bims-mitmed 2025-09-21 papers

bims-mitmed

Biomed News

on Mitochondrial medicine

Issue of 2025–09–21
24 papers selected by
Dario Brunetti, Fondazione IRCCS Istituto Neurologico

Manipulating mitochondrial gene expression.
mtDNA base editing: Mind the gap.
Motor Neuropathy in a Patient With Mitochondrial Disease and a Novel TTC19 Variant: An Underrecognized Phenotypic Feature.
Biallelic TMEM126B Variants as a Novel Cause of Kidney Failure-Implications for Mitochondrial Genetic Testing in Nephrology.
Compartmentalized thymidine phosphorylation by mitochondrial nucleotide kinases TK2 and CMPK2.
Mitoepigenetic Targeting of Age-Related Dysfunction: Mechanisms, Therapeutic Avenues, and Transgenerational Implications.
Genetic background of neurological disorders with basal ganglia calcification.
Leriglitazone improves iron homeostasis and ferroptotic markers in frataxin-deficient dorsal root ganglia neurons.
Dual roles of mTOR in skeletal muscle adaptation: coordinating hypertrophic and mitochondrial biogenesis pathways for exercise-induced chronic disease management.
Sirt1 attenuates necrotizing enterocolitis via Hif-1α deacetylation-mediated suppression of Bnip3-Dependent mitophagy.
Patient-Derived Neurons Exhibit α-Synuclein Pathology and Previously Unrecognized Major Histocompatibility Complex Class I Elevation in Mitochondrial Membrane Protein-Associated Neurodegeneration.
Mapping the genetic landscape of iron metabolism uncovers the SETD2 methyltransferase as a modulator of iron flux.
Whole mitochondrial genome sequencing in individuals with Leber hereditary optic neuropathy negative for the common pathogenic mitochondrial DNA variants.
Tracking dietary exposures with metabolite biomarkers.
Metabolic Reprogramming of Oligodendrocytes in Intrauterine Growth Restriction.
Prenatal Per- and Polyfluoroalkyl Substances (PFAS) Exposures, Newborn Mitochondrial DNA Copy Number, and the Modifying Role of the Maternal Folate Level.
Mitochondrial oxidative stress, cellular damages and stem cell aging in premature aging models with complex II electron transport defect.
Organelle activity organized by the endoplasmic reticulum-mitochondria encounter structure -ERMES- is essential for Podospora anserina development.
World's first AI-designed viruses a step towards AI-generated life.
A rare genetic variant confers resistance to neurodegeneration across multiple neurological disorders by augmenting selective autophagy.
CircNCX1 contributes to mitochondrial fusion in cardiomyocyte by mediating the expression of mitofusin 2.
DP1 Receptor Blockade Attenuates Microglial Senescence and Cognitive Decline Caused by PTGDS in Exosomes From Aged Brains.
This AI tool predicts your risk of 1,000 diseases - by looking at your medical records.
Boosted mitochondria reverse cognitive impairment in mice.

Biol Chem. 2025 Sep 15.

Manipulating mitochondrial gene expression.

Drishan Dahal, Luis D Cruz-Zargoza, Peter Rehling.

  Mitochondria are essential for cellular metabolism, serving as the primary source of adenosine triphosphate (ATP). This energy is generated by the oxidative phosphorylation (OXPHOS) system located in the inner mitochondrial membrane. Impairments in this machinery are linked to serious human diseases, especially in tissues with high energy demands. Assembly of the OXPHOS system requires the coordinated expression of genes encoded by both the nuclear and mitochondrial genomes. The mitochondrial DNA encodes for 13 protein components, which are synthesized by mitochondrial ribosomes and inserted into the inner membrane during translation. Despite progress, key aspects of how mitochondrial gene expression is regulated remain elusive, largely due to the organelle's limited genetic accessibility. However, emerging technologies now offer new tools to manipulate various stages of this process. In this review, we explore recent strategies that expand our ability to target mitochondria genetically.

Keywords:  RNA; gene expression; genetic tools; mitochondria

DOI:  https://doi.org/10.1515/hsz-2025-0170
Mol Cell. 2025 Sep 18. pii: S1097-2765(25)00713-0. [Epub ahead of print]85(18): 3351-3352

mtDNA base editing: Mind the gap.

Jose Domingo Barrera-Paez, Carlos T Moraes.

In this issue of Molecular Cell, Xiang et al.1 provided insights into the mechanism and structure-guided engineering of DdCBE for mitochondrial DNA base editing. More precise editing was achieved by better defining the editing window.

DOI: https://doi.org/10.1016/j.molcel.2025.08.028
J Peripher Nerv Syst. 2025 Sep;30(3): e70060

Motor Neuropathy in a Patient With Mitochondrial Disease and a Novel TTC19 Variant: An Underrecognized Phenotypic Feature.

Daniele Mandia, Charline Benoit, Tanya Stojkovic, Yann Nadjar.

