bims-mitmed 2025-11-09 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–11–09
29 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Mitochondrial Leigh syndrome: the state of the art.
Proteolytic cleavage activates the mitochondrial isoform of TOP3A.
Mitochondrial Activation and Therapeutics: Innovations in Cell- and Organelle-Specific Medicine.
Functionally dominant hotspot mutations of mitochondrial ribosomal RNA genes in cancer.
Silencing of mitochondrial gene expression using polymorpholino chimeras.
Complex IV deficiency due toCOX4I1deep intronic and de novo variants results in progressive motor impairment andLeigh syndrome.
2-Deoxy-D-Glucose restores glial cell mitochondrial function and attenuates neuroinflammation.
Non-canonical role of natural quinones in mitochondrial nucleoid organization for maintaining respiration and protecting cardiac function.
Metabolic environment-driven remodeling of mitochondrial ribosomes regulates translation and biogenesis.
National diagnostic gaps for TK2 Deficiency in Italy: insights from the AIM Multicenter Survey.
Early experience on omaveloxolone in adult patients with Friedreich's ataxia: a real-world observational study.
Transcriptomic analysis of mitohormesis associated with lifespan extension in Caenorhabditis elegans.
An orphan no more: SLC25A45 controls mitochondrial import of methylated amino acids.
Model systems informing mechanisms and drug discovery: a review of POLG-related disease models.
Gut instinct: microbiome as a modifiable target in the management of neurologic symptoms in myoclonic epilepsy with ragged-red fibers (MERRF).
Tunneling nanotube-mediated stem cell immunomodulation dysfunction promotes adipose inflammation and insulin resistance in GDM.
Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology.
Effective in vivo RNA base editing via engineered cytidine deaminase APOBECs fused with PUF proteins.
Microglia alter sex-specific cerebellar myelination following placental hormone loss.
AI-powered neuroimaging markers: a new era in paediatric Leigh syndrome diagnosis.
Continuous cell-type diversification in mouse visual cortex development.
An atlas of mitochondrial ATP synthase activity across the lifespan.
A new UCP1-independent thermogenic mechanism in peroxisomes.
Postnatal development of the dentate gyrus vascular niche.
Barth syndrome: Natural history in infants and young children.
Mitofusin 1 in mitochondrial quality control and anti-inflammatory responses in nucleus pulposus cells during disc degeneration.
Placental gene expression of the AMPK signaling pathway in association with gestational exposure to ambient air pollution.
Proceedings of the 16th International Newborn Brain Conference: Fetal and/or neonatal brain development, both normal and abnormal.
Normalization of trophoblast mTOR signaling rescues impaired function in primary human trophoblast cells isolated from pregnancies complicated by fetal growth restriction.

Arch Pediatr. 2025 Nov 05. pii: S0929-693X(25)00182-4. [Epub ahead of print]

Mitochondrial Leigh syndrome: the state of the art.

Gauthier Toutain, Célia Hoebeke, Marguerite Gastaldi, Mathieu Milh, Brigitte Chabrol.

   BACKGROUND: Leigh syndrome or subacute necrotizing encephalomyelopathy was first recognized as a neuropathological entity in 1951. It is a progressive neurological disease characterized by neuroradiological lesions, particularly in the brainstem and basal ganglia. Leigh's syndrome is a pan-ethnic disorder with onset usually in infancy or early childhood. Over the last six decades, this complex neurodegenerative disorder has been shown to comprise >100 separate monogenic disorders associated with enormous clinical and biochemical heterogeneity. This article reviews clinical, radiological, biochemical and genetic aspects of the disorder.
OBJECTIVES: this overview provides a better understanding of this rare mitochondrial disease by identifying its clinical, radiological and genetic manifestations in order to improve early diagnosis, patient follow-up and genetic counseling.
METHODOLOGY: systematic literature review RESULTS: Leigh syndromes present with childhood developmental regression, a loss of previously achieved developmental milestones. Numerous non-neurological manifestations of Leigh syndrome have been reported, many of which are related to the underlying genetic defects. These include cardiomyopathy, renal tubulopathy, gastrointestinal and endocrine dysfunction, and liver disease. Known genetic causes, including defects in 16 mitochondrial DNA (mtDNA) genes and nearly 100 nuclear genes, are categorized into disorders of subunits and assembly factors of the five oxidative phosphorylation enzymes, disorders of pyruvate metabolism and vitamin and cofactor transport and metabolism, disorders of mtDNA maintenance, and defects in mitochondrial gene expression, protein quality control, lipid remodeling, dynamics and toxicity. An approach to diagnosis is presented, together with known treatable causes and an overview of current supportive management options and emerging therapies on the horizon CONCLUSION: Management of mitochondrial diseases must be multidisciplinary, and in collaboration with a center of reference (CRMR) or a center of competence (CCMR) with expertise in mitochondrial diseases.

Keywords:  Central nervous system; Genetic; Itochondrial DNA; Leigh syndrome; Metabolic disease; Mitochondrial disease; Neurodegeneration; Neuroimaging; Nuclear DNA; OXPHOS; Treatment

DOI:  https://doi.org/10.1016/j.arcped.2025.04.007
Nucleic Acids Res. 2025 Oct 28. pii: gkaf1140. [Epub ahead of print]53(20):

Proteolytic cleavage activates the mitochondrial isoform of TOP3A.

Direnis Erdinc, Christin A Albus, Alejandro Rodríguez-Luis, Katja E Menger, Annika Thorsell, Ilian Atanassov, Urška Rovšnik, Maria Falkenberg, Claes M Gustafsson, Thomas J J Nicholls.

The TOP3A gene encodes two isoforms, one targeted to the nucleus and one to mitochondria. Nuclear TOP3A functions as part of the BTRR complex to resolve double Holliday junctions during homologous recombination, while the mitochondrial isoform separates hemicatenated daughter mitochondrial DNA (mtDNA) molecules following DNA replication. Here, we show that the mitochondrial isoform of TOP3A undergoes proteolytic cleavage by the mitochondrial processing peptidase, removing ~90 amino acids from the C-terminus. This cleavage enhances the enzyme's biochemical properties, increasing single-stranded DNA binding and decatenation activity. Notably, all BTRR complex subunits, except TOP3A, are absent from mitochondria, suggesting that proteolytic processing enables TOP3A to function autonomously in mtDNA maintenance. We propose that this cleavage represents a post-import maturation step that tailors TOP3A to its mitochondrial context by uncoupling it from nuclear protein interactions and enhancing its catalytic efficiency.

