bims-polgdi 2025-04-13 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2025–04–13
27 papers selected by
Luca Bolliger, lxBio

Knockdown of POLG Mimics the Neuronal Pathology of Polymerase-γ Spectrum Disorders in Human Neurons.
Small molecules restore mutant mitochondrial DNA polymerase activity.
Deoxynucleoside supplementation ameliorates the disease associated phenotypes in a zebrafish model of RRM2B mtDNA depletion syndrome.
The Volume of Mitochondria Inherited Impacts mtDNA Homeostasis in Budding Yeast.
Preliminary investigation on the economic cost of mitochondrial disease in Chinese children.
National Creutzfeldt-Jakob disease research biobank, a novel approach to the establishment of the scientific platform: collaboration between patient advocacy group, scientists, regulators and physicians.
HRI protein kinase in cytoplasmic heme sensing and mitochondrial stress response: relevance to hematological and mitochondrial diseases.
Identifying sex-based disparities in porcine mitochondrial function.
Establishing an induced pluripotent stem cell bank using urine cells from pediatric patients with neurogenetic diseases.
Mitochondria in cancer: a comprehensive review, bibliometric analysis, and future perspectives.
Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture.
[Research progress on the relationship between mitochondrial dynamics imbalance and novel coronavirus infection-related acute respiratory distress syndrome].
Selective activation of antioxidant resources and energy deficiency in Marinesco-Sjögren syndrome fibroblasts as an adaptive biological response to Sil1 loss.
Gut bacterial lactate stimulates lung epithelial mitochondria and exacerbates acute lung injury.
Alternative start codon selection shapes mitochondrial function during evolution, homeostasis, and disease.
Cellular interplay in brain organoids: Connecting cell-autonomous and non-cell-autonomous mechanisms in neurodevelopmental disease.
Genotype-phenotype correlation in a cohort of pediatric patients with autoinflammatory diseases carrying NOD2 variants.
Automated Shared Phenotype Discovery in Undiagnosed Cohorts for Rare Disease Research.
Altered Mitochondrial Bioenergetics and Calcium Kinetics in Young-Onset PLA2G6 Parkinson's Disease iPSCs.
Efficacy and safety of modified medium-chain triglyceride ketogenic diet in patients with drug-resistant epilepsy.
Genome Editing in Medicine: A Scoping Review of Ethical, Bioethical, and Medico-Legal Implications.
An update on mammalian and non-mammalian animal models for biomarker development in neurodegenerative disorders.
Mapping the evolution of mitochondrial dynamics research: A bibliometric analysis of global trends and collaborations.
Clinical Exome Sequencing in Pediatric Patients.
The phenotypic spectrum of YWHAG-related epilepsy: From mild febrile seizures to severe developmental delay and epileptic encephalopathy.
Circumstances surrounding sudden unexpected death in epilepsy in children: A national case series.
An effective approach to modulate mitochondrial function in murine primary macrophages by a mitochondria-targeted nanocapsule, MITO-Porter.

Cells. 2025 Mar 22. pii: 480. [Epub ahead of print]14(7):

Knockdown of POLG Mimics the Neuronal Pathology of Polymerase-γ Spectrum Disorders in Human Neurons.

Çağla Çakmak Durmaz, Felix Langerscheidt, Imra Mantey, Xinyu Xia, Hans Zempel.

  Impaired function of Polymerase-γ (Pol-γ) results in impaired replication of the mitochondrial genome (mtDNA). Pathogenic mutations in the POLG gene cause dysfunctional Pol-γ and dysfunctional mitochondria and are associated with a spectrum of neurogenetic disorders referred to as POLG spectrum disorders (POLG-SDs), which are characterized by neurologic dysfunction and premature death. Pathomechanistic studies and human cell models of these diseases are scarce. SH-SY5Y cells (SHC) are an easy-to-handle and low-cost human-derived neuronal cell model commonly used in neuroscientific research. Here, we aimed to study the effect of reduced Pol-γ function using stable lentivirus-based shRNA-mediated knockdown of POLG in SHC, in both the proliferating cells and SHC-derived neurons. POLG knockdown resulted in approximately 50% reductions in POLG mRNA and protein levels in naïve SHC, mimicking the residual Pol-γ activity observed in patients with common pathogenic POLG mutations. Knockdown cells exhibited decreased mtDNA content, reduced levels of mitochondrial-encoded proteins, and altered mitochondrial morphology and distribution. Notably, while chemical induction of mtDNA depletion via ddC could be rescued by the mitochondrial biosynthesis stimulators AICAR, cilostazol and resveratrol (but not MitoQ and formoterol) in control cells, POLG-knockdown cells were resistant to mitochondrial biosynthesis-mediated induction of mtDNA increase, highlighting the specificity of the model, and pathomechanistically hinting towards inefficiency of mitochondrial stimulation without sufficient Pol-γ activity. In differentiated SHC-derived human neurons, POLG-knockdown cells showed impaired neuronal differentiation capacity, disrupted cytoskeletal organization, and abnormal perinuclear clustering of mitochondria. In sum, our model not only recapitulates key features of POLG-SDs such as impaired mtDNA content, which cannot be rescued by mitochondrial biosynthesis stimulation, but also reduced ATP production, perinuclear clustering of mitochondria and impaired neuronal differentiation. It also offers a simple, cost-effective and human (and, as such, disease-relevant) platform for investigating disease mechanisms, one with screening potential for therapeutic approaches for POLG-related mitochondrial dysfunction in human neurons.

Keywords:  Polymerase-γ; SH-SY5Y; mitochondria; mtDNA; neurogenetics; neuronal differentiation

DOI:  https://doi.org/10.3390/cells14070480
Nature. 2025 Apr 09.

Small molecules restore mutant mitochondrial DNA polymerase activity.

Sebastian Valenzuela, Xuefeng Zhu, Bertil Macao, Mattias Stamgren, Carol Geukens, Paul S Charifson, Gunther Kern, Emily Hoberg, Louise Jenninger, Anja V Gruszczyk, Seoeun Lee, Katarina A S Johansson, Javier Miralles Fusté, Yonghong Shi, S Jordan Kerns, Laleh Arabanian, Gabriel Martinez Botella, Sofie Ekström, Jeremy Green, Andrew M Griffin, Carlos Pardo-Hernández, Thomas A Keating, Barbara Küppers-Munther, Nils-Göran Larsson, Cindy Phan, Viktor Posse, Juli E Jones, Xie Xie, Simon Giroux, Claes M Gustafsson, Maria Falkenberg.

Mammalian mitochondrial DNA (mtDNA) is replicated by DNA polymerase γ (POLγ), a heterotrimeric complex consisting of a catalytic POLγA subunit and two accessory POLγB subunits1. More than 300 mutations in POLG, the gene encoding the catalytic subunit, have been linked to severe, progressive conditions with high rates of morbidity and mortality, for which no treatment exists2. Here we report on the discovery and characterization of PZL-A, a first-in-class small-molecule activator of mtDNA synthesis that is capable of restoring function to the most common mutant variants of POLγ. PZL-A binds to an allosteric site at the interface between the catalytic POLγA subunit and the proximal POLγB subunit, a region that is unaffected by nearly all disease-causing mutations. The compound restores wild-type-like activity to mutant forms of POLγ in vitro and activates mtDNA synthesis in cells from paediatric patients with lethal POLG disease, thereby enhancing biogenesis of the oxidative phosphorylation machinery and cellular respiration. Our work demonstrates that a small molecule can restore function to mutant DNA polymerases, offering a promising avenue for treating POLG disorders and other severe conditions linked to depletion of mtDNA.