   BACKGROUND AND AIMS: TTC19 encodes a mitochondrial protein involved in the assembly of complex III of the respiratory chain. Biallelic pathogenic variants cause a rare mitochondrial disorder typically associated with cerebellar ataxia, neuropsychiatric symptoms, and characteristic brain MRI findings within the Leigh syndrome spectrum. Peripheral motor involvement has been described in a minority of cases but has rarely been documented with detailed neurophysiological data. We report a novel TTC19 variant in a patient presenting with a distinctive combination of central and peripheral motor involvement.
CASE REPORT: A male patient of Malian origin presented with cerebellar ataxia and attention deficits from early childhood. During adolescence, he developed additional features including dysarthria, dysphagia, dysexecutive syndrome, and signs of peripheral motor neuropathy. Brain MRI revealed T2-FLAIR hyperintensities in the basal ganglia and brainstem. Genetic testing identified a novel homozygous nonsense variant in TTC19 (c.235G>T, p.(Gly79*)). At age 19, he experienced two acute deteriorations associated with respiratory infections, leading to severe tetraparesis and diaphragmatic weakness. Neurophysiological studies confirmed a diffuse, axonal, pure distal motor neuropathy. Follow-up imaging showed progression and cavitation of brainstem lesions. The patient died from respiratory failure at age 20.
INTERPRETATION: This case, featuring a novel TTC19 variant and detailed electrophysiological data, further supports the presence of pure motor neuropathy within the phenotypic spectrum of TTC19-related disease. The co-occurrence of Leigh syndrome MRI findings and motor neuropathy represents a specific diagnostic clue that may help prioritize genetic testing in patients with overlapping central and peripheral motor involvement.

Keywords:  Leigh syndrome; TTC19; mitochondrial disease; motor neuropathy; respiratory chain complex III

DOI:  https://doi.org/10.1111/jns.70060
Clin Genet. 2025 Sep 19.

Biallelic TMEM126B Variants as a Novel Cause of Kidney Failure-Implications for Mitochondrial Genetic Testing in Nephrology.

Zachary T Sentell, Anthony C T Cheung, Felicia Russo, Chantal Bernard, Rita Suri, Andrey V Cybulsky, Daniela Buhas, Thomas M Kitzler.

  An adult with kidney failure had compound-heterozygous TMEM126B variants causing mitochondrial complex I deficiency. This expands TMEM126B to mitochondrial nephropathy and supports including mitochondrial genes in renal genetic testing.

Keywords:   TMEM126B ; genetic testing; kidney failure; mitochondrial complex I deficiency; mitochondrial nephropathy

DOI:  https://doi.org/10.1111/cge.70073
J Biol Chem. 2025 Sep 16. pii: S0021-9258(25)02585-2. [Epub ahead of print] 110733

Compartmentalized thymidine phosphorylation by mitochondrial nucleotide kinases TK2 and CMPK2.

Avery S Ward, Vasudeva G Kamath, Chia-Heng Hsiung, Zachary J Lizenby, Alexander G Gillish, D Stave Kohtz, Edward E McKee.

  Deoxynucleotides (dNTPs) in post-mitotic tissues rely on deoxynucleoside salvage pathways in order to repair and replicate nuclear and mitochondrial DNA (mtDNA). Previous work from our laboratory showed in perfused rat heart and isolated mitochondria that the only substrate for TTP synthesis is thymidine. When thymidylate (TMP) is provided to bypass thymidine kinase 2 (TK2) the substrate is readily dephosphorylated to thymidine before salvage occurs suggesting compartmentalization within the heart mitochondrial matrix. The goal of this work extends these findings in the heart to mitochondria from other post-mitotic tissues, including rat liver, kidney, and brain. Using AZT to block mitochondrial thymidine kinase 2, we demonstrate that TMP cannot serve as a precursor for TTP synthesis in isolated mitochondria from any of these tissues unless it is de-phosphorylated to thymidine first. Broken mitochondria incubated with labeled TMP showed similar results as intact mitochondria, suggesting the findings are not related to TMP transport across the inner mitochondrial membrane. Further, using proximity labeling with immunofluorescence microscopy we provide evidence supporting the hypothesis that TMP compartmentation is accounted for by the interaction of TK2 and CMPK2 in the mitochondria. Differential fraction experiments provide additional evidence that association with TK2 allows CMPK2 to display TMPK2 activity. Together, the results indicate that a two-step phosphorylation of thymidine to TDP occurs because the proximity of TK2 and CMPK2 in the mitochondria prevents TMP from diffusing from the two enzymes.

Keywords:  cytidine monophosphate kinase 2; mitochondrial disease; mitochondrial metabolism; nucleoside/nucleotide biosynthesis; nucleoside/nucleotide metabolism; thymidine kinase 2

DOI:  https://doi.org/10.1016/j.jbc.2025.110733
Aging Adv. 2025 Sep;2(3): 108-111

Mitoepigenetic Targeting of Age-Related Dysfunction: Mechanisms, Therapeutic Avenues, and Transgenerational Implications.