DOI: https://doi.org/10.1093/nar/gkaf1140
Biol Pharm Bull. 2025 ;48(11): 1652-1666

Mitochondrial Activation and Therapeutics: Innovations in Cell- and Organelle-Specific Medicine.

Itsumi Sato, Masahiro Shiraishi, Kaede Norota, Kaoru Shiraki, Yuma Yamada.

  Mitochondria are essential for cellular functions, including ATP production, calcium homeostasis, oxidative stress regulation, and apoptosis. Mitochondrial dysfunction is associated with a variety of diseases, including neurodegenerative disorders, skeletal muscle diseases, and mitochondrial diseases. This review explores the latest mitochondrial-targeted therapeutic approaches across the following key perspectives: (1) technological innovations in mitochondrial transplantation, focusing on tunnel nanotubes and extracellular vesicles; (2) the role of mitochondria in skeletal muscle diseases and therapeutic activation strategies; (3) advances in mitochondrial enhancement techniques within cell therapy, particularly in pediatric applications; and (4) the latest treatment modalities for mitochondrial diseases, such as gene and cell therapies. Taken together, these strategies demonstrate the transformative potential of mitochondrial targeting in cell- and organelle-specific medicine. Additionally, the MITO-Porter system is highlighted as an innovative drug delivery platform contributing to these advances.

Keywords:  cell therapy; drug delivery system; mitochondria; mitochondrial disease; organelle medicine; skeletal muscle disease

DOI:  https://doi.org/10.1248/bpb.b25-00218
Nat Genet. 2025 Nov 03.

Functionally dominant hotspot mutations of mitochondrial ribosomal RNA genes in cancer.

Sonia Boscenco, Jacqueline Tait-Mulder, Minsoo Kim, Cerise Tang, Tricia Park, Flora McNulty, Sergio Lilla, Sara Zanivan, Alejandro Huerta-Uribe, Benan Nalbant, Mark Zucker, David Sumpton, Geoffray Monteuuis, Christopher B Jackson, Wei Wei, Patrick F Chinnery, Ronan Chaligne, Caleb A Lareau, Ed Reznik, Payam A Gammage.

The vast majority of recurrent somatic mutations arising in tumors affect protein-coding genes in the nuclear genome. Here, through population-scale analysis of 14,106 whole tumor genomes, we report the discovery of highly recurrent mutations affecting both the small (12S, MT-RNR1) and large (16S, MT-RNR2) mitochondrial RNA subunits of the mitochondrial ribosome encoded within mitochondrial DNA (mtDNA). Compared to non-hotspot positions, mitochondrial rRNA hotspots preferentially affected positions under purifying selection in the germline and demonstrated structural clustering within the mitoribosome at mRNA and tRNA interacting positions. Using precision mtDNA base editing, we engineered models of an exemplar MT-RNR1 hotspot mutation, m.1227G>A. Multimodal profiling revealed a heteroplasmy-dependent decrease in mitochondrial function and loss of respiratory chain subunits from a heteroplasmic dosage of ~10%. Mutation of conserved positions in ribosomal RNA that disrupt mitochondrial translation therefore represent a class of functionally dominant, pathogenic mtDNA mutations that are under positive selection in cancer genomes.

DOI: https://doi.org/10.1038/s41588-025-02374-0
Nat Rev Mol Cell Biol. 2025 Nov 03.

Silencing of mitochondrial gene expression using polymorpholino chimeras.

Drishan Dahal.

DOI: https://doi.org/10.1038/s41580-025-00923-3
Mitochondrion. 2025 Nov 05. pii: S1567-7249(25)00092-3. [Epub ahead of print] 102095

Complex IV deficiency due toCOX4I1deep intronic and de novo variants results in progressive motor impairment andLeigh syndrome.

Olatz Ugarteburu, Laia Farré-Tarrats, Gerard Muñoz-Pujol, María Unceta, Javier De Las Heras, Ainhoa Garcia-Ribes, Arantza Arza-Ruesga, Belén de la Morena, Gianluca Arauz-Garofalo, Marina Gay, Gloria Garrabou, Javier Corral, Marta Vilaseca, Antonia Ribes, Judit García-Villoria, Laura Gort, Frederic Tort.

  COX4I1 gene encodes cytochrome c oxidase subunit 4 isoform 1, involved in the early assembly stages of mitochondrial respiratory chain complex IV. To date, COX4I1 pathogenic variants have been reported in only a few cases, each exhibiting heterogeneous clinical phenotypes and limited functional data. Here, we describe the fourth reported case of COX4I1 deficiency associated with human disease, expanding the phenotypic and genetic spectrum of this rare mitochondrial disorder and providing novel clinical, molecular, and functional data. The herein reported individual presented with progressive deterioration of motor skills, intellectual disability and brain imaging abnormalities compatible with Leigh syndrome. Genetic studies combining short and long read next generation sequencing uncovered a peculiar genetic combination in this patient, harboring a de novo COX4I1 nonsense substitution in trans with an inherited deep intronic variant (c.[64C>T];[73+1511A>G]; p.[Arg22Ter];[Glu25ValfsTer9]). Functional studies performed in patient's tissues and transiently transfected cell lines demonstrated that the identified variants mainly exert their pathogenic effect by targeting COX4I1 protein levels, thereby impairing the proper assembly and activity of complex IV.Additionally, proteomic data in patient's fibroblasts suggested an underlying pathomechanism that involves not only the regulation of complex IV function but also the levels of mitoribosomal proteins. In summary, our findings shed light to clarify some of the main clinical features associated with COX4I1 deficiency and the molecular mechanisms involved in the pathogenesis of this disorder.

Keywords:  COX4I1; Leigh syndrome; Long read sequencing; Proteomics; complex IV

DOI:  https://doi.org/10.1016/j.mito.2025.102095
Sci Rep. 2025 Nov 06. 15(1): 38885

2-Deoxy-D-Glucose restores glial cell mitochondrial function and attenuates neuroinflammation.

Payam Gharibani, Yu Guo, Shruthi Shanmukha, Judy J Lee, Katherine Kopp, Paul M Kim, Michael D Kornberg.