DOI: https://doi.org/10.1038/s41586-025-08856-9
Hum Mol Genet. 2025 Apr 11. pii: ddaf047. [Epub ahead of print]

Deoxynucleoside supplementation ameliorates the disease associated phenotypes in a zebrafish model of RRM2B mtDNA depletion syndrome.

Benjamin Munro, Declan Hines, Juliane S Mueller, Rita Horvath.

  Mitochondrial DNA (mtDNA) depletion syndromes (MDDS) are rare, clinically heterogeneous mitochondrial disorders resulting from nuclear variants in genes of the mitochondrial DNA replication or maintenance machinery. Supplementation with pyrimidine deoxynucleosides have been beneficial in patients and mice with TK2-related MDDS, however, it has not been systematically explored in other forms of MDDS. To investigate the effect of deoxynucleoside supplementation in mitigating the disease in mitochondrial DNA depletion due to pathogenic RRM2B variants, we generated a novel zebrafish knock-out model of this disease and studied the effect of different combinations of deoxynucleosides. Zebrafish larvae carrying a homozygous nonsense mutation in rrm2b present with impaired movement, reduced mtDNA copy number and elevated lactate. Supplementation with different combination of deoxynucleosides was performed, resulting in increased mtDNA copy numbers when supplemented with the two purine deoxynucleosides (dGuo and dAdo), while other combinations had no effect or even further compromised mtDNA copy number in zebrafish. In parallel with increased mtDNA copy number, we detected improved movement and reduction of lactate in the rrm2b-/- fish, confirming the beneficial effect of deoxynucleosides on the whole organism. This treatment did not result in any deleterious effect in wild type and heterozygous fish. Our data suggest that supplementation with deoxynucleosides may be beneficial and should be further investigated in RRM2B-related disease, adding to the growing evidence that it is a valid therapeutic approach which can be trialled for treating a wider range of genetic forms of MDDS.

Keywords:  Deoxynucleoside supplementation; MDDS; Mitochondrial DNA depletion syndromes; RRM2B; zebrafish

DOI:  https://doi.org/10.1093/hmg/ddaf047
bioRxiv. 2025 Mar 26. pii: 2025.03.25.645216. [Epub ahead of print]

The Volume of Mitochondria Inherited Impacts mtDNA Homeostasis in Budding Yeast.

Michael W Ray, WeiTing Chen, Chengzhe Duan, Guadalupe Bravo, Kyle Krueger, Erica M Rosario, Alexis A Jacob, Laura L Lackner.

Most eukaryotic cells maintain mitochondria in well-distributed, reticular networks. The size of the mitochondrial network and copy number of its genome scale with cell size. However, while the size scaling features of mitochondria and their genome are interrelated, the fitness consequences of this interdependence are not well understood. We exploit the asymmetric cell division of budding yeast to test the hypothesis that mitochondrial scaling with cell size impacts mitochondrial DNA (mtDNA) function. We find that the volume of mitochondria inherited by daughter cells affects the ability of cells to maintain functional mtDNA; daughter cells that inherit a significantly reduced volume of mitochondria have an increased frequency of losing respiratory competence. In cells with such mitochondrial inheritance defects, mtDNA integrity can be maintained by upregulating mtDNA copy number. Collectively, these data support a bet-hedging model whereby the faithful inheritance of an adequate volume of mitochondria ensures enough mtDNA copies are transmitted to daughter cells to counteract pre-existing and/or inevitable mtDNA mutations.
Summary: Ray et al. demonstrate that the volume of mitochondria inherited impacts mtDNA homeostasis in the model system budding yeast. They propose a model by which inheritance of an adequate mitochondrial volume results in the transmission of sufficient mtDNA copies to counteract existing and/or inevitable mutations.

DOI: https://doi.org/10.1101/2025.03.25.645216
Orphanet J Rare Dis. 2025 Apr 10. 20(1): 172

Preliminary investigation on the economic cost of mitochondrial disease in Chinese children.

Chaolong Xu, Dan Zhao, Xin Duan, Zhimei Liu, Tongyue Li, Yunxi Zhang, Zixuan Zhang, Tianyu Song, Ying Zou, Huafang Jiang, Fang Fang.

   BACKGROUND: The prevalence of mitochondrial diseases is increasing, leading to a significant economic burden on families and society. However, nationwide cost data on their effects on China's economy remain limited. This study aimed to investigate the economic cost of mitochondrial diseases in Chinese children, analyse the relevant influencing factors, and provide a foundation for strategies to reduce the healthcare burden.
METHODS: In this single-centre, cross-sectional study, an online questionnaire was randomly administered to paediatric patients diagnosed with mitochondrial diseases between January 2012 and January 2022. The questionnaire included questions regarding demographic data, clinical information, and expenditure-related costs. Multivariate analysis of economic cost was performed using a generalised linear gamma conjugate model (A1).
RESULTS: The responses to 102 questionnaires were analysed. The median direct economic cost incurred for the diagnosis of mitochondrial disease was $8,520.19, with direct medical and non-medical costs of $6,769.06 and $2,092.98, respectively, and an indirect cost of $3,162.93. Healthcare insurance covers 27.29% of direct medical expenses. Multivariate analysis showed that the economic cost of diagnosing mitochondrial diseases was significantly correlated with the year of disease onset (P < 0.001). The median annual economic cost for treatment and symptom management after diagnosis was $12,292.79, with direct medical and non-medical costs of $10,887.53 and $1,360.44, respectively, and an indirect cost of $5,442.21. Healthcare insurance covered only 15.16% of direct medical expenses. No significant differences were observed between the subgroups after diagnosis and the annual economic costs of treatment or symptom management.
CONCLUSION: The study findings indicated that the economic burden of both the diagnosis and treatment of patients with mitochondrial diseases was substantial. Increased emphasis should be placed on primary and secondary prevention strategies to further reduce the overall economic burden of rare genetic diseases, such as mitochondrial diseases.

Keywords:  Children; China; Economic costs; Mitochondrial disease

DOI:  https://doi.org/10.1186/s13023-025-03708-1
Orphanet J Rare Dis. 2025 Apr 10. 20(1): 170

National Creutzfeldt-Jakob disease research biobank, a novel approach to the establishment of the scientific platform: collaboration between patient advocacy group, scientists, regulators and physicians.

Alice Anane, Doron Pasternak, Shimon A Reisner, Victor Novack.

