both writing and erasing 5-methylcytosine marks are functional in this organelle. CRISPR/Cas9-mediated inactivation of mtDNMT1 and/or DNMT3b activity resulted in a stepwise decrease in mitochondrial methylation across the heavy and light strand promoters of mtDNA, with a significant reduction in transcription of several mtDNA-encoded OXPHOS genes. Interestingly, the effects of mtDNA methylation on mitochondrial transcription are diametrically opposed to the role of promoter methylation in the nucleus, suggesting a novel mode of gene regulation in mitochondria. Cells lacking mtDNMT1 and/or DNMT3b also exhibited a modest reduction in mtDNA content, suggesting that methylation impacts both mtDNA transcription and replication.
    Discussion: These observations implicate mtDNA methylation in the fine-tuning of mitochondrial function and suggest a role for aberrant mitochondrial methylase activity in disease.
    Keywords:  DNA demethylation; DNA methylation; DNA methyltransferase; DNA replication; epigenetics; mitochondrial DNA (mtDNA); transcription
    DOI:  https://doi.org/10.3389/fcell.2025.1677402
  5. Nat Commun. 2025 Oct 31. 16(1): 9644
    A special latch in yeast mitofusin guarantees mitochondrial fusion by stabilizing self-assembly.
    Shu-Jing Huang, Dong-Fei Ma, Caiting Yu, Jing Li, Xinyu Tu, Zi Huang, Yuanbo Qi, Jun-Ying Ou, Jian-Xiong Feng, Bing Yu, Yu-Lu Cao, Jia-Xing Yue, Junjie Hu, Ming Li, Ying Lu, Liming Yan, Song Gao.
      The mitochondrion is a highly dynamic organelle, constantly undergoing fusion and fission, which are critical processes for the health of cells. Fusion of the outer mitochondrial membrane (OMM) is mediated by the mitofusins belonging to the dynamin superfamily of GTPases. Most eukaryotic organisms possess two cooperatively functioning mitofusins, but yeast has only one mitofusin (Fzo1). How Fzo1 solely catalyzes OMM fusion is unclear. Here, we present crystal structures of truncated Fzo1 (Fzo1IM) in different nucleotide-loading states and report a special mechanistic feature of Fzo1 through systematic functional studies. Differing from mammalian mitofusins, Fzo1 contains an extra latch bulge (LB) that is essential for the viability of yeast. Upon GTP loading, Fzo1IM dimerizes via the GTPase domain and prefers the closed conformation. This state is then locked by the subsequent trans interaction mediated by the LB of each protomer, so that Fzo1IM remains dimerized in the closed conformation even after GTP hydrolysis. This special mechanistic feature may be relevant to the previous observation that degradation of Fzo1 by the ubiquitin-proteasome system is required for mitochondrial fusion. Our study reveals how mitochondrial fusion in yeast is efficiently ensured with limited GTP consumption, which broadens current understanding of this fundamental biological process.
    DOI:  https://doi.org/10.1038/s41467-025-64646-x
  6. Acta Neurol Belg. 2025 Oct 31.
    A case of POLG-related mitochondrial DNA maintenance defect.
    Junyi Wang, Changhong Tan, Fen Deng, Xi Liu, Lifen Chen.
      Mitochondrial DNA (mtDNA) maintenance defects (specifically mtDNA depletion syndromes, MDS) are autosomal recessive disorders caused by a severe reduction in mtDNA content, leading to impaired oxidative phosphorylation and energy deficiency in affected tissues. The clinical heterogeneity of mtDNA maintenance defects correlates with specific gene mutations, with POLG being one of the most frequently implicated genes in mitochondrial dysfunction. We report a novel case of mtDNA maintenance defects manifesting with progressive ocular symptoms, including blepharoptosis, blurred vision, and diplopia, associated with a rare homozygous POLG mutation (c.924G > T, p.Gln308His), which is the second reported homozygous variant at this nucleotide site. Among five previously reported POLG c.924G > T-associated MDS cases, 4 are heterozygous (compound heterozygous or combined with other mitochondrial gene variants). POLG encodes DNA polymerase γ, essential for mtDNA replication; mutations impair mitochondrial function, reducing respiratory chain activity and ATP production. This case adds to the existing literature on the phenotypic variability of POLG-related disorders and expands the known spectrum of pathogenic POLG variants. Despite the rarity of this mutation, its clinical presentation is consistent with classic progressive external ophthalmoplegia (PEO), underscoring the importance of genetic testing in diagnosing mtDNA maintenance defects. Further studies are needed to clarify genotype-phenotype correlations and develop targeted therapeutic strategies for POLG-associated mitochondrial dysfunction.