  Neuroinflammation plays a central role in a wide spectrum of neurological diseases, driven generally by reactive microglia and astrocytes. Inflammatory stimulation of microglia and astrocytes leads to a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis, which is required to support pro-inflammatory effector functions. This metabolic reprogramming is associated with impaired mitochondrial dynamics, including reduced biogenesis, increased fragmentation, and loss of membrane potential. Targeting microglia and astrocyte metabolism may offer a novel therapeutic approach for modulating neuroinflammation and restoring homeostatic immune functions. Here, we examined the potential of 2-Deoxy-D-Glucose (2DG), a glycolysis inhibitor, to attenuate neuroinflammation by restoring mitochondrial dynamics. In BV2 and primary glial cultures, low-dose 2DG reversed LPS-induced metabolic reprogramming, restoring OXPHOS, reducing mitochondrial fragmentation, and enhancing biogenesis. In vivo, it preserved spare respiratory capacity and increased complex-V activity in brain mitochondria from LPS-treated mice without affecting oxidative stress. At a mechanistic level, 2DG restored activation of AMP-activated protein kinase, a master regulator of mitochondrial dynamics. In conjunction with these metabolic effects, 2DG suppressed LPS-induced pro-inflammatory gene expression while enhancing markers associated with the resolution of inflammation and tissue repair. Critically, systemic low-dose 2DG reduced neuroinflammation and restored immune homeostasis in two LPS-induced mouse models, highlighting its therapeutic potential in neurological disorders.

Keywords:  2-Deoxy-D-Glucose; Immunometabolism; Mitochondrial dynamics; Mitochondrial function; Neuroinflammation

DOI:  https://doi.org/10.1038/s41598-025-22677-w
J Biochem. 2025 Nov 04. pii: mvaf062. [Epub ahead of print]

Non-canonical role of natural quinones in mitochondrial nucleoid organization for maintaining respiration and protecting cardiac function.

Soumyadip Pal, Takaya Ishihara, Daiki Setoyama, Chang-Lin Chen, Kenta Onoue, Shigenobu Yonemura, Emi Ogasawara, Naotada Ishihara.

  Mitochondria contain their own DNA (mtDNA), which is essential for respiratory function. Multiple copies of mtDNA are assembled into dot-like structures called nucleoids. Nucleoids move dynamically within mitochondria, and their size and distribution are influenced by mitochondrial membrane fission and fusion. However, the molecular mechanisms and their pathophysiological significance, particularly in vivo, remain largely unknown. Here, we identify a novel role for ubiquinone, as well as natural quinones lacking electron-carrying capacity, in the organization of nucleoids and respiratory complexes, independent of their conventional roles. These quinones facilitate the association and packaging of mtDNA on the cardiolipin-enriched mitochondrial inner membrane. This quinone-dependent maintenance of nucleoids protects against mitochondrial dysfunction and heart failure induced by the anticancer drug doxorubicin. Our RNAi screen identifies a set of genes involved in mitochondrial diseases that exhibit nucleoid deformation, suggesting a novel therapeutic approach targeting mitochondrial nucleoids for various pathological conditions associated with mitochondrial dysfunction.

Keywords:  Mitochondrial DNA; cardiotoxicity; nucleoid; respiratory complex; ubiquinone

DOI:  https://doi.org/10.1093/jb/mvaf062
Mol Cell. 2025 Nov 06. pii: S1097-2765(25)00853-6. [Epub ahead of print]

Metabolic environment-driven remodeling of mitochondrial ribosomes regulates translation and biogenesis.

Fan Zheng, Zanlin Yu, Junming Zhuang, Lingraj Vannur, William Nickols, YongQiang Wang, Liying Li, Sho Joseph Ozaki Tan, Seungmin Yoo, Yifan Cheng, Chuankai Zhou.

  Cytosolic translation activity is fine-tuned by environmental conditions primarily through signaling pathways that target translation initiation factors. Although mitochondria possess their own translation machinery, they lack an autonomous signaling network analogous to their cytosolic counterpart for regulating translation activity. Consequently, our understanding of how mitochondrial translation activity is adjusted under different metabolic environments remains very limited. Here, we report a noncanonical mechanism for regulating mitochondrial translation activity via metabolism-dependent changes in the mitochondrial ribosome (mitoribosome) in S. cerevisiae. These changes arise from a metabolism-modulated mitoribosome assembly pathway that regulates the composition and conformation of the mitoribosome, thereby adjusting its translation activity to meet metabolic demands. Moreover, the translation activity of the mitoribosome feeds back to regulate the biogenesis of nuclear-encoded mitochondrial proteins, influencing mitochondrial functions and aging. Such a ribosomal remodeling-based "gear-switching" mechanism represents an orthogonal mode of translation regulation, compensating for the absence of a translation-modulating signaling network within mitochondria.

Keywords:  aging; metabolism; mitochondria; mitoribosome; translation activity

DOI:  https://doi.org/10.1016/j.molcel.2025.10.012
Acta Myol. 2025 Sep;44(3): 93-95

National diagnostic gaps for TK2 Deficiency in Italy: insights from the AIM Multicenter Survey.

Michelangelo Mancuso, Costanza Lamperti, Olimpia Musumeci.

   Objective: Thymidine kinase 2 (TK2) deficiency is a rare mitochondrial disease with variable phenotypes and emerging treatments. Prompt diagnosis is essential to optimize patient outcomes and management. To assess the current awareness, diagnostic approaches, and readiness to include TK2 screening in Italian neuromuscular clinical practice.
Methods: A nationwide survey was distributed to AIM-affiliated clinicians. The questionnaire assessed TK2 awareness, diagnostic pathways, gene panel content, and attitudes towards screening in unresolved cases.
Results: while awareness of TK2 deficiency was almost universal, inclusion of TK2 in genetic panels varied: 85% in metabolic myopathy panels, 56% in LGMD panels. Screening for TK2 in genetically unsolved SMA, FSHD, and OPMD phenotypes was inconsistent.
Conclusions: Although awareness of TK2 deficiency is widespread, diagnostic strategies are inconsistent. Standardizing TK2 inclusion in NGS panels and promoting differential screening are key steps toward earlier diagnosis in the view of future treatment options.

Keywords:  TK2; awareness; mitochondrial disease

DOI:  https://doi.org/10.36185/2532-1900-1424
J Neurol. 2025 Nov 01. 272(11): 742

Early experience on omaveloxolone in adult patients with Friedreich's ataxia: a real-world observational study.

Salvatore Maria Lima, Marta Caltagirone, Christian Messina, Umberto Quartetti, Nicasio Rini, Flora D'Amico, Filippo Brighina, Vincenzo Di Stefano.