  Creutzfeldt-Jakob disease (CJD) is a severe neurodegenerative disorder characterized by the abnormal accumulation of prion proteins. In Israel, a unique epidemiological pattern of CJD has been identified, specifically a genetic form (gCJD) associated with the E200K mutation in the PRNP gene. Investigating rare diseases such as CJD syndrome poses challenges due to their low prevalence, hindering the formation of an adequate patient cohort for comprehensive research and treatment trials. To overcome this limitation, biobanks have emerged as transformative tools for collecting and distributing biological specimens along with corresponding health data. Biobanks offer a solution to the inherent heterogeneity in rare diseases, allowing researchers to access diverse and extensive sample sets, thereby enhancing the understanding of disease nuances toward potential therapy. We introduce a novel collaborative model involving the Negev BioBank (NBB), the Creutzfeldt-Jakob Israel Foundation, the Israeli National BioBank for Research (MIDGAM), and the Israeli Ministry of Health. Each entity contributes unique expertise and resources to establish a comprehensive platform for studying the disease. The goal was to establish a participant pool of 500 individuals, including clinically diagnosed cases, confirmed carriers of the E200K mutation, and their first- and second-degree relatives. During the pilot phase of the last year, 250 participants were enrolled, with each family contributing between 1 and 25 participants. This collaborative approach involving communities, scientists, physicians, and regulatory bodies establishes a model applicable across various fields. These synergistic efforts aim to advance research on CJD and potentially serve as a blueprint for studying other rare diseases.

Keywords:  Biobank; Creutzfeldt–Jakob disease; Fatal familial insomnia; Genetic Creutzfeldt–Jakob disease; Genetics; Gerstmann–sträussler–scheinker disease; PRNP; Prion diseases; Prion proteins

DOI:  https://doi.org/10.1186/s13023-025-03703-6
J Biol Chem. 2025 Apr 08. pii: S0021-9258(25)00343-6. [Epub ahead of print] 108494

HRI protein kinase in cytoplasmic heme sensing and mitochondrial stress response: relevance to hematological and mitochondrial diseases.

Jane-Jane Chen.

  Most iron in humans is bound in heme used as a prosthetic group for hemoglobin. Heme-regulated inhibitor (HRI) is responsible for coordinating heme availability and protein synthesis. Originally characterized in rabbit reticulocyte lysates, HRI was shown in 1976 to phosphorylate the α-subunit of eIF2, revealing a new molecular mechanism for regulating protein synthesis. Since then, HRI research has mostly been focused on the biochemistry of heme inhibition through direct binding, and heme sensing in balancing heme and globin synthesis to prevent proteotoxicity in erythroid cells. Beyond inhibiting translation of highly translated mRNAs, eIF2α phosphorylation also selectively increases translation of certain poorly translated mRNAs, notably ATF4 mRNA, for reprogramming of gene expression to mitigate stress, known as the integrated stress response (ISR). In recent years, there have been novel mechanistic insights of HRI-ISR in oxidative stress, mitochondrial function and erythroid differentiation during heme deficiency. Furthermore, HRI-ISR is activated upon mitochondrial stress in several cell types, establishing the bifunctional nature of HRI protein. The role of HRI and ISR in cancer development and vulnerability is also emerging. Excitingly, the UBR4 ubiquitin ligase complex has been demonstrated to silence the HRI-ISR by degradation of activated HRI proteins, suggesting additional regulatory processes. Together, these recent advancements indicate that the HRI-ISR mechanistic axis is a target for new therapies for hematological and mitochondrial diseases, as well as oncology. This review covers the historical overview of HRI biology, the biochemical mechanisms of regulating HRI, and the biological impacts of the HRI-ISR pathway in human diseases.

Keywords:  ATF4; E3 ubiquitin ligase; Erythropoiesis; Heme; Mitochondrial stress; Protein kinase; Protein synthesis; Proteostasis; Stress response; eIF2

DOI:  https://doi.org/10.1016/j.jbc.2025.108494
Anim Biotechnol. 2025 Dec;36(1): 2488068

Identifying sex-based disparities in porcine mitochondrial function.

Hao Liu, Wenshu Shi, Xing Zhang, Xinmiao He, Xingbo Zhao.

  In pigs, the effect of sex on production and reproductive traits has been largely reported, however, whether sex exerts its influence through regulating mitochondrial function is still unclear. In this study, we constructed 15 male cells and 15 female fibroblasts derived from 35-day and 50-day fetuses, newborn piglets and 1-year-old pigs to identify the sex effect on mitochondrial functions. Results indicated significant differences on cellular and molecular characteristics between male and female cells, including energy metabolic trait, mitochondrial DNA (mtDNA) replication and transcription, and mRNA expressions of mitochondrial biogenesis genes and mitoprotease genes. Referring to sex, males exhibited significantly higher oxygen consumption rate productions, levels of reactive oxygen species (ROS) and mtDNA copy numbers than those with females in muscle and ear fibroblasts. And the expressions of mtDNA, mitochondrial biogenesis genes (POLG, PPARGC1A, TFAM and TWNK) and XPNPEP3 were higher in males than females in ear fibroblasts derived from 1-year-old adult pigs (EFA cells). While, the cell proliferation and expressions of genes related to ROS metabolism were not influenced by sex. The results highlight the effect of sex on mitochondrial function and gene expression, and provide important data for a comprehensive understanding of the mechanisms underlying sex regulation of energy metabolism-related traits in pigs.

Keywords:  Sex; mitochondrion; oxygen consumption rate; porcine; reactive oxygen species

DOI:  https://doi.org/10.1080/10495398.2025.2488068
Clin Exp Pediatr. 2025 Apr 01.

Establishing an induced pluripotent stem cell bank using urine cells from pediatric patients with neurogenetic diseases.

Hien Bao Dieu Thai, WonWoo Jung, Sol Choi, Woo Joong Kim, JangSup Moon, ByungChan Lim.

   Background: Inadequate knowledge of the fundamental mechanisms underlying pediatric neurological disorders impedes their effective treatment. Induced pluripotent stem cells (iPSCs) are essential for exploring the course of neurological diseases because they enable disease modeling at the cellular level.
Purpose: This study aimed to generate an iPSC bank using urine cells (UCs) for clinical applications, particularly the study of pediatric neurogenetic diseases. Urine sample collections can benefit a large donor population because they use a non-invasive, painless, and simple technique that provides plentiful cells for iPSC generation.
Methods: UCs were isolated from the urine of donors with specific diseases (n = 12; seven males, five females). The UCs were reprogrammed into iPSCs using episomal plasmid vectors and key transcription factors (OCT3/4, SOX2, KLF4, L-MYC, and LIN28). Quantitative polymerase chain reaction and immunocytochemical analyses confirmed the expression of pluripotent genes (OCT3/4, SOX2, NANOG, and LIN28) and proteins (OCT4, NANOG, SSEA-4, and TRA-1-60). Trilineage differentiation was investigated by immunostaining embryonic body-derived iPSCs for -tubulin III, smooth muscle actin, and alpha-fetoprotein. The genomic stability of the iPSCs was assessed using chromosomal microarray (CMA).
Results: UCs were successfully isolated from patients with various early-onset neurogenetic diseases and reprogrammed into iPSCs. The iPSCs were confirmed as pluripotent and capable of trilineage differentiation as evidenced by the enhanced expression of relevant genes and proteins. The genomic profiles of the iPSCs were assessed using CMA, which revealed that four of the 12 lines exhibited pathogenic chromosomal deletions or duplications. Interestingly, repeated CMA tests using earlier-passage cells resulted in normal findings in one of the four iPSC lines. These findings highlight the need for genetic screening throughout the culture period.
Conclusion: Here we used UCs to successfully develop an early-onset neurogenetic disease iPSC bank that offers an efficient protocol for expanding patient accessibility in pediatric neurogenetic research.