    Keywords:  DNA polymerase; Mitochondrial DNA (mtDNA) maintenance defects; Progressive external ophthalmoplegia (PEO); The POLG gene
    DOI:  https://doi.org/10.1007/s13760-025-02922-9
  7. iScience. 2025 Oct 17. 28(10): 113563
    Light-evoked activity and BDNF regulate mitochondrial dynamics and mitochondrial localized translation in CNS axons.
    Alexander Kreymerman, Jessica E Weinstein, Nirmal Vadgama, Sahil H Shah, Michael M Nahmou, Kinsley C Belle, Marco H Ji, Xin Xia, Anne Faust, Yolandi Van Der Merwe, David N Buickians, In-Jae Cho, Star K Huynh, Sonya Verma, Kristina Russano, Xiao-Lu Jin, Ioannis Karakikes, Michael B Steketee, Jeffrey L Goldberg.
      Mitochondria coordinate well-described maintenance functions within neuronal axons and dendrites. However, less is known about how mitochondria are regulated during axon development and maturation. Here, we demonstrate that within the developing visual system, retinal ganglion cell (RGC) axons in the retina and optic nerve exhibit increases in mitochondria size, number, and total area in vivo. Our findings indicate that these developmental changes in mitochondria are driven by neuronal activity associated with eye opening and by brain-derived neurotrophic factor (BDNF). These events occur in concert with downstream gene and protein expression changes consistent with mitochondrial biogenesis and energetics pathways. We further demonstrate that activity- and BDNF-regulated transcripts are localized and translated at mitochondria within RGC axons in vivo, concomitant with the regulation of mitochondrial dynamics. These data highlight the previously undescribed regulation of mitochondrial dynamics in axonal maturation, dependent on mechanisms involving neuronal activity and neurotrophic factor signaling, coordinated with mitochondrial-localized translation.
    Keywords:  Biological sciences; Natural sciences; Neuroscience; Systems neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2025.113563
  8. J Vis Exp. 2025 Oct 10.
    Modeling Mitochondrial Disease Using Brain Organoids: A Focus on Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes.
    Shihori Kawano, Chika Saegusa, Yusuke Masano, Franziska Becker, Mari Nakamura, Seiji Shiozawa, Junji Fujikura, Takafumi Toyohara, Takaaki Abe, Hideyuki Okano, Masato Fujioka.
      Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) are mitochondrial disorders most commonly caused by a m.3243A>G variant in mitochondrial tRNALeu. To investigate the pathophysiology of MELAS, we generated brain organoids from multiple induced pluripotent stem cell (iPSC) lines derived from a patient with MELAS carrying the m.3243A>G variant. These lines share an identical nuclear genetic background but differ in their heteroplasmy levels involving the m.3243A>G variant. We observed significant differences in organoid size, morphology, and neural induction efficiency, which correlated with the degree of heteroplasmy. Dissociated neurons from the organoids were transferred into a 2D-culture system, which is convenient and suitable for high-throughput drug screening. The organoids also exhibited significant differences in the formation of neural networks, depending on heteroplasmy levels. Our results suggest that patient-derived iPSC-based organoid models represent a useful platform for studying MELAS mechanisms and for drug screening. This video presents comprehensive and user-friendly methods, including protocols for generating organoids and evaluating phenotypes.
    DOI:  https://doi.org/10.3791/69303
  9. Mol Genet Metab. 2025 Oct 24. pii: S1096-7192(25)00258-6. [Epub ahead of print]146(3): 109266
    Accumulation of complex I assembly intermediates in a novel presentation of RTN4IP1-related disorder with developmental delay, ataxia and dyskinesia.
    Liene Thys, Diane Beysen, Katrien Janssens, Anna C Jansen, Naig Gueguen, Morgane LeMao, Fanny Fontaine, Stéphane Allouche, Guy Lenaers, Marije Meuwissen.
       BACKGROUND: Biallelic variants in RTN4IP1 (OPA10) are associated with a wide phenotypic spectrum including optic atrophy with or without ataxia, impaired intellectual development and seizures (OMIM 616732). Brain imaging ranges from normal to white matter changes and cerebral atrophy. Earlier literature has reported a combined complex I and IV deficiency in RTN4IP1 cases.
