bims-mitmed Biomed News
on Mitochondrial medicine
Issue of 2025–06–08
24 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico
  1. Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh Syndrome mice.
  2. Base editors model mitochondrial disease.
  3. Mitochondrial tRNA processing defects reprogram mitochondrial and cellular homeostasis.
  4. Powering new therapeutics with precision mitochondrial editing.
  5. Evaluating the feasibility of gene replacement strategies to treat MTRFR deficiency.
  6. The developing retina undergoes mitochondrial remodeling via PINK1/PRKN-dependent mitophagy.
  7. Cross-comparison of strains used for mitochondrial imaging in Caenorhabditis elegans during aging.
  8. Biallelic NSUN3 Variants Cause Diverse Phenotypic Spectrum Disease: From Isolated Optic Atrophy to Severe Early-Onset Mitochondrial Disorder.
  9. ROMO1 overexpression protects the mitochondrial cysteinome from oxidations in aging.
  10. Ndufs4-/- mice: a testing ground for longevity interventions.
  11. Tissue-Specific Regulation of Fatty Acid Metabolism in a Mouse Model of Isolated Complex I Deficiency.
  12. A mitochondrial disease model is generated and corrected using engineered base editors in rat zygotes.
  13. Efficient mitochondrial A-to-G base editors for the generation of mitochondrial disease models.
  14. Mitochondrial health, prenatal distress, and gestational age: investigation of cf-mtDNA and GDF15 in two pregnancy studies from the USA and Turkey.
  15. Iron deficiency in pregnant mice causes XY embryos to develop with female characteristics.
  16. Glucose restriction induces degeneration of neurons with mitochondrial DNA depletion by altering ER-mitochondria calcium transfer.
  17. mTOR inhibition triggers mitochondrial fragmentation in cardiomyocytes through proteosome-dependent prohibitin degradation and OPA-1 cleavage.
  18. Mitochondrial function in brain and muscle metabolism: the crucial role during early sensorimotor development.
  19. Dissecting pre- to post-implantation transition of DNA methylome-transcriptome dynamics in early mammalian development.
  20. Senescence and inflammation are unintended adverse consequences of CRISPR-Cas9/AAV6-mediated gene editing in hematopoietic stem cells.
  21. Polyamines regulate mitochondrial metabolism essential for intestinal epithelial renewal and wound healing.
  22. The impact of metformin on placental ageing in humans and mice.
  23. NAD+ Metabolism Maintains the Homeostasis of Decidual Macrophages in Early Pregnancy.
  24. An AI-assisted fluorescence microscopic system for screening mitophagy inducers by simultaneous analysis of mitophagic intermediates.
  1. bioRxiv. 2025 May 16. pii: 2025.05.16.654318. [Epub ahead of print]
    Impaired Complex I dysregulates neural/glial precursors and corpus callosum development revealing postnatal defects in Leigh Syndrome mice.
    Sahitya Ranjan Biswas, Porter L Tomsick, Colin Kelly, Brooke A Lester, Julia P Milner, Sara N Henry, Yaris Soto, Samantha Brindley, Nicole DeFoor, Paul D Morton, Alicia M Pickrell.
      Leigh syndrome (LS) is a complex, genetic mitochondrial disorder defined by neurodegenerative phenotypes with pediatric manifestation. However, recent clinical studies report behavioral phenotypes in human LS patients that are more reminiscent of neurodevelopmental delays. To determine if disruptions in epochs of rapid brain growth during infancy precede the hallmark brain lesions that arise during childhood, we evaluated neural and glial precursor cellular dynamics in a mouse model of LS. Single cell RNA sequencing along with histological and anatomical assessments were performed in NDUFS4 KO mice and compared with controls to determine the impact of Complex I deficiency on neural stem cells, their neuronal and oligodendroglial progeny, lineage progression, and overt differences in specific brain regions. Our findings show disruptions in all categories, specifically within the subventricular zone and corpus callosum. Given that LS is purely considered a neurodegenerative disease, we propose that mitochondrial dysfunction is a neurodevelopmental signature predating classic diagnosis in LS.
    DOI:  https://doi.org/10.1101/2025.05.16.654318
  2. Nat Biotechnol. 2025 Jun 03.
    Base editors model mitochondrial disease.
    Patrick Buchholz, Jens Boch.
      
    DOI:  https://doi.org/10.1038/s41587-025-02706-9
  3. J Biol Chem. 2025 Jun 03. pii: S0021-9258(25)02184-2. [Epub ahead of print] 110334
    Mitochondrial tRNA processing defects reprogram mitochondrial and cellular homeostasis.
    Gao Zhu, Yunfan He, Xincheng Li, Yun Xiao, Huisen Zhan, Maoli Duan, Min-Xin Guan.