Keywords:  Induced stem cells; Neurogenetic disease; Pediatric; Pluripotent; Urine-derived cells

DOI:  https://doi.org/10.3345/cep.2024.01830
Discov Oncol. 2025 Apr 11. 16(1): 517

Mitochondria in cancer: a comprehensive review, bibliometric analysis, and future perspectives.

Abeer El Wakil, Patrick Devos, Heba Abdelmegeed, Alaa Kamel.

   INTRODUCTION: Mitochondria are essential organelles for many aspects of cellular homeostasis. They play an indispensable role in the development and progression of diseases, particularly cancer which is a major cause of death worldwide. We analyzed the scientific research output on mitochondria and cancer via PubMed and Web of Science over the period 1990-2023.
METHODS: Bibliometric analysis was performed by extracting data linking mitochondria to cancer pathogenesis over the period 1990-2023 from the PubMed database which has a precise and specific search engine. Only articles and reviews were considered. Since PubMed does not support analyses by countries or institutions, we utilized InCites, an analytical tool developed and marketed by Clarivate Analytics. We also used the VOSviewer software developed by the Centre for Science and Technology Studies (Bibliometric Department of Leiden University, Leiden, Netherlands), which enables us to graphically represent links between countries, authors or keywords in cluster form. Finally, we used iCite, a tool developed by the NIH (USA) to access a dashboard of bibliometrics for papers associated with a portfolio. This module can therefore be used to measure whether the research carried out is still basic, translational or clinical.
RESULTS: In total, 169,555 publications were identified in PubMed relating to 'mitochondria', of which 34,949 (20.61%) concerned 'mitochondria' and 'dysfunction' and 22,406 (13.21%) regarded 'mitochondria' and 'cancer'. Hence, not all mitochondrial dysfunctions may lead to cancer or enhance its progression. Qualitatively, the disciplines of journals were classified into 166 categories among which cancer specialty accounts for only 4.7% of publications. Quantitatively, our analysis showed that cancer/neoplasms in the liver (2569 articles) were placed in the first position. USA occupied the first position among countries contributing the highest number of publications (5695 articles), whereas Egypt came in the thirty-eight position with 84 publications (0.46%). Importantly, USA is the first-ranked country having both the top 1% and 10% impact indicators with 207 and 1459 articles, respectively. By crossing the query 'liver neoplasms' (155,678) with the query 'mitochondria' (169,555), we identified 1336 articles in PubMed over the study period. Among these publications, research areas were classified into 65 categories with the highest percentage of documents included in biochemistry and molecular biology (28.92%), followed by oncology (23.31%).
CONCLUSIONS: This study underscores the crucial yet underrepresented role of mitochondria in cancer research. Despite their significance in cancer pathogenesis, the proportion of related publications remains relatively low. Our findings highlight the need for further research to deepen our understanding of mitochondrial mechanisms in cancer, which could pave the way for new therapeutic strategies.

Keywords:  Bibliometrics; Breast; Liver; Lung; Mitochondria; Neoplasm

DOI:  https://doi.org/10.1007/s12672-025-02139-5
EMBO Mol Med. 2025 Apr 09.

Clinically translatable mitochondrial gene therapy in muscle using tandem mtZFN architecture.

Pavel A Nash, Keira M Turner, Christopher A Powell, Lindsey Van Haute, Pedro Silva-Pinheiro, Felix Bubeck, Ellen Wiedtke, Eloïse Marques, Dylan G Ryan, Dirk Grimm, Payam A Gammage, Michal Minczuk.

  Mutations in the mitochondrial genome (mtDNA) often lead to clinical pathologies. Mitochondrially-targeted zinc finger nucleases (mtZFNs) have been successful in reducing the levels of mutation-bearing mtDNA both in vivo and in vitro, resulting in a shift in the genetic makeup of affected mitochondria and subsequently to phenotypic rescue. Given the uneven distribution in the mtDNA mutation load across tissues in patients, and a great diversity in pathogenic mutations, it is of interest to develop mutation-specific, selective gene therapies that could be delivered to particular tissues. This study demonstrates the effectiveness of in vivo mitochondrial gene therapy using a novel mtZFN architecture on skeletal muscle using adeno-associated viral (AAV) platforms in a murine model harboring a pathogenic mtDNA mutation. We observed effective reduction in mutation load of cardiac and skeletal muscle, which was accompanied by molecular phenotypic rescue. The gene therapy treatment was shown to be safe when markers of immunity and inflammation were assessed. These results highlight the potential of curative approaches for mitochondrial diseases, paving the way for targeted and effective treatments.

Keywords:  Adeno-Associated Viruses (AAV); Gene Therapy; Skeletal Muscle; Zinc Finger Nuclease (mtZFN); mtDNA Heteroplasmy Modification

DOI:  https://doi.org/10.1038/s44321-025-00231-5
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2025 Mar;37(3): 300-304

[Research progress on the relationship between mitochondrial dynamics imbalance and novel coronavirus infection-related acute respiratory distress syndrome].

Zijia Zhang, Bin Du, Xunyao Wu, Xiaoyun Hu, Shitong Diao, Run Dong.

Patients with severe pneumonia caused by novel coronavirus infection are often complicated with acute respiratory distress syndrome (ARDS), which has a high mortality. ARDS is characterized by diffuse alveolar damage, pulmonary edema, and hypoxemia. Mitochondria are prone to morphological and functional abnormalities under hypoxia and viral infection, which can lead to cell apoptosis and damage, severely impacting the disease progression. Mitochondria maintain homeostasis through fission and fusion. In ARDS, hypoxia leads to the phosphorylation of dynamin-related protein 1 (Drp1), triggering excessive mitochondrial fission and damaging the alveolar epithelial barrier. Animal experiments have shown that inhibiting this process can alleviate lung injury, providing a potential direction for treatment. The pathology of novel coronavirus infection-related ARDS is similar to that of typical ARDS but more severe. Viral infection and hypoxia disrupt the mitochondrial balance, causing fission and autophagy abnormalities, promoting oxidative stress and mitochondrial DNA (mtDNA) release, activating inflammasomes, inducing the expression of hypoxia-inducible factor-1α (HIF-1α), exacerbating viral infection, inflammation, and coagulation reactions, and resulting in multiple organ damage. Mechanical ventilation and glucocorticoids are commonly used in the treatment of novel coronavirus infection-related ARDS. Mechanical ventilation is likely to cause lung and diaphragm injuries and changes in mitochondrial dynamics, while the lung protective ventilation strategy can reduce the adverse effects. Glucocorticoids can regulate mitochondrial function and immune response and improve the patient's condition through multiple pathways. The mitochondrial dynamics imbalance in novel coronavirus infection-related ARDS is caused by hypoxia and viral proteins, leading to lung and multiple organ injuries. To clarify the pathophysiological mechanism of mitochondrial dynamics imbalance in novel coronavirus infection-related ARDS and explore effective strategies for regulating mitochondrial dynamics balance to treat this disease, so as to provide new treatment targets and methods for patients with novel coronavirus infection-related ARDS. The existing treatments have limitations. Future research needs to deeply study the mechanism of mitochondrial dysfunction, develop new therapies and regulatory strategies, and improve the treatment effect.