   INTRODUCTION: Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative spinocerebellar ataxia caused by a homozygous GAA triplet repeat expansion in the frataxin (FXN) gene. FRDA is a multisystem disorder involving the central and peripheral nervous systems, the musculoskeletal system, the heart, and the endocrine pancreas. In recent years, Omaveloxolone, a potent activator of nuclear factor erythroid 2-related factor 2 signaling, showed a significant neurological improvement compared to placebo, with a good safety profile. With this study, we report an early real-life experience on a cohort of FRDA patients treated with omaveloxolone.
MATERIALS AND METHODS: Patients were assessed with an anamnestic profile, general and neurological examination, clinical scales (mFARS, SARA, and FA-ADL) and blood tests, at baseline, at 12 weeks and after 24 weeks of treatment. Inclusion criteria were genetical diagnosis of FRDA, age ≥ 18 years and mFARS < 80. Exclusion criteria included severe hepatic and renal impairment, and severe heart failure. Each patient received oral omaveloxolone at a dose of 150 mg/day.
RESULTS: Twenty patients (65% females) affected by FRDA aged 40.6 ± 12.6 years and a duration of disease of 24.9 ± 9.5 years were treated with omaveloxolone and followed up for 25.2 ± 8.0 weeks. The drug was safe with no significant adverse events during the first 24 weeks and without discontinuations. Indeed, asymptomatic, and transient liver transaminase elevation occurred in 50% of patients. Cardiac function was stable, as well as NT-proBNP and lipids. Clinical scales did not show any significant difference during follow-up, but a significant reduction in IL-6 was reported.
CONCLUSIONS AND DISCUSSION: Omaveloxolone seems to be safe and well-tolerated in adult FRDA patients in the real-life setting. No significant worsening of symptoms was observed with no signs of progression, as well as the improvement of inflammatory biomarkers after 24 weeks of treatment, but no predictive factors for the disease response have been identified. However, the short duration, and the small sample size limit the generalizability of the results. Further studies with longer observation are needed to clearly define the efficacy of omaveloxolone in FRDA.

Keywords:  FRDA; Frataxin; Friedreich’s ataxia; MFARS; Mitochondria; Nrf2; Omaveloxolone; Spinocerebellar ataxia

DOI:  https://doi.org/10.1007/s00415-025-13487-1
Geroscience. 2025 Nov 04.

Transcriptomic analysis of mitohormesis associated with lifespan extension in Caenorhabditis elegans.

Juri Kim, Naibedya Dutta, Gilberto Garcia, Ryo Higuchi-Sanabria.

  Non-lethal exposure to mitochondrial stress has been shown to have beneficial effects due to activation of signaling pathways, including the mitochondrial unfolded protein response (UPRmt). Activation of UPRmt restores the function of the mitochondria and improves general health and longevity in multiple model systems, termed mitohormesis. In C. elegans, mitohormesis can be accomplished by electron transport chain inhibition, a decline in mitochondrial translation, decreased mitochondrial import, and numerous other methods that activate UPRmt. However, not all methods that activate UPRmt promote longevity. These and other studies have started to question whether UPRmt is directly correlated with longevity. Here, we attempt to address this controversy by unraveling the complex molecular regulation of longevity of the nematode under different mitochondrial stressors that induce mitochondrial stress by performing RNA sequencing to profile transcriptome changes. Using this comprehensive and unbiased approach, we aim to determine whether specific transcriptomic changes can reveal a correlation between UPRmt and longevity. Altogether, this study will provide mechanistic insights on mitohormesis and how it correlates with the lifespan of C. elegans.

Keywords:  Aging; Caenorhabditis elegans; Mitohormesis; UPRmt

DOI:  https://doi.org/10.1007/s11357-025-01912-2
Mol Cell. 2025 Nov 06. pii: S1097-2765(25)00858-5. [Epub ahead of print]85(21): 3893-3894

An orphan no more: SLC25A45 controls mitochondrial import of methylated amino acids.

Zachary L Sebo, Navdeep S Chandel.

Solute carrier (SLC) genes encode the largest membrane transporter superfamily, with many orphan members of unknown function. In recent Cell Metabolism and Molecular Cell articles, Khan et al. and Dias et al. identify SLC25A45 as essential for mitochondrial import of methylated amino acids and subsequent carnitine synthesis.

DOI: https://doi.org/10.1016/j.molcel.2025.10.017
Wellcome Open Res. 2023 ;8 33

Model systems informing mechanisms and drug discovery: a review of POLG-related disease models.

Jonathan Meyrick, Renae J Stefanetti, Linda Errington, Robert McFarland, Gráinne S Gorman, Nichola Z Lax.

   Introduction: Pathogenic variants in the gene encoding the catalytic subunit of DNA polymerase gamma ( POLG), comprise an important single-gene cause of inherited mitochondrial disorders. Clinical manifestations are now recognised as an array of overlapping clinical features rather than discrete syndromes as originally conceptualised. Animal and cellular models have been used to address numerous scientific questions, from basic science to the development and assessment of novel therapies. Here, we sought to employ systematic approaches, wherever possible, to investigate the cellular and animal models used in POLG-related research and assess how well they help us understand disease mechanisms in patients.
Methods: Four databases were searched from inception to May 31 st, 2022: MEDLINE, Scopus, Web of Science, and Cochrane Review. Original articles available in English, reporting the use of a model system designed to recapitulate POLG-related disease, or related pathogenicity, were eligible for inclusion. Risk of bias and the methodological quality of articles were assessed by an adapted version of the Cochrane Risk of Bias Tool, with the quality of evidence synthesized across each model.
Results: A total of 55 articles, including seven model organisms (Human, yeast [ Saccharomyces cerevisiae and Schizosaccharomyces pombe], Drosophila, Mouse, Caenorhabditis elegans, and Zebrafish) with 258 distinct variants were included. Of these, 69% (N=38/55) of articles recapitulated mitochondrial DNA (mtDNA) depletion, 33% (N=18/55) utilised tissue-specific models of POLG-related dysfunction, while 13% (N=7/55) investigated the effect of potential therapeutics in POLG-related mitochondrial disorders.
Discussion: While some evidence is available to support the ability of POLG-related disease models to recapitulate molecular mechanisms and phenotypes, much is of limited quality, with inconsistencies evident across the literature. Further success in examining and translating novel therapies into effective treatments will be enhanced by the availability of more robust models that better recapitulate the entire spectrum of POLG-related disease.
PROSPERO registration: CRD42021234883.