      Mitochondrial tRNA processing defects have been associated with some clinical presentations including deafness. Especially, a deafness-linked m.7516delA mutation impaired the 5' end processing of RNA precursors and mitochondrial translation. In this study, we investigated the mechanism by m.7516delA mutation induced-deficiencies mitigate organellular and cellular integrity. The m.7516delA mutation downregulated the expression of nucleus encoding subunits and upregulated assemble factors of complex IV and altered the assembly and activities of oxidative phosphorylation (OXPHOS) complexes. The impairment of OXPHOS alleviated mitochondrial quality control processes, including the imbalanced mitochondrial dynamics via increasing fission with abnormal mitochondrial morphology. The m.7516delA mutation upregulated both ubiquitin-dependent and independent mitophagy pathways, evidenced by increasing levels of Parkin, BNIP3, NIX and MFN2-ubiquitination and altering interaction between MFN2 and MUL1 or Parkin, to facilitate the degradation of severely damaged mitochondria. Strikingly, the m.7516delA mutation activated integrated stress response (ISR) pathway, evidenced by upregulation of GCN2, P-GCN2, p-eIF2α, CHOP, ATF4 and elevating the nucleus-location of ATF5 to minimizes the damages in defective mitochondria. Both activation of ISR and PINK1/Parkin mitophagy pathways ameliorate the cell homeostasis via elevating the autophagy process and upregulating apoptotic pathways. Our findings provide new insights into underlying aberrant RNA processing-induced dysfunctions reprogrammed organelles and cellular integrity.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110334
  4. Nat Biotechnol. 2025 Jun 03.
    Powering new therapeutics with precision mitochondrial editing.
      
    DOI:  https://doi.org/10.1038/s41587-025-02693-x
  5. Dis Model Mech. 2025 May 01. pii: dmm052120. [Epub ahead of print]18(5):
    Evaluating the feasibility of gene replacement strategies to treat MTRFR deficiency.
    Samia L Pratt, Mariana Zarate-Mendez, Lidiia Koludarova, Sonja Jansson, Mikko Airavaara, Irena Hlushchuk, David Coleman, Caleb Heffner, Rita Horvath, Brendan J Battersby, Robert W Burgess.
      Mitochondrial translation release factor in rescue (MTRFR) catalyzes a termination step in protein synthesis, facilitating release of the nascent chain from mitoribosomes. Pathogenic variants in MTRFR cause MTRFR deficiency and are loss-of-function variants. Here, we tested gene replacement as a possible therapeutic strategy. A truncating mutation (K155*) was generated in mice; however, homozygotes die embryonically whereas mice heterozygous for this K155* allele are normal. We also generated transgenic strains expressing either wild-type human MTRFR or a partially functional MTRFR. Despite dose-dependent phenotypes from overexpression in vitro, neither transgene caused adverse effects in vivo. In K155* homozygous mice, the wild-type MTRFR transgene completely rescued the phenotype with only one copy present, whereas the mutant transgene rescued less efficiently. Detailed evaluation of mice rescued with the wild-type MTRFR transgene revealed no abnormalities. In human induced pluripotent stem cell (hiPSC)-derived knockdown neurons, mitochondrial phenotypes were corrected by AAV9-mediated delivery of MTRFR. Thus, we find no toxicity from truncated gene products or overexpression of MTRFR in vivo, and expression of MTRFR corrects phenotypes in both mouse and hiPSC models.
    Keywords:   C12ORF65 ; Behr's syndrome; CMT6; Leigh syndrome; MRPL58; Mitochondrial translation
    DOI:  https://doi.org/10.1242/dmm.052120
  6. J Mol Biol. 2025 Jun 03. pii: S0022-2836(25)00329-8. [Epub ahead of print] 169263
    The developing retina undergoes mitochondrial remodeling via PINK1/PRKN-dependent mitophagy.
    Juan Zapata-Muñoz, Juan Ignacio Jiménez-Loygorri, Michael Stumpe, Beatriz Villarejo-Zori, Sandra Alonso-Gil, Petra Terešak, Benan J Mathai, Ian G Ganley, Anne Simonsen, Jörn Dengjel, Patricia Boya.
      Mitophagy, the selective degradation of mitochondria, is essential for retinal ganglion cell (RGC) differentiation and retinal homeostasis. However, the specific mitophagy pathways involved and their temporal dynamics during retinal development and maturation remain poorly understood. Using proteomics analysis of isolated mouse retinas across developmental stages and the mitophagy reporter mouse line, mito-QC, we characterized mitophagy throughout retinogenesis. While mitolysosomes were more prevalent in the mature retina, we observed two distinct mitophagy peaks during embryonic development. The first, independent of PTEN-induced kinase 1 (PINK1) activation, was associated with RGCs. The second, PINK1-dependent peak was triggered after an increase in retinal oxidative stress. This PINK1-dependent, oxidative stress-induced mitophagy pathway is conserved in mice and zebrafish, providing the first evidence of programmed, PINK1-dependent mitophagy during development.
    Keywords:  PINK1; autophagy; development; mitophagy; retina
    DOI:  https://doi.org/10.1016/j.jmb.2025.169263
  7. Life Sci Alliance. 2025 Aug;pii: e202403189. [Epub ahead of print]8(8):
    Cross-comparison of strains used for mitochondrial imaging in Caenorhabditis elegans during aging.
    Juri Kim, Naibedya Dutta, Matthew Vega, Andrew Bong, Maxim Averbukh, Rebecca Aviles Barahona, Athena Alcala, Jacob T Holmes, Gilberto Garcia, Ryo Higuchi-Sanabria.