Kit Neikirk, Suraj Thapliyal, Sepiso K Masenga, Ashton Oliver, Margaret Mungai, Han Le, Heather K Beasley, Andrea G Marshall, Anthonya T Cooper, Taneisha Gillyard Cheairs, Benjamin I Rodriguez, Edgar Garza-Lopez, Prasanna Katti, Antentor Hinton.

  Mitochondrial epigenetics, a burgeoning field bridging mitochondrial biology and epigenetic regulation, has emerged as a critical determinant of aging and age-related diseases. While nuclear epigenetics is well-characterized, the mechanisms governing mitochondrial DNA (mtDNA) regulation, including nucleoid dynamics, non-coding RNAs (ncRNAs), and metabolite-driven modifications, remain underexplored. This review synthesizes evidence that mitochondrial epigenetics influences cardiovascular pathogenesis through altered DNA methylation and histone acetylation patterns, which dysregulate oxidative phosphorylation and nucleoid stability. In neurodegenerative diseases, endoplasmic reticulum-mitochondrial contact points, disrupted by aging, impair calcium homeostasis and promote neuronal apoptosis, while oxidative stress exacerbates mtDNA instability through inefficient repair mechanisms. Cancer cells exploit mitochondrial metabolic reprogramming, where shifts in acetyl-CoA and α-ketoglutarate levels modulate epigenetic enzymes, fostering drug resistance. Potential therapeutic targets include pharmacological modulation of Mitochondrial transcription factor A acetylation/phosphorylation to enhance mtDNA transcription and dietary interventions to boost NAD+ levels, thereby improving mitochondrial function. Transgenerational studies reveal matrilineal inheritance of mtDNA methylation patterns and stress-induced epigenetic memory, though technical limitations in detecting mtDNA methylation persist. Clinically, mitochondrial epigenetic biomarkers like mtDNA hydroxymethylation and lncRNA expression (e.g., Mitoregulin) show promise for early diagnosis and treatment monitoring. Despite advances, challenges include standardizing methods for mtDNA methylation analysis and translating preclinical findings into therapies. This perspective review underscores the need for integrative approaches combining single-cell sequencing and CRISPR-based technologies to dissect mitochondrial-nuclear crosstalk, ultimately paving the way for precision medicine strategies targeting mitoepigenetic pathways to mitigate age-related decline.

Keywords:  aging; epigenetics; methylation; mitochondria; mitochondrial nucleoid; mtDNA

DOI:  https://doi.org/10.4103/agingadv.agingadv-d-25-00006
J Neurol. 2025 Sep 14. 272(9): 632

Genetic background of neurological disorders with basal ganglia calcification.

Maha Yektay Farahmand, Joel Wallenius, Johan Wasselius, Olof Gråhamn, Andreas Puschmann, Andreea Ilinca.

   BACKGROUND: Bilateral basal ganglia calcifications (BGCs), if severe, are known hallmarks for idiopathic BGC disease (IBGC), but if milder, are often considered radiological findings of unknown significance. In previous studies, only a minority of patients with BGC had monogenic forms of IBGC.
METHODS: We studied consecutive patients from a tertiary neurology clinic with bilateral BGCs of variable severity, and their families. We analyzed known IBGC genes, and an extended panel of genes linked to monogenic stroke and metabolic conditions. Clinical, radiological, and genetic data were collected, including vascular risk factors, cerebrovascular events, imaging findings (total calcification score, white matter hyperintensities, ischemic/hemorrhagic lesions), and relevant family history.
RESULTS: Twenty-four families with BGCs and neurological symptoms were analyzed. Disease-causing variants were identified in 14 families (58.3%). Eight patients had IBGC (variants in SLC20A2, PDGFB, MYORG), 4 had mitochondrial disease (MT-TL1), and 2 had monogenic vascular conditions (GAL, MAP3K6). Three variants were novel. BGC severity was highest in IBGC cases, while vascular and mitochondrial cases had milder calcifications. White matter hyperintensities were seen in 94.7% of cases and correlated highly with the total calcification score. Clinical vascular events had occurred in 41.7% cases. No monogenic cause was found in 10 patients, although many of these showed clinical or radiological features suggestive of monogenic disease.
CONCLUSIONS: Bilateral BGCs can occur in many neurogenetic disorders apart from IBGCs, and a broader genetic search increases the diagnostic yield. Patients with BGCs frequently had clinical cerebrovascular events, which emphasizes the role of cerebrovascular pathology in BGCs.

Keywords:  Basal ganglia calcifications; Monogenic neurological disorders; Stroke; White matter hyperintensities; Whole genome sequencing

DOI:  https://doi.org/10.1007/s00415-025-13344-1
Biomed Pharmacother. 2025 Sep 18. pii: S0753-3322(25)00747-4. [Epub ahead of print]192 118553

Leriglitazone improves iron homeostasis and ferroptotic markers in frataxin-deficient dorsal root ganglia neurons.