Keywords:  POLG; epilepsy; mitochondria; mtDNA; neurological manifestations; preclinical

DOI:  https://doi.org/10.12688/wellcomeopenres.18637.2
Ann Med Surg (Lond). 2025 Oct;87(10): 6904-6905

Gut instinct: microbiome as a modifiable target in the management of neurologic symptoms in myoclonic epilepsy with ragged-red fibers (MERRF).

Amna Rahman, Muneeb Faiz, Maliha Khalid, Muhammad Talha, Aminath Waafira.

  Myoclonic epilepsy with ragged-red fibers (MERRF) is a rare mitochondrial disorder primarily driven by mutations in mitochondrial DNA, particularly the m.8344A>G variant in MT-TK, and is characterized by epilepsy, myoclonus, ataxia, and other multisystemic features. With no curative therapy, recent attention has turned to the gut microbiome as a modifiable factor influencing neurologic symptoms in mitochondrial diseases. Dysbiosis-induced by antibiotics, diet, or preservatives-has been linked to altered microbial metabolites such as short-chain fatty acids and indoxyl sulfate, which may exacerbate neurological dysfunction. Preliminary clinical trials and preclinical studies suggest that probiotics and dietary interventions can modestly improve disease burden and symptoms such as constipation. However, significant challenges remain, including lack of standardization in analytical protocols, heterogeneous host-microbiota responses, and inadequate patient stratification. To fully realize the therapeutic potential of microbiome-based approaches in MERRF, coordinated multicenter trials, clear regulatory guidelines, and machine learning-enhanced stratification will be essential.

Keywords:  MERRF syndrome; gut microbiome; mitochondrial disease; neurologic symptoms

DOI:  https://doi.org/10.1097/MS9.0000000000003777
Cell Rep. 2025 Nov 03. pii: S2211-1247(25)01276-8. [Epub ahead of print]44(11): 116505

Tunneling nanotube-mediated stem cell immunomodulation dysfunction promotes adipose inflammation and insulin resistance in GDM.

Bingnan Chen, Xuyang Chen, Jianxin Li, Ruohan Hu, Lijun Yang, Hongli Li, Xinmi Liu, Richard D Cannon, Richard Saffery, Boris Novakovic, Hongbo Qi, Hua Zhang, Xiaobo Zhou.

  Adipose-derived stem cells (ADSCs) represent a promising therapeutic resource, yet their immunometabolic regulation remains poorly defined. Here, we reveal a tunneling nanotube (TNT)-mediated communication mechanism between ADSCs and adipose tissue macrophages (ATMs) that maintains metabolic homeostasis during pregnancy. Using gestational diabetes mellitus (GDM) mouse models combined with live-cell imaging, scanning electron microscope, and multi-omics approaches, we demonstrate that mitochondrial transfer from ADSCs to ATMs via TNTs sustains ATM metabolic fitness. This process is governed by the WNT5A-RhoA-ROCK1 axis and becomes impaired under metabolic stress, driving ATMs inflammatory polarization and insulin resistance. Importantly, in situ ADSC administration restores mitochondrial transfer and improves metabolic parameters in GDM mice. Collectively, our work establishes TNT-mediated organelle sharing as a fundamental mechanism of stem cell-immune interaction and demonstrates that ADSC-based therapy represents a promising strategy for GDM by reprogramming the metabolism of immune cells.

Keywords:  CP: Metabolism; CP: Stem cell research; adipose tissue macrophages; adipose-derived stem cells; gestational diabetes mellitus; mitochondria; tunneling nanotubes

DOI:  https://doi.org/10.1016/j.celrep.2025.116505
Nat Metab. 2025 Nov 04.

Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology.

Daniel Barnett, Till S Zimmer, Caroline Booraem, Fernando Palaguachi, Samantha M Meadows, Haopeng Xiao, Man Ying Wong, Wenjie Luo, Li Gan, Edward T Chouchani, Anna G Orr, Adam L Orr.

Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signalling, but its triggers, temporal dynamics, targets and disease relevance are not clear. Here, using site-selective suppressors and genetic manipulations together with live mitochondrial ROS imaging and multiomic profiling, we show that CIII is a dominant source of ROS production in astrocytes exposed to neuropathology-related stimuli. Astrocytic CIII ROS production is dependent on nuclear factor-κB and the mitochondrial sodium-calcium exchanger (NCLX) and causes oxidation of select cysteines within immune- and metabolism-associated proteins linked to neurological disease. CIII ROS amplify metabolomic and pathology-associated transcriptional changes in astrocytes, with STAT3 activity as a major mediator, and facilitate neuronal toxicity. Therapeutic suppression of CIII ROS in mice decreases dementia-linked tauopathy and neuroimmune cascades and extends lifespan. Our findings establish CIII ROS as an important immunometabolic signal transducer and tractable therapeutic target in neurodegenerative disease.

DOI: https://doi.org/10.1038/s42255-025-01390-y
Nat Commun. 2025 Nov 04. 16(1): 9727

Effective in vivo RNA base editing via engineered cytidine deaminase APOBECs fused with PUF proteins.

Wenjian Han, Bo Yuan, Xiaojuan Fan, Weike Li, Yiting Yuan, Yuefang Zhang, Shu Wang, Shifang Shan, Markus Hafner, Zefeng Wang, Zilong Qiu.

Base editing stands at the forefront of genetic engineering, heralding precise genetic modifications with broad implications. While CRISPR-based DNA and RNA base editing systems capitalize on sgRNA-guided specificity and diverse deaminase functionalities, the pursuit of efficient C-to-U RNA editing has been hampered by the inherent constraints of cytidine deaminases. Here, we report an RNA base editing platform by refining cytidine deaminases, termed professional APOBECs (ProAPOBECs), through systematic enhancements and AI-driven protein engineering. ProAPOBECs demonstrate unprecedented catalytic versatility, particularly fused with RNA-recognizing Pumilio and FBF (PUF) proteins. We demonstrate that in vivo RNA base editing of Pcsk9 using ProAPOBECs effectively lowers cholesterol levels in mice. Additionally, AAV-mediated RNA base editing with ProAPOBECs in the brain of an autism mouse model not only corrects point mutations in Mef2c mRNAs but also significantly alleviates disease-associated phenotypes. This work introduces a pioneering collection of RNA base editing instruments, emphasizing their therapeutic potential in combatting genetic disorders.