    RESULTS: We report on three siblings, compound heterozygous for novel RTN4IP1 variants who presented with a movement disorder with pronounced dyskinesia along with developmental delay, optic atrophy and ataxia. Furthermore, atypical brain MRI findings with symmetrical bilateral substantia nigra abnormalities were observed in two of them. Blue native polyacrylamide gel electrophoresis performed on fibroblasts of two patients revealed a defect in the complex I assembly process.
    CONCLUSION: Thus, we expand the clinical spectrum of RTN4IP1-associated disease with movement disorder, substantia nigra abnormalities and complex I assembly defects.
    Keywords:  Ataxia; Dyskinesia; Movement disorder; OPA10 syndrome; Optic atrophy; RTN4IP1
    DOI:  https://doi.org/10.1016/j.ymgme.2025.109266
  10. Nat Cell Biol. 2025 Oct 31.
    Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration.
    Qiaochu Li, Konstantin Weiss, Fuateima Niwa, Jan Riemer, Thorsten Hoppe.
      The mitochondrial proteome is remodelled to meet metabolic demands, but how metabolic cues regulate mitochondrial protein turnover remains unclear. Here we identify a conserved, nutrient-responsive mechanism in which the amino acid leucine suppresses ubiquitin-dependent degradation of outer mitochondrial membrane (OMM) proteins, stabilizing key components of the protein import machinery and expanding the mitochondrial proteome to enhance metabolic respiration. Leucine inhibits the amino acid sensor GCN2, which selectively reduces the E3 ubiquitin ligase cofactor SEL1L at mitochondria. Depletion of SEL1L phenocopies the effect of leucine, elevating OMM protein abundance and mitochondrial respiration. Disease-associated defects in leucine catabolism and OMM protein turnover impair fertility in Caenorhabditis elegans and render human lung cancer cells resistant to inhibition of mitochondrial protein import. These findings define a leucine-GCN2-SEL1L axis that links nutrient sensing to mitochondrial proteostasis, with implications for metabolic disorders and cancer.
    DOI:  https://doi.org/10.1038/s41556-025-01799-3
  11. Nat Biomed Eng. 2025 Oct 28.
    Improved specificity and efficiency of in vivo adenine base editing therapies with hybrid guide RNAs.
    Madelynn N Whittaker, Lauren C Testa, Aidan Quigley, Dominique L Brooks, Sarah A Grandinette, Hooda Said, Garima Dwivedi, Ishaan Jindal, Daphne Volpp, Julia L Hacker, Ping Qu, Josh Zhiyong Wang, Michael A Levine, Rebecca C Ahrens-Nicklas, Qiaoli Li, Kiran Musunuru, Mohamad-Gabriel Alameh, William H Peranteau, Xiao Wang.
      Phenylketonuria (PKU), pseudoxanthoma elasticum (PXE) and hereditary tyrosinemia type 1 (HT1) are autosomal recessive disorders linked to the PAH, ABCC6, and FAH and HPD genes, respectively. Here we evaluate the off-target editing profiles of clinical lead guide RNAs (gRNAs) that, when combined with adenine base editors (ABEs), correct the recurrent PAH P281L variant, PAH R408W variant or ABCC6 R1164X variant, or disrupt either of two sites in the HPD gene (a modifier gene of HT1) in human hepatocytes. To mitigate off-target mutagenesis, we systematically screen hybrid gRNAs with DNA nucleotide substitutions. Comprehensive and variant-aware specificity profiling of these hybrid gRNAs reveals dramatically reduced off-target editing and reduced bystander editing in cells. In humanized PAH P281L and ABCC6 R1164X mouse models of PKU and PXE, we show that when formulated in lipid nanoparticles with ABE messenger RNA, selected hybrid gRNAs revert disease phenotypes, reduce off-target editing, increase on-target editing and reduce bystander editing in vivo. These studies highlight the use of hybrid gRNAs to improve the safety and efficiency of adenine base-editing therapies.
    DOI:  https://doi.org/10.1038/s41551-025-01545-y
  12. Nat Commun. 2025 Oct 30. 16(1): 9611
    Mitochondrial organization in the developing proximal tubule is controlled by LRRK2.
    Mohsina Khan, Kyle Bond, Elyse Grilli, Daniel Cameron, Liyang Zhao, Sunder Sims-Lucas, Andrew P McMahon, Thomas J Carroll, Leif Oxburgh.
