bims-curels 2026-01-25 papers

Issue of 2026–01–25
seven papers selected by
Cure Mito Foundation

Adv Sci (Weinh). 2026 Jan 22. e23368

Mitochondrial Transplantation as a Therapeutic Strategy for Inherited Mitochondrial Diseases.

Parmeshar Singh, Amir Tahavvori, Cyrus E Kuschner, Blanca B Espin, Jacob Kazmi, Sofhia V Ramos, Tai Yin, Kei Hayashida, Kanako Ito-Hagiwara, Yusuke Endo, Keitaro Yoshioka, Jun Hagiwara, Avijot Sohi, Alisha Oropallo, Ghania Haddad, Timmy Li, Lance B Becker, Junhwan Kim.

Mitochondria are essential organelles responsible for cellular energy production and diverse metabolic processes. Mitochondrial dysfunction is implicated in a wide range of diseases. Specifically, genetic mitochondrial diseases, arising from mutations in mitochondrial or nuclear DNA, lead to significant mitochondrial deficits, which result in debilitating and often life-threatening symptoms. Conventional treatments frequently fail to address these underlying mitochondrial defects, leaving few therapeutic options. Mitochondrial transplantation (MTx), an emerging therapeutic approach involving the delivery of healthy exogenous mitochondria to target cells, has demonstrated beneficial effects in various mitochondria-mediated diseases in both preclinical and early clinical studies. However, its application to inherited mitochondrial disorders remains largely unexplored and raises important questions about the need for repeated or continuous administration to sustain therapeutic effects. This review systematically examines the potential of MTx for inherited mitochondrial disorders by classifying these diseases by mitochondrial and nuclear DNA origin, critically assessing MTx evidence and mechanisms, and identifying unique translational requirements for chronic inherited disorders. While significant challenges remain, MTx represents a promising approach to directly address mitochondrial dysfunction in these life-threatening conditions with limited therapeutic alternatives.

Keywords: chronic diseases; genetic diseases; mitochondrial transplantation; therapeutics

DOI: https://doi.org/10.1002/advs.202523368

Brain. 2026 Jan 23. pii: awag026. [Epub ahead of print]

Ultrasound-assisted gene therapy mitigates Leigh syndrome pathology.

Mathilde Faideau, Romain Clément, Sébastien Rigollet, Giorgia Benegiamo, Cassandra Cresson, Béatrice Blot, Robin Reynaud-Dulaurier, Sara Yjjou, Fanny Aprahamian, Sylvère Durand, Anthony Delalande, Emmanuel L Barbier, Vasile Stupar, Johan Auwerx, Michael Decressac.

Leigh syndrome (LS) is a fatal neurometabolic disease caused by mutations in genes involved in mitochondrial energy harvesting. While there is currently no cure for this disease, pre-clinical studies showed that gene therapy can afford a therapeutic benefit in a relevant model of LS, the Ndufs4-KO mouse. However, similar results need to be obtained using methods that can be translated in patients. Here, we combined two tools that are approved for clinical interventions. We used low-intensity focused ultrasound (FUS) to transiently permeabilize the blood-brain barrier and thereby facilitate the passage of an AAV9 vector. This approach resulted in transgene expression in the brain and peripheral organs. When applied to one-month old Ndufs4-KO mice, this gene replacement strategy significantly extended the survival of the animals and ameliorated brain and cardiac function. These improvements were associated with the restoration of protein expression and mitochondrial function. These findings support the potential of combining FUS with AAV-mediated gene delivery to treat LS and they warrant further clinical translation. This study also provides the first evidence that ultrasound-assisted gene replacement can exert a therapeutic effect in a condition affecting the central nervous system.

Keywords: AAV vector; focused ultrasound; gene replacement; mitochondrial disease

DOI: https://doi.org/10.1093/brain/awag026

Metabolomics. 2026 Jan 19. 22(1): 17

NMR-based urinary biomarkers in pediatric primary mitochondrial disorders and chronic kidney disease: shared mitochondrial dysfunction, diverging biosignatures.

Margarida Paiva Coelho, João E Rodrigues, Teresa Costa, Aureliano Dias, Inês C R Graça, Hugo Rocha, Laura Vilarinho, Esmeralda Martins, Ana M Gil.