DOI: https://doi.org/10.1038/s41467-025-64748-6
Nat Commun. 2025 Nov 07. 16(1): 9846

Microglia alter sex-specific cerebellar myelination following placental hormone loss.

Jacquelyn Salzbank, Helene Lacaille, Jenah Gaby, Jiaqi J O'Reilly, Michael Kissner, Claire-Marie Vacher, Anna A Penn.

Placental dysfunction is linked to neurodevelopmental disorders, with males showing greater vulnerability to perinatal inflammation-mediated brain injuries. Using our transgenic mouse model, Akr1c14cyp19aKO (plKO), we investigate how reduced placental allopregnanolone (ALLO), an anti-inflammatory neurosteroid, contributes to sex-specific brain injury. plKO mice display sex-divergent cerebellar myelination and male-specific autism-like behaviors. Here we show that placental ALLO insufficiency triggers sex-divergent neuroinflammatory responses and microglial dysfunction. Sex-divergent differential expression of inflammatory genes and distinct inflammatory cytokine/chemokine patterns are seen in the placenta and the brain. Prostaglandin E2 (PGE2)-EP4 signaling is identified as a key regulator and, consistent with male plKO cerebellar hypermyelination, male microglial myelin phagocytosis is impaired by SIRPα-CD47 signaling changes. Postnatal manipulation of these critical pathways can normalize cerebellar myelin content and rescue abnormal behavior in male plKO mice. Sex-divergent microglial dysfunction and prostaglandin signaling drive male-biased neurodevelopmental impairments in our model, suggesting new therapeutic targets to improve brain development following placental dysfunction.

DOI: https://doi.org/10.1038/s41467-025-64814-z
Ann Med Surg (Lond). 2025 Nov;87(11): 7798-7799

AI-powered neuroimaging markers: a new era in paediatric Leigh syndrome diagnosis.

Raiha Yasser, Faiza Imran, Maliha Khalid, Muhammad Talha, Aminath Waafira.

  Leigh syndrome is a severe pediatric mitochondrial disorder characterized by progressive neurological decline and epilepsy as a frequent manifestation. Traditional diagnostic approaches, including EEG and MRI, are often limited in their sensitivity and specificity, leading to diagnostic delays. Artificial intelligence (AI)-powered neuroimaging markers have emerged as promising tools that integrate multimodal patient data - including clinical history, imaging, and genetic sequencing - to enhance diagnostic precision and facilitate early intervention. Recent studies have demonstrated AI's ability to classify epilepsy subtypes, automate EEG interpretation, and detect early neurodegenerative changes, underscoring its clinical potential. However, challenges such as algorithm transparency, dataset bias, and ethical concerns remain. Integrating AI-driven neurotechnology with existing modalities may significantly improve the early diagnosis and prognosis of Leigh syndrome, offering a pathway toward precision neurodiagnostics in pediatric care.

Keywords:  Leigh syndrome; artificial intelligence; neuroimaging; pediatric neurology

DOI:  https://doi.org/10.1097/MS9.0000000000003999
Nature. 2025 Nov;647(8088): 127-142

Continuous cell-type diversification in mouse visual cortex development.

Yuan Gao, Cindy T J van Velthoven, Changkyu Lee, Emma D Thomas, Rémi Mathieu, Angela P Ayala, Stuard Barta, Darren Bertagnolli, Jazmin Campos, Trangthanh Cardenas, Daniel Carey, Tamara Casper, Anish Bhaswanth Chakka, Rushil Chakrabarty, Megan Chiang, Lindsey Ching, Michael Clark, Marie J Desierto, Rebecca Ferrer, Jessica Gloe, Jeff Goldy, Nathan Guilford, Junitta Guzman, Carliana R Halterman, Samantha D Hastings, Daniel Hirschstein, Windy Ho, Katelyn James, Zoe Juneau, Naomi Martin, Rachel McCue, Emma Meyerdierks, Amanda C Mitchell, Josh S Nagra, Beagan Nguy, Thuc Nghi Nguyen, Paul Olsen, Alana A Oyama, Nick Pena, Jacob Quon, Qingzhong Ren, Augustin Ruiz, Nadiya V Shapovalova, Josef Sulc, Amy Torkelson, Alex Tran, Herman Tung, Nasmil Valera Cuevas, Justin Wang, Jeanelle Ariza, Delissa A M McMillen, Jack Waters, Michael Kunst, Kara Ronellenfitch, Boaz Levi, Michael J Hawrylycz, Chelsea Pagan, Nick Dee, Kimberly A Smith, Bosiljka Tasic, Zizhen Yao, Hongkui Zeng.

The mammalian cortex is composed of a highly diverse set of cell types and develops through a series of temporally regulated events1-3. Single-cell transcriptomics enables a systematic study of cell types across the entire timeline of cortical development. Here we present a comprehensive and high-resolution transcriptomic and epigenomic cell-type atlas of the developing mouse visual cortex. The atlas is built from a single-cell RNA sequencing dataset of 568,654 high-quality single-cell transcriptomes and a single-nucleus Multiome dataset of 200,061 high-quality nuclei, which were densely sampled across the embryonic and postnatal developmental stages (from embryonic day 11.5 to postnatal day 56). We computationally reconstructed a transcriptomic developmental trajectory map of all excitatory, inhibitory and non-neuronal cell types in the visual cortex. Branching points that mark the emergence of new cell types at specific developmental ages and molecular signatures of cellular diversification are identified. The trajectory map shows that neurogenesis, gliogenesis and early postmitotic maturation in the embryonic stage give rise to all cell classes and nearly all subclasses in a staggered parallel manner. Increasingly refined cell types emerge throughout the postnatal differentiation process, including the late emergence of many cell types during the eye-opening stage and the onset of critical period, suggesting that there is continuous cell-type diversification at different stages of cortical development. Throughout development, there are cooperative dynamic changes in gene expression and chromatin accessibility in specific cell types. We identify cell-type-specific and temporally resolved gene regulatory networks that link transcription factors and downstream target genes through accessible chromatin motifs. Collectively, our study provides a detailed dynamic molecular map directly associated with individual cell types and specific temporal events that can reveal the molecular logic underlying the complex and multifaceted cortical cell type and circuit development.

DOI: https://doi.org/10.1038/s41586-025-09644-1
Mol Metab. 2025 Oct 31. pii: S2212-8778(25)00185-1. [Epub ahead of print] 102278

An atlas of mitochondrial ATP synthase activity across the lifespan.