Marta Portillo-Carrasquer, Arabela Sanz-Alcázar, Fabien Delaspre, Maria Pazos-Gil, Luiza Oliveira-Jorge, Cristina Vergara, Laura Rodríguez-Pascau, Pilar Pizcueta, Jordi Tamarit, Joaquim Ros, Elisa Cabiscol.

  Friedreich ataxia (FA) is a neurodegenerative disease characterized by degeneration of the large sensory neurons and spinocerebellar tracts, muscle weakness, and hypertrophic cardiomyopathy. It is caused by a deficiency of the mitochondrial protein frataxin, leading to iron dyshomeostasis, defective energy production, and oxidative stress. Peroxisome proliferator-activated receptor gamma (PPARγ) and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathways play crucial roles in regulating mitochondrial function and protecting against oxidative stress, and their dysregulation contributes to neuronal degeneration in FA. In this study, we used frataxin-deficient primary cultures of dorsal root ganglia neurons to better understand the mechanism of action of leriglitazone, a novel brain-penetrant, full, and selective PPARγ agonist, by assessing the rescue of several cellular markers altered under frataxin deficiency. Leriglitazone improved most of the analyzed parameters, including cell survival, mitochondrial respiratory activity, iron homeostasis, and oxidative stress. Moreover, increased lipid peroxidation, a key marker of ferroptosis, was almost completely rescued by leriglitazone. NRF2 and PPARγ coactivator 1 alpha (PGC1α) levels that were decreased in frataxin-deficient neurons were normalized by leriglitazone. Interestingly, the combination of leriglitazone and the NRF2 activator omaveloxolone, a drug that has been approved to treat FA, was able to rescue both survival and mitochondrial function. In summary, our findings in this neuronal model suggest that targeting the PPARγ pathway with leriglitazone may be a promising therapeutic strategy for FA by improving mitochondrial function, bioenergetic cell alterations, and iron homeostasis. Likewise, a combination therapy with omaveloxolone may be an alternative for FA patients.

Keywords:  Dorsal root ganglia; Ferroptosis; Friedreich ataxia; Leriglitazone; Mitochondria; Omaveloxolone

DOI:  https://doi.org/10.1016/j.biopha.2025.118553
Front Med (Lausanne). 2025 ;12 1635219

Dual roles of mTOR in skeletal muscle adaptation: coordinating hypertrophic and mitochondrial biogenesis pathways for exercise-induced chronic disease management.

Yong-Cai Zhao.



Keywords:  exercise; hypertrophy; mammalian target of rapamycin (mTOR); mitochondrial biogenesis; skeletal muscle

DOI:  https://doi.org/10.3389/fmed.2025.1635219
Free Radic Biol Med. 2025 Sep 12. pii: S0891-5849(25)00977-3. [Epub ahead of print]241 150-160

Sirt1 attenuates necrotizing enterocolitis via Hif-1α deacetylation-mediated suppression of Bnip3-Dependent mitophagy.

Lin Zhu, Mei Huang, Lu He, Zhihui Rong.

  Necrotizing enterocolitis (NEC), a life-threatening neonatal disease, involves mitochondrial dysfunction whose regulation remains unclear. This study identifies a novel Sir1/Hif-1α regulatory axis in NEC pathogenesis. We demonstrate that Sirt1 downregulation in NEC leads to Hif-1α hyperacetylation, resulting in Bnip3-mediated mitophagy activation and intestinal epithelial injury. Using clinical samples and experimental models, we show that Sirt1 downregulation correlates with mitochondrial dysfunction and intestinal barrier disruption. Pharmacological Sirt1 activation by SRT1720 effectively attenuated NEC progression through Hif-1α deacetylation and subsequent mitophagy inhibition. Importantly, we provide the first evidence that Sirt1 directly regulates Hif-1α acetylation status in intestinal epithelial cells, establishing a new molecular mechanism linking protein acetylation to mitochondrial quality control in NEC. These findings reveal Sirt1 as a master regulator of intestinal homeostasis and highlight Sirt1 activation as a promising therapeutic approach for NEC treatment.

Keywords:  Acetylation; Hif-1α; Inflammation; Mitophagy; Necrotizing enterocolitis; Sirt1

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.09.020
Mov Disord. 2025 Sep 15.

Patient-Derived Neurons Exhibit α-Synuclein Pathology and Previously Unrecognized Major Histocompatibility Complex Class I Elevation in Mitochondrial Membrane Protein-Associated Neurodegeneration.

Leonie M Heger, Leonie Kertess, Clara Kaufhold, Francesco Gubinelli, Aida Cardona-Alberich, Gamze Özata, Stephan A Müller, Sarah K Tschirner, Oliver Stehling, Martina Schifferer, Camille Peron, Valeria Tiranti, Roland Lill, Arcangela Iuso, Luigi Zecca, Michael Strupp, Wolfgang Oertel, Stefan F Lichtenthaler, Lena F Burbulla.