      Measurements of mitochondrial morphology are a powerful proxy for assessing mitochondrial health, particularly during aging when organelle dynamics are disrupted. Caenorhabditis elegans provides an ideal system for in vivo mitochondrial imaging, but widely used high-copy transgenic strains can induce artifacts that confound interpretation because of their impact on cellular and organismal health and physiology. Here, we present and validate a suite of C. elegans strains expressing single-copy, matrix-localized GFP in the muscle, intestine, and hypodermis using the MosSCI technology. These strains enable robust, tissue-specific visualization of mitochondrial morphology without the caveats associated with multi-copy reporters. We benchmark their performance against existing models and demonstrate that our mitochondrial reporters are similarly capable of assessing age-associated mitochondrial morphology, while avoiding defects in cellular and physiological health associated with the multi-copy reporters. Furthermore, we assess how aging methods, bacterial diets, and inhibition of fusion and fission machinery impact mitochondrial morphology during aging. Our findings provide a standardized and physiologically relevant platform for studying mitochondrial dynamics during aging in C. elegans.
    DOI:  https://doi.org/10.26508/lsa.202403189
  8. Invest Ophthalmol Vis Sci. 2025 Jun 02. 66(6): 17
    Biallelic NSUN3 Variants Cause Diverse Phenotypic Spectrum Disease: From Isolated Optic Atrophy to Severe Early-Onset Mitochondrial Disorder.
    Neringa Jurkute, Heiko Brennenstuhl, Monika Kustermann, Lindsey Van Haute, Christian D Mutti, Enrico Bugiardini, Takayuki Handa, Masaru Shimura, Axel Petzold, James Acheson, Anthony G Robson, William L Macken, Michael G Hanna, Robert D S Pitceathly, Ashirwad Merve, Urania Kotzaeridou, Stefan Kölker, Michael Freilinger, Marcus Erdler, Reginald E Bittner, Johannes A Mayr, Yasushi Okazaki, Kei Murayama, Holger Prokisch, Andrew R Webster, Michal Minczuk, Gavin Arno, Berthold Pemp, Georg F Hoffmann, Wolfgang M Schmidt, Patrick Yu-Wai-Man.
       Purpose: Primary mitochondrial disorders (PMDs) are a clinically heterogeneous group of genetic disorders that can affect many tissues, with a broad phenotypic spectrum ranging from isolated organ involvement to severe early-onset multisystem disease. Visual loss from optic atrophy is a frequent clinical manifestation of mitochondrial cytopathies. This study aimed to identify the missing heritability in previously unsolved cases of suspected isolated or syndromic optic neuropathy. Based on three recent reports on biallelic NSUN3 variants causing early-onset PMD, we explored in detail the genetic and clinical spectrum of NSUN3-associated disease.
    Methods: Affected individuals were analyzed by exome or genome sequencing. In silico variant analysis and functional assays were performed to investigate the consequences of the identified variants. Detailed phenotyping data were collected from medical records and direct questioning after the identification of candidate-likely pathogenic variants.
    Results: Interrogation of exome and genome sequencing data led to the identification of six candidate NSUN3 variants in eight affected individuals from five unrelated families (including a previously reported case). A broad phenotypic spectrum was observed ranging from isolated optic atrophy to severe early-onset PMD. Identified NSUN3 variants impairing NSUN3 activity are located within the S-adenosylmethionine-dependent methyltransferases domain and loss of function variants were associated with a more severe phenotype. Remarkably, bilateral optic atrophy was a unifying clinical feature observed in almost all affected individuals.
    Conclusions: Pathogenic or likely pathogenic biallelic variants in NSUN3 disrupt mt-tRNAMet methylation and mitochondrial translation leading to mitochondrial disease ranging from mild isolated optic atrophy to a severe multisystemic phenotype with possible limited life expectancy.
    DOI:  https://doi.org/10.1167/iovs.66.6.17
  9. Nat Commun. 2025 Jun 03. 16(1): 5133
    ROMO1 overexpression protects the mitochondrial cysteinome from oxidations in aging.
    Fengli Xu, Haipeng Huang, Kun Peng, Chongshu Jian, Hao Wu, Zhiwen Jing, Shan Qiu, Ying Chen, Keke Liu, Ling Fu, Yanru Wang, Jing Yang, Xiaotao Duan, Chu Wang, Heping Cheng, Xianhua Wang.
      Reactive thiols of proteinaceous cysteines are vital to cell biology by serving as sensor, effector and buffer of environmental redox fluctuations. Being the major source, as well as the prime target, of reactive oxygen species (ROS), mitochondria confront great challenges in preserving their thiol pool. Here we show that ROS modulator 1 (ROMO1), a small inner mitochondrial membrane protein, plays a role in protecting the mitochondrial cysteinome. ROMO1 is redox sensitive and reactive and overexpression can prevent deleterious oxidation of proteinaceous thiols. ROMO1 upregulation leads to a reductive shift of the mitochondrial cysteinome, exerting beneficial effects on mitochondria, such as promoting energy metabolism and Ca2+ uniport while inhibiting vicious membrane permeability transition. Importantly, ROMO1 overexpression reverses mitochondrial cysteinome oxidations in multiple organs and slows functional decline in aged male mice. These findings unravel a redox regulatory mechanism of the mitochondrial cysteinome and mark ROMO1 as a potential target for combating oxidative stress and improving healthspan.