Muzna Saqib, Dylan C Sarver, Christy M Nguyen, Fangluo Chen, Marcus M Seldin, G William Wong.

Mitochondrial dysfunction and declining energy production are hallmarks of aging, yet we lack a comprehensive systems-level view of ATP synthase (Complex V) activity across tissues, sex, and age. To overcome this, we leveraged a recently developed method to directly quantify complex V hydrolytic activity at scale in 32 tissues from young (10 weeks) and old (80 weeks) male and female mice. Our high-resolution atlas reveals several notable findings: 1) complex V activity differs markedly across tissues, with the highest levels seen in contractile organs such as the heart and striated muscles (quadriceps, hamstring, diaphragm, tongue); 2) sex influences complex V activity in a tissue-specific manner, with significant differences seen in the heart, liver, fat depots, pancreas, spleen, tongue, and cortex; 3) aging has a much larger impact than sex on complex V activity, with a greater number of age-dependent changes seen across tissues; 4) the directionality and magnitude of change in complex V activity across sex and age is variable and tissue dependent; 5) the expression of complex V related genes in human and mouse tissues across age shows only partial concordance with complex V activity, suggesting functional modulation by posttranscriptional mechanisms. This compendium of ATP synthase activity highlights organ-level variations in the mode and tempo of aging, affording an unprecedented view of the shared and divergent changes in ATP synthase function across sex and organ systems. Our data provide a valuable reference for comparative studies of mitochondrial adaptations across space and time, and in pathophysiological contexts.

DOI: https://doi.org/10.1016/j.molmet.2025.102278
Mol Cell. 2025 Nov 06. pii: S1097-2765(25)00857-3. [Epub ahead of print]85(21): 3895-3897

A new UCP1-independent thermogenic mechanism in peroxisomes.

Anthony R P Verkerke, Shingo Kajimura.

In a recent publication in Nature, Liu et al.1 report a UCP1-independent thermogenic mechanism in which peroxisomes generate heat in brown adipose tissue through active synthesis and oxidation of monomethyl branched-chain fatty acids (mmBCFAs) derived from branched-chain amino acids.

DOI: https://doi.org/10.1016/j.molcel.2025.10.016
Sci Rep. 2025 Nov 04. 15(1): 38550

Postnatal development of the dentate gyrus vascular niche.

Nidhi Devasthali, India Carter, Angela I Saulsbery, Elizabeth D Kirby.

  Lifelong neurogenesis in the dentate gyrus (DG) of the hippocampus supports cognitive and emotional functions in most adult mammals. The subgranular zone (SGZ) of the DG contains dense vasculature where neural stem and progenitor cells (NSPCs) reside in close proximity to local capillaries. This arrangement likely supports NSPCs by providing access to oxygen, circulating molecules, and endothelial-derived factors. While SGZ vessel density and NSPC association with vessels are well established in adulthood, when these niche attributes emerge in development remains unclear. Here, we show that while blood vessel density in the SGZ remained stable from initial layer formation (2 weeks of age) into young adulthood (9 weeks of age) in male and female mice, the average distance from NSPC somas to the nearest blood vessel decreased progressively over postnatal development. This finding was accompanied by a symmetrical compression of proliferating cells within the SGZ, and a gradual shift of quiescent neural stem cell somas towards the granule cell layer of the DG. Our findings imply that the DG neurogenic vascular niche continues to refine postnatally, suggesting that the NSPC vascular niche has a unique functional role in supporting mature adult neurogenesis.

Keywords:  Blood vessels; Dentate gyrus; Hippocampal neurogenic niche; Neural stem cells; Postnatal development

DOI:  https://doi.org/10.1038/s41598-025-22591-1
Mol Genet Metab. 2025 Oct 30. pii: S1096-7192(25)00262-8. [Epub ahead of print]146(4): 109270

Barth syndrome: Natural history in infants and young children.

Sharada Vishwanath, Anne Brockmeyer, Brittany Hornby, W Reid Thompson, Hilary J Vernon.

  Barth syndrome (BTHS) is a rare X-linked mitochondrial disorder caused by pathogenic variants in TAFAZZIN. It is characterized by cardiomyopathy, neutropenia, growth delay, skeletal myopathy, and developmental concerns. Advances in genetic testing have enabled earlier diagnoses, creating opportunities to better define the natural history of disease in infancy and early childhood. We conducted a longitudinal, observational study of 21 male patients (ages 0-48 months) with genetically confirmed BTHS evaluated at the Barth Syndrome Interdisciplinary Clinic at Kennedy Krieger Institute. Data collected included perinatal history, growth, feeding, cardiac function, hematologic findings, gross motor development, quality of life, and pain assessment. Gross motor skills were assessed via milestone acquisition and the Peabody Developmental Motor Scales (PDMS-2/3). Quality of life was evaluated using the PedsQL™ parent-proxy questionnaire. The most common presenting features were cardiomyopathy (n = 10) and failure to thrive (n = 6), with an average age at diagnosis of 5.5 months, which was significantly earlier than historical cohorts. Eighteen patients developed cardiac dysfunction, 25 % required heart transplantation, and one death occurred due to cardiopulmonary arrest. Feeding difficulties were frequent, with 16 patients affected and 7 requiring gastrostomy tubes. Growth delay was common, though height/weight ratios were often preserved. Neutropenia was present in 19 patients, with variable severity and infection risk. Gross motor development was delayed, particularly for standing and walking, with progressive deficits on PDMS subtests. Quality of life scores indicated substantial impairment, especially in fatigue and general functioning domains. Pain was rarely reported. We conclude that infants and toddlers with BTHS present with significant cardiac, growth, and developmental abnormalities. Earlier diagnosis facilitated by genetic testing allows for earlier intervention and monitoring. These findings highlight the need for proactive cardiac surveillance, nutritional support, and early therapeutic interventions to optimize outcomes, and they provide critical endpoints for future clinical trials in this young age group.

Keywords:  Barth syndrome; Cardiomyopathy; Natural history; Neutropenia

DOI:  https://doi.org/10.1016/j.ymgme.2025.109270
Sci Rep. 2025 Nov 04. 15(1): 38530

Mitofusin 1 in mitochondrial quality control and anti-inflammatory responses in nucleus pulposus cells during disc degeneration.

Jae Won Shin, Young Mi Kang, Hak Sun Kim, Seong Hwan Moon, Kyung Soo Suk, Si Young Park, Byung Ho Lee, Ji Won Kwon.