   BACKGROUND: Mitochondrial membrane protein-associated neurodegeneration (MPAN) from the neurodegeneration with brain iron accumulation (NBIA) family is a rare neurodegenerative disease marked by α-synuclein aggregation, brain iron accumulation, and midbrain dopaminergic neuron degeneration.
OBJECTIVE: The mechanisms driving neuron vulnerability remain unclear. Our study aimed to develop a patient-derived disease model replicating key pathologies of patient brains.
METHODS: We generated induced pluripotent stem cell-derived midbrain dopaminergic neurons from MPAN patients and examined ultrastructural and biochemical markers of pathology.
RESULTS: MPAN patient neurons displayed α-synuclein aggregation, axonal swellings, iron accumulation, and severe membrane destruction. In addition, levels of the major histocompatibility complex class I (MHC-I), linked to cellular stress and neurodegenerative processes, were elevated in patient neurons. Treatment with acetyl-leucine, a potentially neuroprotective compound, decreased MHC-I.
CONCLUSIONS: This first patient-derived neuronal model of MPAN provides a useful tool for further research aimed at unraveling the complexities of this disease and developing potential therapeutic interventions. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords:  MPAN; NBIA; dopaminergic neurons; iPSC disease modeling; α‐synuclein

DOI:  https://doi.org/10.1002/mds.70029
Sci Adv. 2025 Sep 19. 11(38): eadw9095

Mapping the genetic landscape of iron metabolism uncovers the SETD2 methyltransferase as a modulator of iron flux.

Anthony W Martinelli, Chun-Pei Wu, Tristan Vornbäumen, Hudson W Coates, Louise H Jordon, Niek Wit, Jia J Sia, Anneliese O Speak, James A Nathan.

Cellular iron levels must be tightly regulated to ensure sufficient iron for essential enzymatic functions while avoiding the harmful generation of toxic species. Here, to better understand how iron levels are controlled, we carry out genome-wide mutagenesis screens in human cells. Alongside mapping known components of iron sensing, we determine the relative contributions of iron uptake, iron recycling, ferritin breakdown, and mitochondrial flux in controlling the labile iron pool. We also identify SETD2, a histone methyltransferase, as a chromatin modifying enzyme that controls intracellular iron availability through ferritin breakdown. Functionally, we show that SETD2 inhibition or cancer-associated SETD2 mutations render cells iron deficient, thereby driving resistance to ferroptosis and potentially explaining how some tumors evade antitumoral immunity.

DOI: https://doi.org/10.1126/sciadv.adw9095
Front Neurol. 2025 ;16 1584748

Whole mitochondrial genome sequencing in individuals with Leber hereditary optic neuropathy negative for the common pathogenic mitochondrial DNA variants.

Sundaramurthy Srilekha, Selvakumar Ambika, Nagarajan Hemavathy, Dharani Vidhya, Patrick Yu-Wai-Man.

   Purpose: This study aimed to explore the role of additional mitochondrial DNA (mtDNA) variants in the development of Leber hereditary optic neuropathy (LHON) by screening the entire mitochondrial genome in individuals who had previously tested negative for the three common mtDNA variants: m.3460G > A (MT-ND1), m.11778G > A (MT-ND4), and m.14484 T > C (MT-ND6), by conventional Sanger sequencing.
Methods: Forty-one individuals with a suspected clinical diagnosis of LHON were recruited from the neuro-ophthalmology clinic. Each participant had undergone a comprehensive neuro-ophthalmic examination, including slit lamp examination, indirect ophthalmoscopy, visual field perimetry, optical coherence tomography, and MRI of the brain and orbits. Targeted re-sequencing was conducted using next-generation sequencing (NGS) on the HiSeqX 10 platform (Illumina, San Diego, California) with a 2 × 150 bp paired-end configuration. The sequencing reads were aligned to the human mitochondrial genome sequence (hg19). Variants were filtered with the VariMAT tool (v.2.3.9). Haplogroup analysis was performed using Haplogrep 2 (v2.0). To assess the deleteriousness of nonsynonymous variations, bioinformatics prediction tools such as PolyPhen2, SIFT, CADD, and Mutation Assessor were utilized. In addition, while tools like Consurf, PredictSNP, DynaMut, ENCoM, DUET, SDM, mCSM, were employed to evaluate evolutionary conservation, pathogenicity, structural stability, and functional impact.
Results: Whole mitochondrial genome sequencing of 41 clinically suspected LHON cases identified a total of 1,518 mtDNA variants. Of these, 822 were located in the coding regions, including 555 synonymous and 273 non-synonymous variants. Two heteroplasmic disease-causing variants (m.11778G > A and m.3460G > A) were identified in one individual each (90.0 and 63.6%, respectively). Additionally, rare mtDNA variants listed in Mitomap were found in five individuals (5/41, 12.1%), namely, MT-ND1 (m.3335 T > C, m.3394 T > C, m.3395A > G), MT-ND4L (m.10680G > A), and MT-ND6 (m.14502 T > C), with variants in MT-ND1 being the most prevalent (3/41, 7.3%).
Conclusion: Our study of a well-characterized Indian LHON cohort uncovered rare mtDNA variants that should be considered when assessing undiagnosed optic neuropathy cases. Additionally, it underscores the effectiveness of NGS in identifying heteroplasmic mtDNA variants. This indicates that whole mitochondrial genome sequencing via NGS is a more efficient and preferred approach for routine molecular genetic testing.