    DOI:  https://doi.org/10.1038/s41467-025-60503-z
  10. Geroscience. 2025 Jun 05.
    Ndufs4-/- mice: a testing ground for longevity interventions.
    Jackson Nuss, Matt Kaeberlein, Alessandro Bitto, Anthony S Grillo.
      Mice missing the complex I subunit Ndufs4 of the electron transport chain are widely used as a leading animal model of Leigh syndrome, a pediatric neurodegenerative disorder that leads to premature death. More broadly, this animal model has enabled a better understanding of the pathophysiology of mitochondrial disease and mitochondrial dysfunction in sporadic disorders. Intriguingly, longevity interventions are very effective at treating symptoms of disease in this model. Herein, we introduce the model and its notable features that may help provide insights in longevity research. We performed a retrospective analysis of historical data from our laboratories over the past 10 years regarding the use of this animal model in aging studies, the manifestation and progression of mitochondrial disease, and factors that influence their premature death. We observed a correlation between weight and lifespan in female animals and a sex-independent correlation between the onset of clasping, a typical neurodegenerative symptom, and overall survival. We observed a sexual dimorphism in lifespan with female mice being more resilient despite a similar age of onset of disease symptoms. Lastly, we report increased lifespan and delayed onset of disease symptoms following treatment with 17-alpha-estradiol, a non-feminizing estrogen which can extend lifespan in genetically heterogeneous mice. This analysis serves as a useful guide for researchers utilizing this animal in the discovery of effective interventions for longevity and to prevent the onset of disease. It suggests there may be unprecedented underlying sex-specific differences in patients with Leigh syndrome and further strengthens the connection between normative aging and mitochondrial dysfunction.
    Keywords:  Interventions; Longevity; Mitochondrial dysfunction; Vertebrate models
    DOI:  https://doi.org/10.1007/s11357-025-01704-8
  11. Proteomics. 2025 Jun 01. e13969
    Tissue-Specific Regulation of Fatty Acid Metabolism in a Mouse Model of Isolated Complex I Deficiency.
    Sibonelo Glen Khumalo, Jeremie Zander Lindeque, Marianne Venter.
      Isolated complex I deficiency (ICD) is commonly associated with mitochondrial diseases and closely mimics subacute necrotising encephalomyelopathy. This disorder is characterised by metabolic perturbations that affect energy metabolism pathways, including fatty acid metabolism. Here, we examined the tissue-specific changes in fatty acid metabolism in the Ndufs4 KO mice by employing mass-spectrometry-based proteomics as a hypothesis-generating approach. We investigated proteomic changes in six tissues, including brain regions (brainstem, cerebellum, olfactory bulb), heart, kidney and liver, focusing on proteins involved in fatty acid metabolism. Although it is expected that most tissues, except for the brain, will utilise fatty acids as alternative energy sources when oxidative phosphorylation (OXPHOS) is deficient, our data revealed a more complex response. In the liver, fatty acid consumption (oxidation) was favoured as expected, but in the heart, fatty acid synthesis was favoured. In the kidney, proteins involved in almost all fatty acid metabolic processes (oxidation and synthesis) were downregulated. Our data demonstrate that metabolic adaptations in fatty acid metabolism to ICD were tissue-specific and often in opposing directions. Understanding the differential adaptations across tissues could inform future treatment targets for mitochondrial disorders.
    Keywords:  NDUFS4 knock out; complex I deficiency; fatty acid metabolism; proteomics
    DOI:  https://doi.org/10.1002/pmic.13969
  12. Nat Biotechnol. 2025 Jun 03.
    A mitochondrial disease model is generated and corrected using engineered base editors in rat zygotes.
    Liang Chen, Changming Luan, Mengjia Hong, Meng Yuan, Hao Huang, Debo Gao, Xinyuan Guo, Zhengxin Chen, Yongmei Li, Lei Yang, Zongyi Yi, Wensheng Wei, Mingyao Liu, Liangcai Gao, Honghui Han, Dali Li.
      Efficient generation and correction of mutations in mitochondrial DNA (mtDNA) is challenging. Here, through embryonic injection of an mtDNA adenine base editor (eTd-mtABE), Leigh syndrome rat models were generated efficiently (up to 74%) in the F0 generation, exhibiting severe defects. To correct this mutation, a precise mtDNA C-to-T base editor was engineered and injected into mutated embryos. It achieved restoration of wild-type alleles to an average of 53%, leading to amelioration of disease symptoms.
    DOI:  https://doi.org/10.1038/s41587-025-02684-y
  13. Nat Biotechnol. 2025 Jun 03.
    Efficient mitochondrial A-to-G base editors for the generation of mitochondrial disease models.
    Liang Chen, Mengjia Hong, Changming Luan, Meng Yuan, Yiming Wang, Xinyuan Guo, Yue Fang, Hao Huang, Xiaohua Dong, Hongyi Gao, Dan Zhang, Xi Chen, Dihao Meng, Molin Huang, Zongyi Yi, Mingyao Liu, Wensheng Wei, Liangcai Gao, Gaojie Song, Xiaoming Zhou, Dali Li.