DOI: https://doi.org/10.3760/cma.j.cn121430-20241126-00957
Sci Rep. 2025 Apr 11. 15(1): 12510

Selective activation of antioxidant resources and energy deficiency in Marinesco-Sjögren syndrome fibroblasts as an adaptive biological response to Sil1 loss.

Valeria Panella, Francesca Potenza, Carla Tatone, Lorenza Speranza, Fernanda Amicarelli, Michele Sallese.

  Marinesco-Sjögren syndrome (MSS) is a neuromuscular disease which presents with ataxia, muscle weakness and cataracts. This syndrome is typically caused by mutations in SIL1 gene, an ER co-chaperone that disrupts protein folding. Although it is known that accumulation of misfolded proteins in the ER profoundly affect reduction-oxidation (redox) homeostasis and energy production, the possible role of these processes in MSS was not investigated to date. In patient-derived fibroblasts, both maximal mitochondrial respiration and mitochondrial ATP production rates were diminished, while the glycolytic fraction remained unaffected. Catalase and superoxide dismutase activities were increased, while glutathione peroxidase and glutathione reductase were decreased. Oxidative damage to lipids, proteins, and DNA was comparable or even lower to that observed in control cells. Similar alterations were observed in the muscle tissue of the woozy mouse model of MSS. In conclusion, we identified a mitochondrial energy deficit and an adaptive cellular mechanism that effectively manage oxidative stress in Sil1-deficient cells.

Keywords:  Ataxia; Catalase; Energy deficiency; Mitochondria; Neurodegenerative disease; ROS; Sil1; Superoxide dismutase

DOI:  https://doi.org/10.1038/s41598-025-96467-9
bioRxiv. 2025 Mar 25. pii: 2025.03.24.645052. [Epub ahead of print]

Gut bacterial lactate stimulates lung epithelial mitochondria and exacerbates acute lung injury.

Vaibhav Upadhyay, Edwin F Ortega, Luis A Ramirez Hernandez, Margaret Alexander, Gagandeep Kaur, Kai Trepka, Rachel R Rock, Rafaella T Shima, W Colby Cheshire, Narges Alipanah-Lechner, Carolyn S Calfee, Michael A Matthay, Joyce V Lee, Andrei Goga, Isha H Jain, Peter J Turnbaugh.

Acute respiratory distress syndrome (ARDS) is an often fatal critical illness where lung epithelial injury leads to intrapulmonary fluid accumulation. ARDS became widespread during the COVID-19 pandemic, motivating a renewed effort to understand the complex etiology of this disease. Rigorous prior work has implicated lung endothelial and epithelial injury in response to an insult such as bacterial infection; however, the impact of microorganisms found in other organs on ARDS remains unclear. Here, we use a combination of gnotobiotic mice, cell culture experiments, and re-analyses of a large metabolomics dataset from ARDS patients to reveal that gut bacteria impact lung cellular respiration by releasing metabolites that alter mitochondrial activity in lung epithelium. Colonization of germ-free mice with a complex gut microbiota stimulated lung mitochondrial gene expression. A single human gut bacterial species, Bifidobacterium adolescentis, was sufficient to replicate this effect, leading to a significant increase in mitochondrial membrane potential in lung epithelial cells. We then used genome sequencing and mass spectrometry to confirm that B. adolescentis produces L -lactate, which was sufficient to increase mitochondrial activity in lung epithelial cells. Finally, we found that serum lactate was significantly associated with disease severity in patients with ARDS from the Early Assessment of Renal and Lung Injury (EARLI) cohort. Together, these results emphasize the importance of more broadly characterizing the microbial etiology of ARDS and other lung diseases given the ability of gut bacterial metabolites to remotely control lung cellular respiration. Our discovery of a single bacteria-metabolite pair provides a proof-of-concept for systematically testing other microbial metabolites and a mechanistic biomarker that could be pursued in future clinical studies. Furthermore, our work adds to the growing literature linking the microbiome to mitochondrial function, raising intriguing questions as to the bidirectional communication between our endo- and ecto-symbionts.

DOI: https://doi.org/10.1101/2025.03.24.645052
bioRxiv. 2025 Mar 27. pii: 2025.03.27.645657. [Epub ahead of print]

Alternative start codon selection shapes mitochondrial function during evolution, homeostasis, and disease.

Jimmy Ly, Yi Fei Tao, Matteo Di Bernardo, Ekaterina Khalizeva, Christopher J Giuliano, Sebastian Lourido, Mark D Fleming, Iain M Cheeseman.

Mitochondrial endosymbiosis was a pivotal event in eukaryotic evolution, requiring core proteins to adapt to function both within the mitochondria and in the host cell. Here, we systematically profile the localization of protein isoforms generated by alternate start codon selection during translation. We identify hundreds of pairs of differentially-localized protein isoforms, many of which affect mitochondrial targeting and are essential for mitochondrial function. The emergence of dual-localized mitochondrial protein isoforms coincides with mitochondrial acquisition during early eukaryotic evolution. We further reveal that eukaryotes use diverse mechanisms-such as leaky ribosome scanning, alternative transcription, and paralog duplication-to maintain the production of dual-localized isoforms. Finally, we identify multiple isoforms that are specifically dysregulated by rare disease patient mutations and demonstrate how these mutations can help explain unique clinical presentations. Together, our findings illuminate the evolutionary and pathological relevance of alternative translation initiation, offering new insights into the molecular underpinnings of mitochondrial biology.

DOI: https://doi.org/10.1101/2025.03.27.645657
Curr Opin Neurobiol. 2025 Apr 10. pii: S0959-4388(25)00049-2. [Epub ahead of print]92 103018

Cellular interplay in brain organoids: Connecting cell-autonomous and non-cell-autonomous mechanisms in neurodevelopmental disease.

Giovanna Berto, M Veronica Pravata, Silvia Cappello.

The field of brain organoids has experienced a period of rapid and transformative growth, enabling researchers to investigate complex human biological mechanisms that were previously deemed intractable. This review provides an overview of the current landscape of brain organoids, with a particular focus on their relevance in the context of neurodevelopmental disorders. It also emphasizes the crucial role these models play in elucidating both cell-autonomous and non-cell-autonomous mechanisms. We describe how these two mechanisms, often considered to be independent, are intricately interconnected. In conclusion, this review aims to highlight how the utilization of brain organoids has considerably advanced our comprehension of neurodevelopmental disorders, while also delineating prospective avenues for investigating these complex conditions.

DOI: https://doi.org/10.1016/j.conb.2025.103018
Front Immunol. 2025 ;16 1439333

Genotype-phenotype correlation in a cohort of pediatric patients with autoinflammatory diseases carrying NOD2 variants.