Keywords:  bioinformatics analysis; haplogroup analysis; homoplasmy; next generation sequencing; rare variants

DOI:  https://doi.org/10.3389/fneur.2025.1584748
Nat Metab. 2025 Sep 17.

Tracking dietary exposures with metabolite biomarkers.

DOI: https://doi.org/10.1038/s42255-025-01370-2
Dev Neurosci. 2025 Sep 15. 1-22

Metabolic Reprogramming of Oligodendrocytes in Intrauterine Growth Restriction.

Hannah Peters, Camille M Fung, Robert W Dettman, Maria L V Dizon, Jill Chang.

Introduction Intrauterine growth restriction (IUGR) has been shown to adversely affect developing white matter, putting infants at risk for neurodevelopmental disability including cerebral palsy (CP). White matter injury (WMI) has been well documented in both human and animal studies of IUGR with sexual dimorphism. Currently the underlying cellular mechanisms leading to WMI in IUGR remain poorly understood but energy failure is a likely candidate. Methods To address these gaps, we evaluated for sex-specific changes to oligodendrocyte (OL) differentiation and the OL transcriptome leveraging cell-specific epitope tagging and RNA isolation in a placental insufficiency-induced IUGR mouse model. OL mitochondrial respiration was further evaluated using primary cell isolation and Agilent Seahorse technology. Results We found an early sex-specific arrest of OL differentiation in IUGR females, which was followed by late catch-up differentiation and proliferation. Cell-specific RNA sequencing demonstrated downregulation of genes involved in oxidative phosphorylation (OXPHOS) in IUGR. IUGR males demonstrated a greater downregulation of electron transport chain (ETC) genes and proteins than their IUGR female counterparts. Quantification of O4+ oligodendrocyte mitochondrial respiration also demonstrated decreased ATP generation in IUGR males via OXPHOS that was consistent with ETC gene and protein expression findings. Conclusion Our findings demonstrate sex-specific differences in OL differentiation and in mitochondrial metabolism in IUGR. These results provide insight into the different neurodevelopmental outcomes seen between IUGR males and females. These results also lay the foundation for investigation into targeted nutritional and pharmacologic management.

DOI: https://doi.org/10.1159/000548455
Environ Sci Technol. 2025 Sep 15.

Prenatal Per- and Polyfluoroalkyl Substances (PFAS) Exposures, Newborn Mitochondrial DNA Copy Number, and the Modifying Role of the Maternal Folate Level.

Zeyu Li, Xueqi Qu, Xiumei Hong, Guoying Wang, Mingyang Song, Giehae Choi, Jessie P Buckley, Xiaobin Wang.

  Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) may damage newborn mitochondrial function indicated by lower mitochondrial DNA copy number (mtDNAcn), which may help explain the mechanisms underlying adverse health outcomes in offspring. Adequate maternal folate levels may offer protection. We investigated associations between maternal PFAS exposures and newborn mtDNAcn and examined effect modification by maternal folate levels in 572 mother-newborn dyads from the Boston Birth Cohort. We measured eight PFAS in maternal plasma collected 24-72 h postpartum using HPLC-MS/MS and mtDNAcn in cord blood using targeted sequencing. We used multivariable linear regression and Bayesian kernel machine regression models to estimate associations between PFAS and mtDNAcn Z-score, overall and stratified by newborn sex and maternal folate level. We observed that associations varied by PFAS species, including an inverse association with PFOS and nonlinear associations with Me-PFOSA-AcOH, PFDeA, and PFNA. Associations of PFHxS and PFOS with mtDNAcn differed by sex. Notably, we found inverse associations of Me-PFOSA-AcOH, PFOS, and the PFAS mixture only among newborns whose mothers had low folate levels. In conclusion, prenatal exposures to specific PFAS and the PFAS mixture were associated with altered cord blood mtDNAcn, with adequate maternal folate levels potentially mitigating the associations.

Keywords:  PFAS; folate; mechanism; mitochondrial DNA; mixture; modifiable factor; prenatal exposure; sex-specific

DOI:  https://doi.org/10.1021/acs.est.5c06494
J Clin Biochem Nutr. 2025 Sep 01. 77(2): 101-112

Mitochondrial oxidative stress, cellular damages and stem cell aging in premature aging models with complex II electron transport defect.