      Existing A-to-G base editors for mitochondrial DNA (mtDNA) are limited by low efficiency. We used directed evolution to discover variants of the TadA-8e base editors that have substantially increased activity and expanded targeting compatibility for both nuclear and mitochondrial adenine base editing, especially in previously unfavored sequence contexts. The engineered mtDNA editors (eTd-mtABEs) showed up to 87% editing efficiency in human cells, with greatly reduced DNA and RNA off-target effects. Strand-selective A-to-G editing was enhanced by an average of 3.2-fold with substitution of DddA to DNA nickases in eTd-mtABE backbones compared to mitochondrial ABEs. In rat cells, editing efficiencies of eTd-mtABEs were up to 145-fold higher compared to split DddA transcription activator-like effector-linked deaminase. We also generated rats with sensorineural hearing loss by installing targeted mutations with frequencies of up to 44% through embryonic injection. The developed eTd-mtABEs are efficient and precise mtDNA-engineering tools for basic research and translational studies.
    DOI:  https://doi.org/10.1038/s41587-025-02685-x
  14. Mitochondrion. 2025 Jun 03. pii: S1567-7249(25)00054-6. [Epub ahead of print] 102057
    Mitochondrial health, prenatal distress, and gestational age: investigation of cf-mtDNA and GDF15 in two pregnancy studies from the USA and Turkey.
    Qiuhan Huang, David Shire, Fiona Hollis, Sameera Abuaish, Martin Picard, Catherine Monk, Elif Aysimi Duman, Caroline Trumpff.
       BACKGROUND: Pregnancy outcomes are influenced by maternal distress but the pathways underlying these effects are still unknown. Mitochondria, crucial for energy production and stress adaptation, may link psychosocial stress to its biological effects, especially during pregnancy when energy demands significantly increase. This study explores two mitochondrial markers-circulating cell-free mitochondrial DNA (cf-mtDNA) and Growth Differentiation Factor-15 (GDF15)-as potential mitochondrial health indicators linking maternal distress to pregnancy outcomes in two longitudinal studies from the USA and Turkey.
    METHODS: We analyzed biological, demographic, and psychological data from women in two pregnancy studies: EPI (N = 187, USA) and BABIP (N = 198, Turkey). Data were collected at multiple timepoints during the perinatal period, including late 2nd and 3rd trimester, with EPI also including additional data at early 2nd trimester and 4-14 months postpartum. Prenatal maternal psychological distress was measured as perceived stress, anxiety, and depressive symptoms. Plasma cf-mtDNA and GDF15 levels were assessed using qPCR and ELISA, respectively. Statistical analyses included Wilcoxon signed-rank tests, Spearman correlations, and Mann-Whitney tests.
    RESULTS: Plasma cf-mtDNA levels did not significantly vary across pregnancy, while plasma GDF15 levels increased from early to late pregnancy and decreased postpartum. Late 2nd trimester plasma GDF15 was negatively correlated with pre-pregnancy BMI (p = 0.035) and gestational age (p = 0.0048) at birth. Early 2nd trimester maternal distress was associated with lower cf-mtDNA (all p-values < 0.05) and a trend for lower GDF15. Higher pre-pregnancy BMI and late-pregnancy maternal distress were linked to smaller postpartum GDF15 declines in EPI (all p-values < 0.05).
    CONCLUSIONS: This study identified distinct patterns of plasma cf-mtDNA and GDF15 levels during the perinatal period across studies from two countries, linking these mitochondrial markers to maternal distress and pregnancy outcomes.
    Keywords:  GDF15; Longitudinal studies; Maternal distress; Perinatal period; Pregnancy outcomes; Psychobiology; cf-mtDNA
    DOI:  https://doi.org/10.1016/j.mito.2025.102057
  15. Nature. 2025 Jun 04.
    Iron deficiency in pregnant mice causes XY embryos to develop with female characteristics.
    Shannon Dupont, Blanche Capel.
      
    Keywords:  Developmental biology; Epigenetics; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-025-01456-7
  16. Mol Psychiatry. 2025 Jun 03.
    Glucose restriction induces degeneration of neurons with mitochondrial DNA depletion by altering ER-mitochondria calcium transfer.
    Lingyan Zhou, Feixiang Bao, Jiajun Zheng, Yingzhe Ding, Jiahui Xiao, Jian Zhang, Yongpeng Qin, Liang Yang, Yi Wu, Qi Meng, Manjiao Lu, Qi Long, Lingli Hu, Chong Li, Haitao Wang, Shijuan Huang, Linpeng Li, Junwei Wang, Wuming Wang, Gang Lu, Wai-Yee Chan, Dajiang Qin, Gong Chen, Xingguo Liu.