BACKGROUND: Renal involvement is a recognized feature of primary mitochondrial disorders (PMD), either at presentation or during the disease course. Simultaneously, the metabolomic fingerprint of chronic kidney disease (CKD) is often associated with underlying mitochondrial dysfunction. This study aimed to characterize urinary metabolic signatures in genetically confirmed paediatric PMD without chronic kidney disease, comparing them to healthy controls, suspected (unconfirmed) mitochondrial disease (SMD), and non-mitochondrial CKD.
METHODS: We performed untargeted 1H NMR metabolomic profiling of 76 urine samples from 51 paediatric patients and 10 healthy controls. PMD patients in acute decompensation or known CKD and statistical outlier samples were excluded. Final comparisons included genetically confirmed PMD without CKD (n = 13), SMD (n = 10), non-mitochondrial CKD (n = 28; 17 at stages 1-2 and 9 at stages 3-5), and healthy controls (n = 10). Spectral data were analyzed using multivariate statistical approaches-including principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA)-as well as univariate methods with Mann-Whitney U for pairwise group metabolite comparison.
RESULTS: Urinary metabolic profiles of PMD patients differed from healthy controls and CKD patients. Multivariate analysis revealed a strong discriminative ability between PMD and controls (Q² = 0.53) and advanced CKD (Q2 = 0.78). Compared to controls, PMD patients had increased levels of Krebs cycle intermediates (cis-aconitate, fumarate and succinate), creatine, tryptophan, homovanillate (HVA) and hypoxanthine, as well as decreased histidine. All, except fumarate and histidine, remained discriminative when comparing PMD to CKD. CKD patients showed a diverging metabolomic fingerprint with 1-methylnicotinamide (MNA) and 2-hydroxyisobutyrate emerging as potential CKD-specific biomarkers, effectively discriminating between CKD stage 3-5 from earlier stages and controls. A five-metabolite panel comprising cis-aconitate, fumarate, HVA, tryptophan and histidine achieved high diagnostic performance for identifying PMD, with an area under the curve (AUC) of 0.836 (PMD vs. controls) and AUC = 0.783 across all groups. This biosignature integrates metabolites involved in distinct functional domains including energy metabolism, neurotransmitter turnover and amino acid metabolism and renal handling.
CONCLUSION: Urinary metabolomic profiling by NMR revealed a distinct biosignature in pediatric PMD patients without renal involvement, characterized by elevated levels of tryptophan, HVA, and Krebs cycle intermediates, and diminished histidine. The divergent changes in tryptophan, histidine and HVA, suggest a mitochondria-specific metabolic phenotype in PMD. These findings support the use of urinary NMR metabolomics as a non-invasive tool for biomarker discovery in PMD and highlight the potential of integrated, multiparametric metabolic fingerprints for diagnostic refinement and patient stratification.

Keywords: Biomarkers; Metabolomics; NMR; Pediatric CKD; Primary mitochondrial disorders; Urine

DOI: https://doi.org/10.1007/s11306-025-02363-8

Front Immunol. 2025 ;16 1734203

NDUFS4, a mitochondrial complex I subunit, is essential for T-cell metabolic fitness and immune function.

Oded Shamriz, Zahala Bar-On, Omri Yosef, Leonor Cohen-Daniel, Ayelet Sheer, Or Reuven, Wajeeh Salaymeh, Amijai Saragovi, Raz Somech, Atar Lev, Hagar Mor-Shaked, Yuval Tal, Aviva Fattal-Valevski, Simon Edvardson, Michael Berger.

Introduction: Mitochondrial metabolism is essential for T-cell function, but the roles of individual electron transport chain (ETC) components are unclear. Here, we aimed to explore the role of mitochondrial complex I (CI) subunit NADH:ubiquinone oxidoreductase iron-sulfur protein 4 (NDUFS4) in T-cell metabolic fitness and immunity.
Methods: We used a T cell-specific Ndufs4 knockout mouse model to find that NDUFS4 deficiency disrupts CI function, leading to metabolic and redox imbalances. Additionally, T cells from a patient with Leigh syndrome induced by NDUFS4 loss-of-function were analyzed.
Results: Ndufs4-deficient T cells exhibit impaired OXPHOS, reduced respiratory capacity, and increased glycolysis, accompanied by reactive oxygen species (ROS) accumulation and defective TCR-driven activation, including reduced proliferation and cytokine production. In vivo, Ndufs4(-/-) mice show T-cell lymphopenia and impaired humoral and cytotoxic immunity. Importantly, T cells from a single Leigh syndrome patient with an NDUFS4 loss-of-function variant showed similar defects, including impaired activation and proliferation.
Discussion: These findings highlight the importance of NDUFS4 for human immunity and establish a mechanistic link between complex I dysfunction and T-cell immunodeficiency. Our results identify NDUFS4 as a key regulator connecting mitochondrial integrity to adaptive immune function.