      The proximal tubule of the nephron performs energy-demanding functions such as resorption of water, amino acids and glucose. Formation of the energy-producing machinery is an essential step in proximal tubule epithelial cell differentiation, and this report asks how mitochondria are localized within these cells. We show that mitochondria move from the apical to basolateral side of the proximal tubule cell coincident with the initiation of lumen flow and that proximal tubules deficient in filtration maintain mitochondria in the apical position. Mitochondrial localization depends on the activity of LRRK2 and modeling fluid flow on cultured proximal tubule epithelial cells demonstrates that LRRK2 activity is regulated by fluid shear stress, explaining how onset of flow in the newly differentiated proximal tubule may trigger the apical-to-basolateral dissemination of mitochondria. These findings indicate that mitochondrial redistribution is one component of a cellular program in the nascent proximal tubule that drives function and that this process is triggered by flow.
    DOI:  https://doi.org/10.1038/s41467-025-64598-2
  13. Dis Model Mech. 2025 Oct 01. pii: dmm052510. [Epub ahead of print]18(10):
    Brain organoid models of Huntington's disease shift the focus towards neurodevelopment.
    Wenqing Xu, Alessandro Prigione.
      Huntington's disease (HD) is traditionally viewed as an age-related disorder. Emerging evidence suggests that mutant huntingtin (mHTT) disrupts early neurodevelopment, although the contribution of developmental alterations to the late disease onset remains to be clarified. Leveraging human pluripotent stem cell-derived brain organoids, we and others are exploring how mHTT affects the developing human brain. These models reveal impaired neural progenitor organization and function, accompanied by a mitochondrial stress response, indicating reduced capacity to manage cellular stress. Enhancing mitochondrial health and promoting neural cell resilience may thus represent potential strategies for improving the brain's compensatory mechanisms, thereby prolonging a healthy state. These insights highlight a potential window of opportunity for therapeutic interventions. Targeting mitochondrial fitness and neurodevelopmental pathways at early stages - long before clinical symptoms emerge - could help prevent or delay disease onset and progression in affected individuals.
    DOI:  https://doi.org/10.1242/dmm.052510
  14. Reproduction. 2025 Dec 01. pii: e250338. [Epub ahead of print]170(6):
    mTORC1-dependent suppression of autophagic activity in somatic cell nuclear transfer mouse embryos.
    Takaki Tatebe, Dinh Quoc Pham, Atsuo Ogura, Kimiko Inoue.
       In brief: The non-genomic factors responsible for developmental arrest in SCNT embryos remain poorly understood. Using live-cell fluorescence imaging, we revealed that autophagic activity is impaired in preimplantation SCNT embryos, possibly due to ectopic activation of the mTORC1 signaling pathway, providing new insights into cytoplasmic barriers to cloning efficiency.
    Abstract: Activation of autophagy after fertilization is essential for mammalian embryonic development, as it supplies embryos with nutrients and energy. Somatic cell nuclear transfer (SCNT) embryos frequently exhibit developmental arrest, largely because of incomplete genomic reprogramming; however, the role of non-genomic factors remains unclear. Here, we investigated autophagy dynamics in mouse SCNT embryos using immunostaining and live-cell fluorescence imaging. In fertilized embryos, autophagy increased markedly from the late 2-cell stage and peaked at the morula stage. SCNT embryos followed a similar timeline but consistently showed reduced autophagic activity. Notably, the autophagic activity levels varied among SCNT embryos and positively correlated with their developmental potential. Attempts to enhance genomic reprogramming, including the removal of somatic histone methylation, did not restore autophagy. Instead, transcriptome analysis revealed ectopic activation of mTORC1 signaling as a likely cause of impaired autophagy. Consistently, treatment with an mTORC1 inhibitor successfully rescued autophagic activity in SCNT embryos. These findings identify a persistent autophagy defect during preimplantation development in SCNT embryos and suggest that modulation of non-genomic pathways, such as mTORC1 signaling, could improve SCNT efficiency.
    Keywords:  autophagy; mTORC1; preimplantation embryo; somatic cell nuclear transfer
    DOI:  https://doi.org/10.1530/REP-25-0338
  15. Acta Biochim Biophys Sin (Shanghai). 2025 Oct 30.
    Mitochondrial dysfunction in adipocyte differentiation: implications for obesity and metabolic syndrome intervention.
    Yunwen Xu, Shiqin Xie, Luoyang Han, Liang Xu, Yuqin Zhu.