      Mitochondrial DNA (mtDNA) mutations and/or depletion are implicated in epilepsy and many neurodegenerative diseases. However, systematic investigation into how mtDNA alterations relate to epilepsy and neural degeneration is needed. Here, we established a mouse model in which mtDNA depletion is induced by the Herpes Simplex Virus Type 1 (HSV-1) protein UL12.5 in the brain led to an epileptic phenotype characterized by abnormal electroencephalography (EEG) patterns and increased neural excitability in hippocampus. We also found that UL12.5 mediated mtDNA depletion in neurons in vitro (rho-) causes epilepsy-like abnormal EEG. Caloric restriction (CR) or glucose restriction (GR) is a strategy proven to reduce epileptic activity, however GR mimetic 2-deoxy-D-glucose (2-DG), induced degeneration in mtDNA depleted neurons. Mechanistically, mtDNA depletion increased mitochondria-endoplasmic reticulum (ER) contacts, facilitating GR-induced mitochondrial calcium overload. Rho- neurons did not show changes in mitochondrial motility or membrane potential. Our study revealed an unexpected axis of mtDNA depletion, ER-mitochondrial contacts, and calcium overload in the rho- neuron model. Fasting-induced GR causes early motor dysfunction, accelerates epilepsy progression, and worsens neurodegeneration in UL12.5 mice. Importantly, the IP3R inhibitor 2-APB blocks the neurodegeneration induced by fasting. This is the first description of animal and neuronal models of mitochondrial epilepsy. Our findings with these models suggest that GR may not be a viable clinical intervention in patients with mtDNA depletion.
    DOI:  https://doi.org/10.1038/s41380-025-03069-y
  17. Cell Commun Signal. 2025 May 31. 23(1): 256
    mTOR inhibition triggers mitochondrial fragmentation in cardiomyocytes through proteosome-dependent prohibitin degradation and OPA-1 cleavage.
    Hugo E Verdejo, Valentina Parra, Andrea Del Campo, Cesar Vasquez-Trincado, Damian Gatica, Camila Lopez-Crisosto, Jovan Kuzmicic, Leslye Venegas-Zamora, Ursula Zuñiga-Cuevas, Mayarling F Troncoso, Rodrigo Troncoso, Beverly A Rothermel, Mario Chiong, E Dale Abel, Sergio Lavandero.
       INTRODUCTION: Cardiac mitochondrial function is intricately regulated by various processes, ultimately impacting metabolic performance. Additionally, protein turnover is crucial for sustained metabolic homeostasis in cardiomyocytes.
    OBJECTIVE: Here, we studied the role of mTOR in OPA-1 cleavage and its consequent effects on mitochondrial dynamics and energetics in cardiomyocytes.
    RESULTS: Cultured rat cardiomyocytes treated with rapamycin for 6-24 h showed a significant reduction in phosphorylation of p70S6K, indicative of sustained inhibition of mTOR. Structural and functional analysis revealed increased mitochondrial fragmentation and impaired bioenergetics characterized by decreases in ROS production, oxygen consumption, and cellular ATP. Depletion of either the mitochondrial protease OMA1 or the mTOR regulator TSC2 by siRNA, coupled with an inducible, cardiomyocyte-specific knockout of mTOR in vivo, suggested that inhibition of mTOR promotes mitochondrial fragmentation through a mechanism involving OMA1 processing of OPA-1. Under homeostatic conditions, OMA1 activity is kept under check through an interaction with microdomains in the inner mitochondrial membrane that requires prohibitin proteins (PHB). Loss of these microdomains releases OMA1 to cleave its substrates. We found that rapamycin both increased ubiquitination of PHB1 and decreased its abundance, suggesting proteasomal degradation. Consistent with this, the proteasome inhibitor MG-132 maintained OPA-1 content in rapamycin-treated cardiomyocytes. Using pharmacological activation and inhibition of AMPK our data supports the hypothesis that this mTOR-PHB1-OMA-OPA-1 pathway impacts mitochondrial morphology under stress conditions, where it mediates dynamic changes in metabolic status.
    CONCLUSIONS: These data suggest that mTOR inhibition disrupts mitochondrial integrity in cardiomyocytes by promoting the degradation of prohibitins and OPA-1, leading to mitochondrial fragmentation and metabolic dysfunction, particularly under conditions of metabolic stress.
    Keywords:  AMPK; Mitochondrial fusion; OMA1; OPA-1; Prohibitin; Rapamycin; mTOR
    DOI:  https://doi.org/10.1186/s12964-025-02240-w
  18. J Physiol. 2025 May 31.
    Mitochondrial function in brain and muscle metabolism: the crucial role during early sensorimotor development.
    Fernanda Silva Carneiro, Larissa Moreira Dias, Matheus Biscaro Rocha.
      
    Keywords:  brain; mitochondria; muscle; sensorimotor restriction
    DOI:  https://doi.org/10.1113/JP288770
  19. Cell Rep. 2025 Jun 03. pii: S2211-1247(25)00561-3. [Epub ahead of print]44(6): 115790
    Dissecting pre- to post-implantation transition of DNA methylome-transcriptome dynamics in early mammalian development.
    Qingyuan Zhu, Ying Liu, Xin Hao, Shengyi Yan, Jitao Ge, Changqing Zheng, Xianwen Ren, Fan Zhou.
      Pre- to post-implantation transition is an essential step for early mammalian development. The epigenome dynamics such as DNA methylome and transcriptome of embryos have been analyzed, while the coordination between these two molecular layers controlling lineage fate remained elusive. Here, with a multidimensional profiling of peri-implantation embryos, we present the emerging lineage-specific DNA methylation (DNAme) patterns across species. The maternal and paternal DNA methylation levels exhibit differential dynamics in transposon elements. Genes with lineage-specific unmethylated promoters early in development retain this state and are expressed later, suggesting a role in lineage fate determination. By measuring both molecular dimensions simultaneously in individual developing cells, we identified a group of gene promoters with positive correlation between DNAme and RNAex along epiblast development. Functional validation suggested DNAme at these promoters contributes to non-canonical DNAme-RNAex dynamics, potentially via complex TF-mediated or epigenetic regulation. This study provides clues for understanding molecular regulation of peri-implantation embryogenesis.