Marco Francesco Natale, Camilla Celani, Silvia Federici, Chiara Passarelli, Chiara Perrone, Emiliano Marasco, Fabrizio De Benedetti, Antonella Insalaco.

   Background: Autoinflammatory diseases (AIDs) are a group of disease characterized by excessive activation of the innate immune system with episodes of spontaneous inflammation that can affect different organs. Many monogenic or acquired autoinflammatory diseases are described in literature. More recently the concept of disease with polygenic or complex inheritance has been introduced. Nucleotide binding oligomerization domain containing 2 (NOD2) gene variants are associated with Crohn's disease (CD), Blau syndrome and most recently with a polygenic autoinflammatory disease with onset in adult called NOD2-associated autoinflammatory disease (NAID).
Objective: The aim of our study is to describe a pediatric cohort of patients with autoinflammatory disease carrying NOD2 variants and to evaluate genotype-phenotype correlation.
Methods: Twenty-five children with autoinflammatory disease and NOD2 variants were enrolled in the study. Patients were divided into 3 groups based on the protein domain involved. Demographic and clinical features, imaging, laboratory exams and treatment were analyzed. The characteristics of our patients were compared with those of the adult cohort described by Yao in 2016-2018.
Results: Fever was the main clinical characteristic of our children (68%) with long episodes and irregular pattern of recurrence. The disease typically affected skin (40%), joints (72%), bowel (60%) and lymphatic system (52%). Serositis and sensorineural deafness were less frequent. Excluding non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids were frequently used with satisfactory clinical response in the majority of patients. In patients with poor disease control or new flares after glucocorticoid tapering, non-biologic and biologic drugs were used with variable response. The comparison between the two most represented groups showed that patients with variants located on the NOD domain presented more homogeneous clinical characteristics with involvement of some target organs. Our patients were compared with the adult cohort described in literature with few differences.
Conclusion: This is the first study to evaluate genotypic/phenotypic characteristics of children with systemic autoinflammatory disease and NOD2 variants. The results, albeit preliminary and affected by the sample size, do not allow a definitive conclusion on a monogenic disease caused by mutation in NOD2, with the obvious exception of Blau syndrome. Variants in the NOD domain seem to be associated with a more homogenous clinical phenotype.

Keywords:  NOD2 gene; autoinflammatory diseases; children; monogenic diseases; polygenic or complex inheritance

DOI:  https://doi.org/10.3389/fimmu.2025.1439333
Proc Int Conf Mach Learn Appl. 2024 Dec;2024 1025-1030

Automated Shared Phenotype Discovery in Undiagnosed Cohorts for Rare Disease Research.

Aaron J Masino, Ranga Baminiwatte.

  Rare disease diagnosis is challenging in large part due to incomplete knowledge of gene-to-phenotype associations. One way to address this is to adopt a gene-to-patient paradigm wherein one selects an in-silico predicted pathogenic variant, identifies individuals with the variant, and then determines if the individuals have a shared phenotype. Most studies following this paradigm determine presence of a shared phenotype through manual review of ontology terms in the patient record. We propose a novel automated method to identify the shared phenotype via genetic search using a fitness function that compares the similarity of phenotype term embeddings generated by advanced NLP models applied to the term's text descriptions. Leveraging Human Phenotype Ontology resources, we generated a library of simulated patients across 5,076 Mendelian diseases. Applying our approach to these simulated disease cohorts, we found that the solution phenotypes included a closely matching term for the majority of terms in the disease phenotype under variable conditions of annotation imprecision and noise. We anticipate these methods can aid gene-to-phenotype association discovery for rare diseases by enabling a scalable gene-to-patient research paradigm.

Keywords:  NLP; biomedical informatics; genetic algorithms; ontology; phenotypes

DOI:  https://doi.org/10.1109/icmla61862.2024.00154
J Neurochem. 2025 Apr;169(4): e70059

Altered Mitochondrial Bioenergetics and Calcium Kinetics in Young-Onset PLA2G6 Parkinson's Disease iPSCs.

Thasneem Musthafa, Syed Kavish Nizami, Ankita Mishra, Gaiti Hasan, Renjitha Gopurappilly.

  Parkinson's disease (PD) has emerged as a multisystem disorder affecting multiple cellular and organellar systems in addition to the dopaminergic neurons. Disease-specific induced pluripotent stem cells (iPSCs) model early developmental changes and cellular perturbations that are otherwise inaccessible from clinical settings. Here, we report the early changes in patient-derived iPSCs carrying a homozygous recessive mutation, R741Q, in the PLA2G6 gene. A gene-edited R747W iPSC line mirrored these phenotypes, thus validating our initial findings. Bioenergetic dysfunction and hyperpolarization of mitochondrial membrane potentials were hallmarks of the PD iPSCs. Further, a concomitant increase in glycolytic activity indicated a possible compensation for mitochondrial respiration. Elevated basal reactive oxygen species (ROS) and decreased catalase expression were also observed in the disease iPSCs. No change in autophagy was detected. These inceptive changes could be potential targets for early intervention of prodromal PD in the absence of disease-modifying therapies. However, additional investigations are crucial to delineate the cause-effect relationships of these observations.

Keywords:  PLA2G6; Parkinson's disease; disease modeling; human iPSC; mitochondrial dysfunction

DOI:  https://doi.org/10.1111/jnc.70059
Acta Epileptol. 2024 Mar 06. 6(1): 9

Efficacy and safety of modified medium-chain triglyceride ketogenic diet in patients with drug-resistant epilepsy.

Hua Li, Yao Wang, Jing Guo, Peiqi Zhang, Zheng Xu, Kai Peng, Xiaoli Dong, Liming Zhao.

   BACKGROUND: Medium-chain triglyceride ketogenic diet (MCTKD) is previously less commonly used in China. This study was aimed to assess the efficacy and safety of the modified MCTKD in the treatment of drug-resistant epilepsy in Chinese patients.
METHODS: Patients with drug-resistant epilepsy were enrolled to receive treatment with modified MCTKD in Guangdong Sanjiu Brain Hospital during December 2020 and September 2022. The modified MCTKD contained fat that provided 50-70% of the total energy, as well as proteins and carbohydrates that provided 20-30% and 20% of energy, respectively. The fat component was composed of 20-30% medium-chain triglycerides (MCTs) and 30-40% long-chain triglycerides. The efficacy and safety of the diet were assessed at 1, 3 and 6 months.
RESULTS: A total of 123 patients aged 2.5 to 65 years, were included in this study. The response rates at 1, 3 and 6 months were 49.6%, 43.1%, and 30.9%, respectively. The seizure freedom rates at 1, 3 and 6 months were 12.2%, 10.6%, and 6.5%, respectively. The retention rates at 1, 3 and 6 months were 98.4%, 65.0% and 33.3% respectively. Side effects occurred in 21.14% of patients, which were predominantly gastrointestinal symptoms such as abdominal pain, diarrhea, vomiting, and constipation, and most of them resolved after dietary adjustments. A total of 82 patients (66.7%) discontinued the treatment with the reason of refusing to eat (8.1%), poor efficacy (35.0%), poor compliance (4.9%), and inability to follow-up (9.8%). Only 4 patients (3.3%) withdrew the diet due to side effects.
CONCLUSIONS: The modified MCTKD with MCTs providing 20-30% of energy has a good safety in patients with drug-resistant epilepsy, but its effectiveness needs to be enhanced. Further modifications of MCTKD with an optimal energy ratio are required to achieve a better efficacy and safety.