      Mitochondrial dysfunction critically disrupts adipocyte remodeling by impairing the thermogenic browning process essential for combating obesity through the upregulation of uncoupling protein 1 (UCP1) and mitochondrial biogenesis. Deficiencies in mitochondrial metabolism, dynamics (including fusion/fission), and autophagy suppress adipocyte plasticity, directly inhibiting UCP1 expression and destabilizing the PPAR-γ/PGC-1α and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling pathways. These disruptions reduce energy expenditure, exacerbate insulin resistance, and promote metabolic syndrome. Moreover, mitochondrial inactivation intersects with neurodegenerative disorders via oxidative stress induced by β-amyloid and α-synuclein aggregation, amplifying systemic metabolic dysregulation. Structural mitochondrial anomalies further impede lipid utilization and adipose tissue adaptation, but unresolved crosstalk between mtDNA and nuclear DNA complicates therapeutic targeting. Future research must prioritize spatiotemporal mapping of mitochondrial dynamics in adipocyte differentiation via single-cell omics to identify key regulatory nodes. Addressing these mechanisms could unlock precision therapies, such as gene editing, to restore mitochondrial function, enhance adipocyte browning, and mitigate obesity, related pathologies alongside neurodegenerative and age-associated diseases.
    Keywords:  adipocyte browning; metabolic syndrome; mitochondria; mitochondrial dysfunction; obesity
    DOI:  https://doi.org/10.3724/abbs.2025153
  16. BBA Adv. 2025 ;8 100171
    VDAC1 inhibitor DIDS uncouples respiration in isolated tissue mitochondria and induces mitochondrial hyperfusion in mammalian cells.
    Surajit Das, Arpita Dutta, Minakshi Bedi, Arumay Pal, Shubhra Majumder, Alok Ghosh.
      Mitochondrial outer membrane protein, voltage-dependent anion channel 1 (VDAC1), is a gatekeeper of transport, metabolism, and cellular apoptosis. Ablation of VDAC1 or treatment with small molecular VDAC1 inhibitors often causes metabolic reprogramming in cells. However, the mechanism of VDAC1-mediated reprogramming of mitochondrial oxidative phosphorylation (OXPHOS) is still unclear. To address this problem, we tested how the high-affinity VDAC1 inhibitor, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), changes cell viability and mitochondrial functions. The IC50 value of DIDS was found 508 µM and 580 µM after 24 h of treatment on human osteosarcoma U2OS and mouse NIH-3T3 fibroblast cells. Moreover, when we inhibited mitochondrial OXPHOS by oligomycin A, 500 µM DIDS was found to uncouple the respiration like the conventional uncoupler CCCP in both the cells. Additionally, we observed that 50-200 µM DIDS, even after 2 h of treatment, depolarizes mitochondrial membrane potential. Also, brief DIDS treatment leads to an increase in cell population with hyperfused mitochondria and attenuation of DRP1 recruitment to mitochondria in U2OS cells. However, no significant alteration in the steady-state level of mitochondrial respiratory chain complex I and complex V subunits was noticed after DIDS treatment. Similar to cell lines, DIDS treatment also showed significant respiratory uncoupling in isolated mitochondria prepared from the normal muscle, liver, and sarcoma tumor tissues of mice. Finally, in silico modeling using AutoDock Vina and AlphaFold3 identified that DIDS binds inside the beta-barrel structure of VDAC1. Together, our findings directly demonstrate that DIDS binds to the VDAC1 inner pocket, uncouples OXPHOS, and promotes mitochondrial hyperfusion.
    Keywords:  DIDS; Mitochondrial dynamics; OXPHOS; Uncoupling; VDAC1; mitochondria
    DOI:  https://doi.org/10.1016/j.bbadva.2025.100171
  17. Cell Death Discov. 2025 Oct 27. 11(1): 490
    Loss of Ezrin triggers mitochondrial dysfunction and oxidative stress, associated with neuronal cell death.
    Giuliana Giamundo, Iolanda Carratù, Chiara Barone, Rossella De Cegli, Giovanna Trinchese, Maria Pina Mollica, Dario Antonini, Ivan Conte.