    Keywords:  CP: Developmental biology; CP: Molecular biology; DNA methylome; early mammalian development; pre- to post-implantation transition; transcriptome
    DOI:  https://doi.org/10.1016/j.celrep.2025.115790
  20. Cell Rep Med. 2025 May 30. pii: S2666-3791(25)00230-7. [Epub ahead of print] 102157
    Senescence and inflammation are unintended adverse consequences of CRISPR-Cas9/AAV6-mediated gene editing in hematopoietic stem cells.
    Anastasia Conti, Kety Giannetti, Federico Midena, Stefano Beretta, Nicolò Gualandi, Rosaria De Marco, Edoardo Carsana, Angelica Varesi, Teresa Tavella, Laura Alessandrini, Parinaz Zarghamian, Alessandra Weber, Samuele Ferrari, Chiara Brombin, Diego Gilioli, Lucrezia Della Volpe, Stephanie Z Xie, Ivan Merelli, Toni Cathomen, Luigi Naldini, Raffaella Di Micco.
      Gene editing (GE) using homology-directed repair (HDR) in hematopoietic stem and progenitor cells (HSPCs) offers promise for long-range gene correction of inherited genetic disorders. However, cellular responses induced by CRISPR-Cas9/AAV6 engineering impair the long-term repopulating potential of HDR-edited HSPCs, adversely impacting the safety and efficacy of clinical translation. Our study uncovers a durable senescence-like response in genetically engineered HSPCs triggered by p53 and interleukin (IL)-1/nuclear factor κB (NF-κB) activation, which restricts graft size and clonal diversity in long-term transplantation assays. We show that transient p53 inhibition or blocking inflammatory pathways mitigates senescence-associated responses, improving the repopulating capacity of edited HSPCs. Importantly, we identify treatment with Anakinra, an IL-1 signaling antagonist, as a promising strategy to enhance polyclonal output in HDR-edited cells while minimizing genotoxicity risks associated with the editing procedure. Overall, our findings present strategies to overcome key hurdles in HDR-based HSPC gene therapies, providing a framework for enhancing their efficacy and safety in clinical applications.
    Keywords:  CRISPR-Cas9; DNA damage; gene editing; gene therapy; genome integrity; hematopoietic stem cells; inflammatory programs; p53; senescence; viral vectors
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102157
  21. Am J Physiol Gastrointest Liver Physiol. 2025 Jun 05.
    Polyamines regulate mitochondrial metabolism essential for intestinal epithelial renewal and wound healing.
    Cassandra A Cairns, Ting Chen, Naomi Han, Hongxia Chen, Hee K Chung, Lan Xiao, Jian-Ying Wang.
      Homeostasis of the mammalian intestinal epithelium is tightly regulated by multiple factors including cellular polyamines, but the exact mechanism underlying polyamines in this process remains largely unknown. Mitochondria are the powerhouse of cells and can also function as signaling organelles by releasing metabolic by-products. Here we determined whether polyamines regulate intestinal epithelial renewal and wound healing by altering mitochondrial activity. Depletion of cellular polyamines by inhibiting ornithine decarboxylase with α-difluoromethylornithine (DFMO) resulted in mitochondrial dysfunction as evidenced by decreases in basal and maximal respiration levels, ATP production, and spare respiration capacity. Polyamines depletion by DFMO also decreased the levels of mitochondria-associated proteins prohibitin 1 and COX-IV. Mitochondrial dysfunction induced by DFMO was associated with an inhibition of intestinal organoid growth and epithelial repair after wounding and this inhibition was ameliorated by administration of the mitochondrial activator Mito-Tempo or exogenous polyamine putrescine. These results indicate that polyamines are necessary for mitochondrial metabolism, in turn controlling constant intestinal mucosal growth and epithelial repair after acute injury.
    Keywords:  Mito-Tempo; intestinal epithelial integrity; mitochondral proteins; ornithine decarboxylase
    DOI:  https://doi.org/10.1152/ajpgi.00023.2025
  22. J Physiol. 2025 May 31.
    The impact of metformin on placental ageing in humans and mice.
    Grace J Hattersley, Liu Yang, Jane L Tarry-Adkins, Antonia Hufnagel, Kwun Kiu Wong, Denise S Fernandez-Twinn, Maria Chukanova, India G Robinson, Amanda J Drake, Rebecca M Reynolds, Susan E Ozanne, Catherine E Aiken.