Keywords:  Drug-resistant epilepsy; Efficacy; Ketogenic diet; Medium-chain triglyceride ketogenic diet; Safety

DOI:  https://doi.org/10.1186/s42494-024-00150-x
J Law Med Ethics. 2025 Apr 08. 1-9

Genome Editing in Medicine: A Scoping Review of Ethical, Bioethical, and Medico-Legal Implications.

Filippo Gibelli, Giovanna Ricci, Paolo Bailo.

  Genome editing, prominently led by the revolutionary CRISPR-Cas9 technology, is a powerful tool with significant applications in diverse fields, particularly in medicine and agriculture. It empowers scientists with the ability to effect precise genetic modifications, thereby potentially paving the way for advanced treatments for genetic disorders such as Huntington's disease, hemophilia, and cystic fibrosis. Yet, the significant capabilities of this technology also brings to the fore a myriad of intricate bioethical, legal, and regulatory dilemmas. In light of these complexities, this article endeavors to conduct a comprehensive scoping review of the existing literature on the most significant ethical implications emanating from genome editing. In conducting this review, we utilized the power of software tools like EndNote and Rayyan to aid in the systematic and thorough review of the literature. EndNote, a reference management software, was instrumental in organizing and managing the references and bibliographies, while Rayyan, a web application designed for managing and screening records for systematic and scoping reviews, proved crucial in the import and management of text records for the review.The review identified as main aspects of ethical, bioethical and medico-legal interest the exacerbation of social inequalities, safety concerns such as off-target mutations and immunological risks, ecological and evolutionary implications, and challenges to human dignity. It highlights the necessity for equitable access, rigorous regulation, and public engagement to address these issues responsibly.The ultimate objective of this article is to underscore the importance of an informed and inclusive dialogue regarding genome editing. Such dialogue is pivotal for fostering responsible innovation in this rapidly advancing field, ensuring that scientific progress aligns with ethical considerations. By presenting a comprehensive examination of the ethical implications of genome editing, we aim to contribute to this ongoing dialogue and promote a balanced and nuanced understanding of this impactful technology.

Keywords:  CRISPR-Cas9; Ethical implications; Genome editing; Regulation; Responsible innovation

DOI:  https://doi.org/10.1017/jme.2025.48
Cell Mol Life Sci. 2025 Apr 07. 82(1): 147

An update on mammalian and non-mammalian animal models for biomarker development in neurodegenerative disorders.

Ribhav Mishra, Arun Upadhyay.

  Neurodegeneration is one of the leading factor for death globally, affecting millions of people. Developing animal models are critical to understand biological processes and comprehend pathological hallmarks of neurodegenerative diseases. For decades, many animal models have served as excellent tools to determine the disease progression, develop diagnostic methods and design novel therapies against distinct pathologies. Here, we provide a comprehensive overview of both, mammalian and non-mammalian animal models, with a focus on three most common and aggressive neurodegenerative disorders: Alzheimer's disease, Parkinson's disease and Spinocerebellar ataxia-1. We highlight various approaches including transgene, gene transfer, and chemically-induced methods used to develop disease models. In particular, we discuss applications of both non-mammalian and mammalian contributions in research on neurodegeneration. It is exciting to learn the roles of animal models in disease pathomechanisms, identifying biomarkers and hence devising novel interventions to treat neuropathological conditions.

Keywords:  Alzheimer’s disease; Animal models; Biomarkers; Neurodegeneration; Non-human primates; Parkinson disease; Spinocerebellar ataxia-1

DOI:  https://doi.org/10.1007/s00018-025-05668-y
Adv Clin Exp Med. 2025 Apr 11.

Mapping the evolution of mitochondrial dynamics research: A bibliometric analysis of global trends and collaborations.

Fugang Huang, Ke Sun, Zexuan Wu, Guanqun Xie, Jie Bao, Yongsheng Fan.

   BACKGROUND: Mitochondrial dynamics is an important field in cell biology, encompassing mitochondrial fission and fusion. The balance between fission and fusion is responsible for the stability of the mitochondrial network and can be a regulator of mitochondrial function. Recent studies have emphasized that an imbalance in mitochondrial dynamics is the root cause of dysfunction and is involved in various stages, such as oxidative stress, inflammation and apoptosis. Reversing this imbalance can effectively alleviate disease conditions. Although the importance of mitochondrial dynamics has been widely recognized, there is still a lack of literature on the qualitative and quantitative description and analysis of advances in this field.
OBJECTIVES: This study is a bibliometric analysis of research trends, collaboration networks and thematic evolution in mitochondrial dynamics from 2000 to 2023.
MATERIAL AND METHODS: Using the Web of Science Core Collection (WoSCC) database, we performed a bibliometric review, applying VOSviewer and CiteSpace to visualize and analyze publications, citations, collaborations, and key word trends.
RESULTS: We analyzed 332 publications, identifying China and the USA as leaders in research output and international collaborations. Significant contributions were made by institutions like Chiang Mai University and the California Institute of Technology (Caltech), with major research shifts from basic mitochondrial functions to roles in diseases like Alzheimer's and cardiovascular disease.
CONCLUSION: Mitochondrial dynamics research has expanded, with increasing attention to its role in disease mechanisms. Future research should further explore these connections, potentially leading to innovative treatments.

Keywords:  CiteSpace; Science Citation Index; VOSviewer; bibliometrics; mitochondrial dynamics

DOI:  https://doi.org/10.17219/acem/196720
Cureus. 2025 Mar;17(3): e80330

Clinical Exome Sequencing in Pediatric Patients.

Orhan Görükmez, Özlem Görükmez, Ali Topak, Hanife Ayşegül Arsoy.

   INTRODUCTION: The development of genomic sequencing techniques has led to the effective diagnosis of genetic diseases. In this study, clinical exome sequencing (CES) results applied to genetic disorders are reported.
METHODS: The CES results of pediatric patients with different system involvements and whose complaints were thought to be of genetic origin were evaluated retrospectively.
RESULTS: Significant variants associated with complaints were detected in 41 (60%) of 68 patients. Copy number variations were detected in two patients, and single nucleotide variants (SNVs) were detected in the other 39 patients. A total of 46 SNVs were detected in these 39 patients. Sixteen of the detected SNVs were previously reported in the literature, but 30 were novel.
CONCLUSIONS: This study shows that CES can provide a high diagnosis rate (60%) in childhood genetic diseases. Novel mutations (30) have contributed to the mutation profiles of genetic disorders.

Keywords:  clinical exome sequence; copy number of variants (cnv); next generation sequencing (ngs); novel mutation; orphan diseases

DOI:  https://doi.org/10.7759/cureus.80330
Dev Med Child Neurol. 2025 Apr 05.