      EZRIN is a key player in assembling and coordinating molecular signaling, acting as a linker between receptors in plasma membrane and the actin cytoskeleton. High EZRIN expression level has been extensively studied and often associated with metastasis and cancer progression. Recent reports independently suggested associations between Ezrin and mitochondrial alterations or apoptotic processes, the mechanism by which Ezrin modulates these events remain largely unclear. Here we report that the lack of EZRIN-mediated EGFR internalization and translocation on mitochondria is critical for mitochondrial metabolism. Ezrin-deficient (Ezrin-/-) cells exhibit marked impairments in mitochondrial respiratory chain (MRC) activity. These cells also show significantly reduced ATP production and elevated mitochondrial ROS levels, revealing cell metabolism deficit. Furthermore, Ezrin loss induces mitochondrial ROS-mediated apoptosis. In vivo, Medaka fish lacking Ezrin display neuronal cell death associated with inflammation, which appear linked to the compromised mitochondrial metabolism and oxidative stress. Our findings reveal a key mechanism within endo-lysosomal signaling that involves Ezrin and the EGFR/TSC complex. both of which are essential for neuronal homeostasis. In conclusion, our data identify a novel molecular pathway in which the Ezrin/EGFR axis regulates mitochondrial metabolism, thereby supporting cellular energy balance and promoting neuronal cell survival.
    DOI:  https://doi.org/10.1038/s41420-025-02790-5
  18. Mol Cell. 2025 Oct 28. pii: S1097-2765(25)00819-6. [Epub ahead of print]
    Accumulation of succinate suppresses de novo purine synthesis through succinylation-mediated control of the mitochondrial folate cycle.
    Mushtaq A Nengroo, Austin T Klein, Heather S Carr, Olivia Vidal-Cruchez, Umakant Sahu, Daniel J McGrail, Nidhi Sahni, Niklas B Thompson, Peter A Faull, Peng Gao, John M Asara, Hardik Shah, Marc L Mendillo, Issam Ben-Sahra.
      The de novo purine synthesis pathway is fundamental for nucleotide production, yet the role of mitochondrial metabolism in modulating this process remains underexplored. Here, we identify that succinate dehydrogenase (SDH) is essential for maintaining de novo purine synthesis. Genetic or pharmacological inhibition of SDH suppresses purine synthesis, contributing to a decrease in cell proliferation. Mechanistically, SDH inhibition elevates succinate, which in turn promotes the succinylation of serine hydroxymethyltransferase 2 (SHMT2) within the mitochondrial tetrahydrofolate (THF) cycle. This post-translational modification lowers formate output, depriving cells of one-carbon units needed for purine assembly. In turn, cancer cells activate the purine salvage pathway, a metabolic compensatory adaptation that represents a therapeutic vulnerability. Notably, co-inhibition of SDH and purine salvage induces pronounced antiproliferative and antitumoral effects in preclinical models. These findings reveal a signaling role for mitochondrial succinate in tuning nucleotide metabolism and highlight a dual-targeted strategy to exploit metabolic dependencies in cancer.
    Keywords:  TCA cycle; cancer; formate; mitochondrial metabolism; nucleotide metabolism; succinate
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.002
  19. Int J Mol Sci. 2025 Oct 14. pii: 9991. [Epub ahead of print]26(20):
    Marf- and Opa1-Dependent Formation of Mitochondrial Network Structure Is Required for Cell Growth and Subsequent Meiosis in Drosophila Males.
    Tatsuru Matsuo, Mitsuki Yamanaka, Yoshihiro H Inoue.
      Mitochondria are dynamic organelles that undergo repeated fusion and fission. We studied how the distribution and shape of mitochondria change during Drosophila spermatogenesis and whether factors that regulate their dynamics are necessary for these changes. Unlike the shortened mitochondria seen in mitosis, an interconnected network of elongated mitochondria forms before meiosis and is maintained during meiotic divisions. Mitochondria are evenly divided into daughter cells, relying on microtubules and F-actin. To explore the role of mitochondrial network structure in cell growth and meiosis, we depleted the mitochondrial fusion factors Opa1 and Marf and the morphology proteins Letm1 and EndoB in spermatocytes. This knockdown led to inhibited cell growth and failed meiosis. As a result, the spermatocytes differentiated into spermatids without completing meiosis. The knockdown also inhibited the cytoplasmic and nuclear accumulation of Cyclin B before meiosis, and Cdk1 was not fully activated at the onset of meiosis. Notably, ectopic overexpression of Cyclin B partially rescued the failure of meiosis. Many spermatids from the spermatocytes subjected to the knockdowns contained multiple smaller nuclei and abnormally shaped Nebenkerns. These findings suggest that mitochondrial network structure, maintained by fusion and morphology factors, is essential for meiosis progression and Nebenkern formation in Drosophila spermatogenesis.