  Mitochondrial dysfunction drives intervertebral disc degeneration, and mitochondrial dynamics are regulated by mitofusins (MFNs). In this study, we evaluated the roles of MFN1 and MFN2 in mitochondrial quality control and their responses to inflammation and antioxidant treatment in grade I and III disc nucleus pulposus cells (NPCs). Human NPCs were isolated from intervertebral disc tissues of patients. Tumor necrosis factor-α (TNF-α)-induced inflammation was treated with vitamin E (Vit E) or saponin. Mitochondrial quality control was evaluated via quantitative polymerase chain reaction, western blotting, and immunocytochemistry. Sulfated glycosaminoglycan levels were quantified to assess extracellular matrix (ECM) integrity. Mitochondrial morphology and function were assessed via transmission electron microscopy and a xenograft model using MFN1-knockout NPCs. TNF-α significantly upregulated MFN1 and MFN2, with MFN1 showing heightened sensitivity in grade III disc NPCs, leading to mitochondrial fragmentation and ECM degradation. Antioxidants mitigated these effects, with Vit E proving more effective than saponin in reducing MFN1 expression, preserving mitochondrial structure, and stabilizing ECM composition. Vit E maintained mitochondrial integrity, whereas TNF-α induced mitochondrial swelling. In vivo, MFN1-knockout NPCs exhibited reduced ECM proteoglycan levels, reinforcing its role in disc homeostasis. These findings suggest that although MFN1 and MFN2 respond to TNF-α, MFN1 reacts more robustly, making it a more promising target under inflammatory stress.

Keywords:  Degenerative disc diseases; Inflammation; Mitochondrial function; Mitochondrial quality control; Mitofusin; Nucleus pulposus cells

DOI:  https://doi.org/10.1038/s41598-025-19540-3
Environ Res. 2025 Nov 05. pii: S0013-9351(25)02533-2. [Epub ahead of print] 123280

Placental gene expression of the AMPK signaling pathway in association with gestational exposure to ambient air pollution.

Joline L Millen, Dries S Martens, Rossella Alfano, Theo M de Kok, Michelle Plusquin, Florence Debacq-Chainiaux, Thierry Arnould, Tim S Nawrot.

   OBJECTIVE: Prenatal ambient air pollution exposure is able to reach the fetus by crossing the placenta, a highly metabolically active organ. The adenosine monophosphate-activated protein kinase (AMPK) signaling pathway is a crucial regulator of the placental cellular metabolism, necessary for normal placental and fetal development. This study investigates the association between in utero exposure to BC, NO2, and PM2.5, and differences in placental gene expression of the AMPK signaling pathway at birth.
MATERIAL AND METHODS: Transcription data from 182 placentas of the ENVIRONAGE birth cohort were obtained through microarray analysis. Exposure levels were estimated using a spatio-temporal model for the mothers' residential address during pregnancy. The associations between transcription levels of 76 genes, clustered by the cascades of the AMPK signaling pathway, and the air pollution exposures during different time windows of pregnancy were analyzed using a mixed-effects model adjusting for potential confounders.
RESULTS: Higher prenatal levels of BC, NO2, and PM2.5 were associated with downregulated gene expression of the central AMPK gene cluster and multiple upstream and downstream cascades of the AMPK signaling pathway. In a multi-pollutant model, the observed patterns of downregulation remained, supporting the robustness of the associations when considering co-exposure to different air pollutants.
CONCLUSION: This study provides new insights into the possible adverse effects of ambient air pollution exposure on placental development, affecting the placental metabolism at the transcript level. Whether reduced placental AMPK signaling may play a role in air pollution-induced birth outcomes and their long-term consequences needs to be further addressed.

Keywords:  AMPK signaling pathway; air pollution; gene expression; gestation; metabolism; placenta

DOI:  https://doi.org/10.1016/j.envres.2025.123280
J Neonatal Perinatal Med. 2025 Nov;18(1_suppl): 3-35

Proceedings of the 16th International Newborn Brain Conference: Fetal and/or neonatal brain development, both normal and abnormal.

DOI: https://doi.org/10.1177/19345798251375190
Cell Death Discov. 2025 Nov 07. 11(1): 513

Normalization of trophoblast mTOR signaling rescues impaired function in primary human trophoblast cells isolated from pregnancies complicated by fetal growth restriction.

Ellen C Francis, Hiroshi Shimada, Theresa L Powell, Kristen E Boyle, Dana Dabelea, Thomas Jansson, Fredrick J Rosario.

Fetal growth restriction (FGR) is associated with inhibition of placental mTOR signaling and amino acid transport. mTOR is a positive regulator of amino acid transport mediated by controlling the plasma membrane trafficking of SNAT2, a System A amino acid transporter isoform, and LAT1 an isoform involved in System L amino acid transport. Inhibition of mTOR complex 1 decreases SNAT2 and LAT1 plasma membrane trafficking by activating of Nedd4-2, an E3 ubiquitin ligase, and inhibition of mTOR Complex 2 decreases the protein expression of Cdc42 which limits transporter trafficking to the plasma membrane. We isolated human primary trophoblast (PHT) cells from FGR placentas and demonstrate that they maintain the in vivo FGR phenotype with increased expression of DEPTOR, an endogenous inhibitor of mTOR, reduced mTOR signaling, increased Nedd4-2 expression, lower expression of Cdc42, and decreased SNAT2 and LAT 1 protein expression in the plasma membrane, and decreased System A and L activity. We silenced DEPTOR in FGR PHT cells using siRNA and found normalized mTOR signaling, Nedd4-2 and Cdc42 protein expression, SNAT2 and LAT1 plasma membrane trafficking and System A and L amino acid transport activity. We also show that hypoxia induces DEPTOR upregulation in PHT cells. In the Healthy Start Study, a longitudinal pre-birth cohort, placental DEPTOR expression was correlated with lower birth weight percentile and with higher systolic and diastolic blood pressure in children at 4-6 years of age. Together, our studies provide mechanistic and translational insight into how placental DEPTOR may serve as potential mediator of fetal growth and long-term health risk. We identify a mechanistic link between increased trophoblast DEPTOR expression in FGR and decreased placental mTOR signaling and amino acid transport. Intervention strategies aimed at normalizing trophoblast mTOR signaling may be effective to improve trophoblast nutrient transport and fetal growth in FGR.

DOI: https://doi.org/10.1038/s41420-025-02801-5