The phenotypic spectrum of YWHAG-related epilepsy: From mild febrile seizures to severe developmental delay and epileptic encephalopathy.

Quanzhen Tan, Miaomiao Cheng, Ying Yang, Ting Wang, Shijia Ouyang, Changhao Liu, Xiaoling Yang, Wenwei Liu, Ye Wu, Yuehua Zhang.

AIM: To explore the phenotypic spectrum and refine the genotype-phenotype correlation of YWHAG-related epilepsy.
METHOD: This study used a retrospective cohort design to evaluate the clinical data of 15 patients with epilepsy and YWHAG variants in our Chinese cohort (nine males, six females; median age: 6 years 4 months; range: 1 year 6 months-12 years 8 months) and 40 patients with epilepsy with YWHAG variants from published studies (21 males, 19 females; median age: 10 years; range: 3 years-67 years).
RESULTS: In our cohort, seven variants were de novo and five were new. Seizure onset for 14 of 15 patients occurred within the first 2 years of life. Nine of 15 patients had a history of febrile seizures. Seizure types included generalized tonic-clonic seizures (GTCS) and myoclonic seizures. Developmental delay was present in 11 of 15 patients. Three patients were diagnosed with febrile seizures plus, one was diagnosed with myoclonic epilepsy in infancy, one had infantile epileptic spasm syndrome, and 10 had developmental and epileptic encephalopathy that could not be further classified into a specific epilepsy syndrome. Seizures were controlled in 7 of 15 patients; most were treated with valproate and levetiracetam. Collectively, in our cohort and from published studies, most variants (38 of 55, 69.1%) were located in the highly conserved triad (HCT) domain of Arg132-Arg57-Tyr133. Mild phenotypes were more frequently observed in patients with variants located outside the HCT domain, with a significant difference of 70.6% versus 27.0% (p < 0.01).
INTERPRETATION: Most patients with YWHAG variants were diagnosed during infancy. The most common seizure types were GTCS and myoclonic seizures. The phenotypic spectrum of epilepsy ranged from mild febrile seizures to severe developmental delay and epileptic encephalopathy. Most variants were localized in the HCT domain; variants residing outside the HCT domain were correlated with milder phenotypes.

DOI: https://doi.org/10.1111/dmcn.16320
Epilepsia. 2025 Apr 05.

Circumstances surrounding sudden unexpected death in epilepsy in children: A national case series.

Robyn Whitney, Anne Keller, Shelly-Anne Li, Anita N Datta, Matthew MacDonald, Maryam Nabavi Nouri, Daniela Pohl, Erick Sell, Gabriel M Ronen, Mandeep Sidhu, Elisabeth Simard-Tremblay, Michael S Pollanen, Elizabeth J Donner.

   OBJECTIVE: This study was undertaken to understand the circumstances surrounding pediatric sudden unexpected death in epilepsy (SUDEP) and identify clinical factors that may be associated with SUDEP in childhood.
METHODS: A retrospective case series was conducted. Pediatric SUDEP cases were collected across Canada from the Ontario Forensic Pathology Service, Canadian Pediatric Surveillance Program, and Canadian Pediatric Epilepsy Network. Demographics, epilepsy history, comorbidities, and circumstances surrounding death were analyzed.
RESULTS: Forty-nine children with pediatric SUDEP were analyzed; 25 (51%) were females, and the median age at death was 8 years. Six children (12%) were <2 years of age at the time of death. Information on seizure types 6 months before death was known in 35 children. Twenty-two had tonic-clonic seizures within the last 6 months prior to death (63%). Seven children (18%) had no tonic-clonic seizures in their lifetime. Two thirds of children were treated with ≥2 antiseizure medications. Genetic etiologies were most common (55%). Data on global developmental delay (GDD) was known in 46 children; 12 children (26%) had no impairment, and 34 were globally delayed (74%). Children with GDD had earlier age at seizure onset (p < .001); however, epilepsy duration was similar to those without GDD (p = .170). Similar to adult cohorts, death was often unwitnessed (n = 41/46, 89%). Information on recent infection before death was known in 37 children. Seventeen children (46%) had a recent infection.
SIGNIFICANCE: Our study represents the largest pediatric SUDEP case series to date. SUDEP occurred in children of all ages, including infants, with a spectrum of epilepsies with and without neurodevelopmental impairment. The circumstances around death (i.e., timing of death, witnessed/unwitnessed) were similar to previous SUDEP cohorts. A recent infection was often observed, which could decrease seizure threshold and trigger a terminal seizure and may suggest that times of increased seizure risk could warrant heightened surveillance for SUDEP. However, further research is needed to determine the significance of this finding.

Keywords:  SUDEP; mortality; pediatric epilepsy; prevention; tonic–clonic seizures

DOI:  https://doi.org/10.1111/epi.18339
Biomed Pharmacother. 2025 Apr 03. pii: S0753-3322(25)00213-6. [Epub ahead of print]186 118019

An effective approach to modulate mitochondrial function in murine primary macrophages by a mitochondria-targeted nanocapsule, MITO-Porter.

Mitsue Hibino, Tobia Filosi, Libia Lara Carrion, Emilio Porcu, Ankit Malhotra, Kerstin Lüdtke-Buzug, Saleh M Ibrahim, Yuma Yamada, Misa Hirose.

  Macrophages play crucial roles in various pathological conditions as well as maintenance of homeostasis. Many chronic inflammatory conditions, such as atherosclerosis, rheumatoid arthritis, and obesity, are known to involve the polarization of macrophages into a proinflammatory state. Therefore, controlling the function of macrophages is a potential strategy to intervene in such pathological conditions. Modulation of immune cell metabolism has recently received attention as a novel therapeutic strategy to counteract such conditions. Recently, a unique nanocapsule (MITO-Porter) that can deliver macromolecules specifically into mitochondria was generated, and its application to improve mitochondrial function was achieved by the direct action of the molecules at the site of the mitochondria in a wide range of cell types but not in immune cells. Therefore, we initiated this study by investigating the feasibility of mitochondria-targeted delivery of coenzyme Q10 (CoQ10), a known antioxidant and cofactor of mitochondrial oxidative phosphorylation, in primary murine bone marrow macrophages (BMDMs) and then evaluated the functional consequences of the treatment with MITO-Porter on mitochondrial function in BMDMs. At steady state, CoQ10-loaded MITO-Porter containing octaarginine (R8) was successfully delivered into the mitochondria, resulting in significant antioxidant effects and increased mitochondrial respiration. Furthermore, the effect of CoQ10 on mitochondrial function in BMDMs was more pronounced when CoQ10 was encapsulated in R8(+) MITO-Porter than when CoQ10 was added alone. This proof-of-concept study highlights the potential of the application of MITO-Porter in macrophages and other immune cells as a novel immunomodulatory therapy for chronic inflammatory conditions.

Keywords:  Bone-marrow-derived macrophages; Cell metabolism; Coenzyme Q10 (CoQ10); MITO-Porter; Macrophages; Mitochondria-targeted delivery

DOI:  https://doi.org/10.1016/j.biopha.2025.118019