Takamasa Ishii, Kayo Yasuda, Masaki Miyazawa, Hiromi Onouchi, Sumino Yanase, Naoaki Ishii.

  Mitochondria which are the major intracellular reactive oxygen species (ROS) sources produce especially superoxide anion (O2 •-) as a byproduct of energy production. It has been well known that O2 •- is converted from oxygen (O2) and is overproduced by excessive electron leakage from the mitochondrial electron transport chain (ETC), mainly complexes I and III. However we have previously reported that several point mutations (specifically G71E in C. elegans, I71E in Drosophila and V69E in mouse) in succinate dehydrogenase C subunit (SDHC) of complex II cause mitochondrial electron transport defect leading to O2 •- overproduction from mitochondria. These mutations can cause endogenous oxidative stress resulting in tumorigenesis and apoptosis as well as premature death. Recently, we have also demonstrated that premature aging of hematopoietic stem cell with a mutation in SDHC is developed after the growth phase and normal development. Here, we review cellular damages by complex II electron transport defect-induced endogenous oxidative stress in premature aging models.

Keywords:  aging; apoptosis; complex II; mitochondria; oxidative stress

DOI:  https://doi.org/10.3164/jcbn.25-62
Microb Cell. 2025 ;12 255-273

Organelle activity organized by the endoplasmic reticulum-mitochondria encounter structure -ERMES- is essential for Podospora anserina development.

Melisa Álvarez-Sánchez, Matías Ramírez-Noguez, Beatriz Aguirre-López, Leonardo Peraza-Reyes.

  Eucaryotic cell functioning and development depend on the concerted activity of its organelles. In the model fungus Podospora anserina, sexual development involves a dynamic regulation of mitochondria, peroxisomes and the endoplasmic reticulum (ER), suggesting that their activity during this process is coordinated. The ER-Mitochondria Encounter Structure (ERMES) is a tether complex composed of the ER protein Mmm1 and the mitochondrial proteins Mdm10, Mdm12 and Mdm34, which mediates membrane contact-site formation between these organelles. This complex also mediates interactions between mitochondria and peroxisomes. Here we analyzed the role of the ERMES complex during P. anserina development. By studying a thermosensitive MDM10 mutant, we show that MDM10 is required for mitochondrial morphology and distribution, as well as for peroxisome membrane-remodeling and motility. We discovered that lipid droplets exhibit a subapical hyphal localization, which depends on MDM10. MDM10 is also required for ER shaping and dynamics, notably of the apical ER domains of the polarized-growing hyphal region, in a process that involves the activity of the protein YOP1. We also show that apical ER shaping involves a Spitzenkörper-associated membrane traffic, which implicates MDM10, and that the mycelial growth defect of mdm10 mutants is exacerbated when the ER-shaping proteins YOP1 or RTN1 are loss. Finaly, we show that MMM1 is strictly required for mycelial growth and sexual development, suggesting that its activity is essential. Our results show that the activity of distinct organelles depends on the ERMES complex, and that the function of this complex is critical for P. anserina growth and development.

Keywords:  endoplasmic reticulum; fungi; lipid droplets; mitochondria; organelle interactions; peroxisomes; sexual development

DOI:  https://doi.org/10.15698/mic2025.09.860
Nature. 2025 Sep 19.

World's first AI-designed viruses a step towards AI-generated life.

Katie Kavanagh.



Keywords:  Molecular biology; Synthetic biology

DOI:  https://doi.org/10.1038/d41586-025-03055-y
Neuron. 2025 Sep 12. pii: S0896-6273(25)00624-5. [Epub ahead of print]

A rare genetic variant confers resistance to neurodegeneration across multiple neurological disorders by augmenting selective autophagy.

Katherine R Croce, Christopher Ng, Serihy Pankiv, Eddy Albarran, Peter Langfelder, Ana Ramos de Jesus, Glenn M Duncan, Nan Wang, Anna Basile, Caitlin McHugh, Nicole A Litt, Alina Li, Sophia Friedman, Etty P Cortes, Michael C Zody, X William Yang, Jun B Ding, Jean Paul G Vonsattel, Anne Simonsen, David E Housman, Nancy S Wexler, Ai Yamamoto.

  The study of disease modifiers is a powerful way to identify patho-mechanisms associated with disease. Using the strong genetic traits of Huntington's disease (HD), we identified a rare, single-nucleotide polymorphism (SNP) in WDFY3 associated with a delayed age of onset of up to 23 years. Remarkably, the introduction of the orthologous SNP into mice recapitulates this neuroprotection, significantly delaying neuropathological and behavioral dysfunction in two models of HD. The SNP increases expression of the protein autophagy-linked Fab1, YOTB, Vac1, and EEA1 (FYVE) protein (Alfy), an autophagy adaptor protein for the clearance of aggregated proteins, whose ectopic overexpression is sufficient to capture the neuroprotective effects of the variant. Increasing Alfy expression protects not only against HD but also against the toxicity due to phospho-α-synuclein and AT8-positive accumulation. By combining human and mouse genetics, we have uncovered a pathway that protects against multiple proteinopathies, revealing a much-sought-after, shared therapeutic target across a broad range of neurodegenerative diseases.