    Keywords:  Cyclin B; Drosophila; meiosis; mitochondrial dynamics; nebenkern; spermatogenesis
    DOI:  https://doi.org/10.3390/ijms26209991
  20. Nature. 2025 Oct 31.
    Personalized gene editing helped one baby: can it be rolled out widely?
      
    Keywords:  CRISPR-Cas9 genome editing; Genetics; Medical research; Personalized medicine
    DOI:  https://doi.org/10.1038/d41586-025-03566-8
  21. Sci Adv. 2025 Oct 31. 11(44): eadz3944
    Targeted cell interconversions reveal inner hair cell control of organ of Corti cytoarchitecture.
    Ignacio García-Gómez, Jemma L Webber, Berta Soria-Izquierdo, John C Clancy, Anne Duggan, Yingjie Zhou, Charles P Murphey, Trevor D M Harriman, Jianghong Wang, Mary Ann Cheatham, Jaime García-Añoveros.
      The mammalian organ of Corti is a precisely intercalated mosaic of two types of mechanosensory hair cells (HCs) and six types of supporting cells (SCs) arranged in 11 parallel rows. Differentially specialized SCs surround inner HCs (IHCs) and outer HCs (OHCs). To elucidate the developmental roles of IHCs and OHCs in the formation, differentiation, and assembly of the various SCs, we genetically switched HC identities at several developmental stages and also generated mice lacking IHCs. We find that IHCs promote or induce the (i) differentiation of one SC type (outer pillar) at the expense of another (Deiters'), so that each completely and exclusively populates separate rows; (ii) packing density, but not identity, of inner pillar cells; and (iii) embryonic formation and (iv) cytoplasmic attraction of adjacent inner phalangeal cells, which envelop IHCs. Hence, developing IHCs dictate major aspects of SC identity and distribution to assemble the complex organ of Corti.
    DOI:  https://doi.org/10.1126/sciadv.adz3944
  22. Nat Aging. 2025 Oct 31.
    Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial.
    Dominic Denk, Anurag Singh, Herbert G Kasler, Davide D'Amico, Julia Rey, Lucía Alcober-Boquet, Johanna M Gorol, Christoph Steup, Ritesh Tiwari, Ryan Kwok, Rafael J Argüello, Julie Faitg, Kathrin Sprinzl, Stefan Zeuzem, Valentina Nekljudova, Sibylle Loibl, Eric Verdin, Chris Rinsch, Florian R Greten.
      Mitochondrial dysfunction and stem cell exhaustion contribute to age-related immune decline, yet clinical interventions targeting immune aging are lacking. Recently, we demonstrated that urolithin A (UA), a mitophagy inducer, expands T memory stem cells (TSCM) and naive T cells in mice. In this randomized, double-blind, placebo-controlled trial, 50 healthy middle-aged adults received oral UA (1,000 mg day-1) or placebo for 4 weeks; time points of analysis were baseline and day 28. Primary outcomes were phenotypical changes in peripheral CD3+ T cell subsets and immune metabolic remodeling. UA expanded peripheral naive-like, less terminally exhausted CD8+ cells (treatment difference 0.50 percentage points; 95% CI = 0.16 to 0.83; P = 0.0437) while also increasing CD8+ fatty acid oxidation capacity (treatment difference = 14.72 percentage points; 95% confidence interval (CI) = 6.46 to 22.99; P = 0.0061). Secondary outcomes included changes in plasma cytokine levels (IL-6, TNF, IL-1β, IL-10), immune populations assessed via flow cytometry, immune cell function, and mitochondrial content. Analysis revealed augmented mitochondrial biogenesis in CD8+ cells, increased peripheral CD56dimCD16bright NK cells, and nonclassical CD14loCD16hi monocytes in UA-treated participants, as well as improved activation-elicited TNF secretion in T cells and bacterial uptake by monocytes. Exploratory single-cell RNA sequencing demonstrated UA-driven transcriptional shifts across immune populations, modulating pathways linked to inflammation and metabolism. These findings indicate that short-term UA supplementation modulates human immune cell composition and function, supporting its potential to counteract age-related immune decline and inflammaging. ClinicalTrials.gov registration number: NCT05735886 .
    DOI:  https://doi.org/10.1038/s43587-025-00996-x
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