      Placental ageing refers to the physiological accumulation of a senescent phenotype over a healthy pregnancy. In pregnancies affected by complications such as pre-eclampsia and fetal growth restriction, placental ageing is notably accelerated and observed at an earlier gestational age. Metformin is used during pregnancy for an increasing variety of indications, including treatment of gestational diabetes, and may have a role in slowing cellular ageing. It is therefore essential to understand the potential impact of metformin on placental ageing. Placental samples (n = 105) were obtained from women with body mass index ≥30 kg/m2 and who were randomized to treatment with metformin or placebo during pregnancy. Ageing was assessed by measuring telomere length, histological examination, and using array-based technologies to investigate gene expression and methylation. Results were validated using isolated human trophoblasts treated in vitro with metformin, and in a complementary mouse model. There were no differences between metformin-exposed and control placentas in terms of telomere length, fibrosis or calcification. There were no differences in placental gene expression or methylation patterns by metformin status. In our mouse model, no genes classically associated with cellular ageing were differentially expressed and no senescence pathway showed evidence of enrichment with metformin treatment. There was no evidence that metformin either slows or accelerates placental ageing pathways in the complementary models that we investigated. Our findings are reassuring with regard to the safety of metformin used to treat gestational diabetes, but do not support a role for metformin in the prevention of adverse pregnancy outcomes in non-diabetic women. KEY POINTS: Accelerated placental ageing, where the senescent phenotype that normally accumulates over a healthy pregnancy is observed at a premature gestational age, is associated with adverse pregnancy outcomes. Metformin has been proposed as an anti-ageing drug elsewhere. Therefore, metformin could alter the trajectory of placental ageing and prevent associated pregnancy complications. The present study incorporated human data from a randomized clinical trial and complementary models. Metformin did not impact methylation-predicted gestational age, telomere length, gene expression or histological ageing in human placentas treated in vivo, isolated trophoblasts treated in vitro or mouse models. Metformin neither decelerated nor accelerated placental ageing, thereby supporting its continued use in the obstetric setting, for instance in the treatment of gestational diabetes. Metformin cannot be recommended to prevent adverse pregnancy outcomes because we found no evidence suggesting it decelerates placental ageing. Further research is warranted to find drug therapies for this purpose.
    Keywords:  fetus; gestational diabetes; metformin; placenta; pregnancy; trophoblast
    DOI:  https://doi.org/10.1113/JP288710
  23. FASEB J. 2025 Jun 15. 39(11): e70674
    NAD+ Metabolism Maintains the Homeostasis of Decidual Macrophages in Early Pregnancy.
    Yongbo Zhao, Yun Lu, Yijun Zhang, Jiani Sun, Wenxuan Li, Luyi Cai, Liping Jin.
      Disruption of decidual macrophage (dMφ) homeostasis is related to adverse pregnancy outcomes such as recurrent spontaneous abortion (RSA). Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, converts nicotinamide (NAM) to NAD+ precursor nicotinamide mononucleotide (NMN). Although restriction of NAD+ metabolism has been implicated in leading to fetal loss in pregnant mice, whether NAMPT is involved in regulating maternal-fetal maintenance and the underlying mechanism has been poorly understood. Here, we demonstrated that primary decidual macrophages from RSA patients showed decreased expression of NAMPT and impaired NAD+ metabolism. Nampt+/- mice exhibited a significant elevation in the embryonic absorption rate compared with that of wild-type (WT) mice, and adoptive transferring WT macrophages into Nampt+/- mice significantly ameliorated the adverse pregnancy outcome. Genetic and pharmacological interference of NAMPT disrupted the differentiation of M1 macrophages. Mechanically, deficiency of NAMPT inhibited gasdermin D (GSDMD) cleavage independently from canonical pyroptosis. The cleaved N-terminal fragment of GSDMD functioned as a stimulus to activate the NF-κB pathway and subsequently promoted TNF-α transcription by phospho-P65 (S536). NMN replenishment ameliorated the dysregulation of M1 macrophage differentiation, the infiltration of trophoblasts, and fetal loss. Our study reveals an NAMPT-associated immunopathogenesis of early pregnancy loss and provides a new idea for the therapeutic strategy for RSA patients.
    DOI:  https://doi.org/10.1096/fj.202500462R
  24. Nat Commun. 2025 Jun 04. 16(1): 5179
    An AI-assisted fluorescence microscopic system for screening mitophagy inducers by simultaneous analysis of mitophagic intermediates.
    Yicheng Wang, Pengfei Song, Heqing Zhou, Pengwei Wang, Yan Li, Zhiyong Shao, Lu Wang, Yan You, Zuhai Lei, Jinhua Yu, Cong Li.
      Mitophagy, the selective autophagic elimination of mitochondria, is essential for maintaining mitochondrial quality and cell homeostasis. Impairment of mitophagy flux, a process involving multiple sequential intermediates, is implicated in the onset of numerous neurodegenerative diseases. Screening mitophagy inducers, particularly understanding their impact on mitophagic intermediates, is crucial for neurodegenerative disease treatment. However, existing techniques do not allow simultaneous visualization of distinct mitophagic intermediates in live cells. Here, we introduce an artificial intelligence-assisted fluorescence microscopic system (AI-FM) that enables the uninterrupted recognition and quantification of key mitophagic intermediates by extracting mitochondrial pH and morphological features. Using AI-FM, we identify a potential mitophagy modulator, Y040-7904, which enhances mitophagy by promoting mitochondria transport to autophagosomes and the fusion of autophagosomes with autolysosomes. Y040-7904 also reduces amyloid-β pathologies in both in vitro and in vivo models of Alzheimer's disease. This work offers an approach for visualizing the entire mitophagy flux, advancing the understanding of mitophagy-related mechanisms and enabling the discovery of mitophagy inducers for neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41467-025-60315-1
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