Keywords:  Huntington’s disease; Parkinson’s disease; WDFY3/Alfy; autophagy; neurodegeneration; proteinopathy; selective autophagy; synuclein; tauopathy

DOI:  https://doi.org/10.1016/j.neuron.2025.08.018
Int J Biol Macromol. 2025 Sep 17. pii: S0141-8130(25)08295-9. [Epub ahead of print] 147738

CircNCX1 contributes to mitochondrial fusion in cardiomyocyte by mediating the expression of mitofusin 2.

Heng Zhang, Jiaxin Li, Yu Wang, Qi Li, Lin Song, Mengyang Li.

  Mature mammalian cardiomyocytes highly utilize fatty acid-dependent aerobic respiration to produce energy effectively. However, even embryonic and neonatal cardiomyocytes prefer anaerobic glycolysis. The underlying molecular mechanism of this transformation during cardiomyocyte maturation hasn't been fully understood. Circular RNA-circNCX1 (also named circSLC8A1) is enriched in cardiomyocytes and previously demonstrated to inhibit cardiomyocyte proliferation. Here, our study further indicates that circNCX1 is also essential for mitochondria maturation in cardiomyocytes. It was observed that circNCX1 facilitates mitochondrial fusion and closure of the mitochondrial permeability transition pore, leading to an increase in mitochondrial function and metabolic remodeling in cardiomyocytes. Mechanistically, circNCX1 functions in a mitofusin 2 (MFN2)-dependent manner. It up-regulates MFN2 by inhibiting the expression of miR-16-5p. At the animal level, cardiomyocyte-specific silencing of circNCX1 can simultaneously cause mitochondrial dynamics dysfunction and activate cardiomyocyte proliferation, resulting in non-pathological cardiac enlargement with preserved heart function. In summary, our study revealed the regulatory mechanism of circNCX1 on cardiomyocyte maturation and its therapeutic potential in heart disease treatment.

Keywords:  Cardiomyocyte maturation; Circular RNA; MFN2; Metabolic remodeling; Mitochondria; circNCX1; miR-16

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.147738
Aging Cell. 2025 Sep 19. e70228

DP1 Receptor Blockade Attenuates Microglial Senescence and Cognitive Decline Caused by PTGDS in Exosomes From Aged Brains.

Yaru Liu, Pan Liao, Bo Yan, Dai Li, Shishuang Zhang, Wei Zhang, Zexi Jia, Zihan Zhang, Han Gao, Qiang Liu, Fanglian Chen, Ping Lei, Zhenyu Yin.

  Aging leads to neurodegenerative diseases, such as cognitive decline, which are induced by persistent chronic low-grade inflammation in the brain driven by microglial activation. However, whether and how brain-derived exosomes from aged mice (A-exo) induce a pro-inflammatory state and cellular senescence in microglia within the aging brain is poorly understood. Here, we report that brain-derived exosomes from aged mice (A-exo) cause cognitive decline in normal young mice, inducing microglial overactivation, lipid droplet accumulation, and senescence-associated secretory phenotype (SASP) secretion. This abnormal microglial activity arises from the elevated expression of PTGDS in A-exo due to mouse aging, resulting in increased central and peripheral D-prostanoid receptor 1 (DP1) ligand PGD2 levels, which subsequently leads to sustained DP1 signaling activation. Consequently, this process promotes myeloid cell infiltration, cellular senescence, and cognitive decline by generating a senescent, pro-inflammatory microglial phenotype. Blocking the DP1 receptor ameliorates A-exo-mediated microglial overactivation, myeloid cell infiltration, and cellular senescence. Strikingly, DP1 receptor blockade improves cellular senescence, neuroinflammation, and cognitive decline in aged mice. Our findings reveal a systemic mechanism underlying the sustained activation of microglia following brain aging, paving the way for improving chronic neuroinflammation, cellular senescence, and cognitive decline associated with aging.

Keywords:  DP1 receptors; aging; exosomes; microglia; neuroinflammation

DOI:  https://doi.org/10.1111/acel.70228
Nature. 2025 Sep 17.

This AI tool predicts your risk of 1,000 diseases - by looking at your medical records.

Shamini Bundell, Nick Petrić Howe.



Keywords:  Biotechnology; Medical research; Society

DOI:  https://doi.org/10.1038/d41586-025-03026-3
Nat Biotechnol. 2025 Sep;43(9): 1425

Boosted mitochondria reverse cognitive impairment in mice.

Iris Marchal.

DOI: https://doi.org/10.1038/s41587-025-02823-5