Keywords: NDUFS4; NDUFS4 knockout mice; T cells; leigh syndrome (LS); mitochondria

DOI: https://doi.org/10.3389/fimmu.2025.1734203

Patient Educ Couns. 2026 Jan 17. pii: S0738-3991(26)00025-X. [Epub ahead of print]145 109492

Patient and clinician engagement with generative artificial intelligence (GenAI): A scoping review of implications for patient-centered communication.

Jessica Hahne, Brian D Carpenter.

OBJECTIVE: To examine the influence of the emerging use of generative artificial intelligence (GenAI) within electronic health records and among the public on the patient-centeredness of communication in healthcare.
METHOD: In this scoping review, we conducted a systematic search for peer-reviewed studies in PubMed and PsycInfo that empirically examined GenAI involvement in clinical communication. We then mapped study findings onto a well-established framework for patient-centered communication.
RESULTS: Our search yielded 67 studies for analysis. Results suggest that integration of GenAI into healthcare communication has the potential to increase clinician efficiency in interacting with patients, to expand channels for patients to obtain information about their healthcare, and to enhance empathy in clinical communication. However, findings also indicate variability in the quality of information produced by GenAI, the potential for GenAI to recast the clinician as a technical supervisor rather than a humanistic care provider, and several issues of equity and privacy raised by engagement with GenAI.
CONCLUSION: As GenAI becomes more prevalent in healthcare, rigorous examination of GenAI is needed to ensure that its development and implementation aids rather than hinders patient-centered communication. We conclude with an agenda for further research on GenAI grounded in the PCC framework underlying our review.
PRACTICE IMPLICATIONS: Findings from this review highlight the current potential benefits and limitations of GenAI as a third party to clinical communication. Continued efforts toward developing and applying GenAI for effective healthcare communication should focus on protecting patients from potential drawbacks and maximizing nascent benefits for patient-centered communication.

Keywords: Digital health technology; Electronic health records; Generative artificial intelligence; Patient-centered communication

DOI: https://doi.org/10.1016/j.pec.2026.109492

Ther Innov Regul Sci. 2026 Jan 21.

The Utilization of Externally Sourced Data and Data Collected and Analyzed from Previously Completed Studies Using Modelling and Simulation and Other Methodologies to Support Pediatric-Focused Regulatory Commitments.

Nancy A Sherman, Kevin D Wolter, Elena Soto.

There can be many challenges to conducting and completing clinical research trials, which may impact the successful and timely achievement of regulatory commitments. General difficulties can include a rare disease under study which limits the available study population, a relatively low number of interested study sites that have potential study participants, numerous required study procedures, invasive study procedures and, with regard to pediatric clinical trials, parents may be unwilling to provide consent for their children to participate. The utilization of externally sourced data as well as data collected and analyzed from internal previously completed clinical trials can be a useful and strategic method of supplementing clinical trial data that is needed to meet regulatory requirements. However, this strategy may not be widely known, understood or leveraged. The authors conducted a review of clinical trials and other types of regulatory commitments that successfully included external data and data that was collected and analyzed from previously completed studies, to meet regulatory requirements. It was concluded that the use of externally sourced data and data from other internally sponsored completed studies can offer a critical source of information, thereby adding robustness to regulatory submissions, particularly when there are gaps in clinical trials due to recruitment barriers and other challenges.

Keywords: External data; NDA; New drug applications; Pediatric studies; Population modelling analysis reports; Published data; Published studies; Real-world data; Regulatory submissions; Supplemental new drug applications; sNDA

DOI: https://doi.org/10.1007/s43441-025-00909-5

Orphanet J Rare Dis. 2026 Jan 20.

Optimizing recruitment in rare disease research: a cross-sectional online study evaluating sampling strategies for hard-to-reach populations.

Shalice Baffour, Bernd Löwe, Annika Braun, Natalie Uhlenbusch.

Keywords: Location-based sampling; Medical research; Online-based sampling; Patient recruitment; Rare diseases; Respondent-driven sampling; Sampling strategy; Vulnerable populations

DOI: https://doi.org/10.1186/s13023-025-04192-3