bims-polgdi 2026-05-24 papers

bims-polgdi

Biomed News

on POLG disease

Issue of 2026–05–24
forty-two papers selected by
Luca Bolliger, lxBio

Electron microscopy visualization of cell-free mitochondrial DNA-associated vesicular structures in human plasma, serum, and saliva.
Mitoredox Shifts in Mitochondrial Dysfunction.
Collaboration as a Catalyst for Advancing Rare Disease Research: The Experience of the Rare Diseases Clinical Research Network.
Dynamic disorder is crucial for mitochondrial protein import.
Detecting comorbidity patterns in rare disease patients with machine learning.
Review article: Improving Mitochondrial Function: Current Therapeutic Perspectives in Neurodegenerative Diseases.
Shared molecular mechanisms in aging and neurodegenerative diseases: from mechanistic insights to therapeutic strategies.
Harnessing Patient-Generated Data for Rare Disease Knowledge Enrichment: A Pilot Study.
Challenging mtDNA tRNA variant guidelines: Emphasizing single-cell analysis through four novel variants.
Mitochondrial Dynamics and Transfer in Mesenchymal Stromal Cells: Redox Regulation, Therapeutic Mechanisms, and Engineering Strategies.
Telomere biology disorders as an example of rare disease advocacy.
The importance of mitochondrial DNA introgression for conservation.
Complex correlations between mitochondrial DNA variants and gut microbiome in major depressive disorder: a genome-wide association analysis.
Crosstalk between endoplasmic reticulum stress and mitochondrial homeostasis: A new perspective on ophthalmic disease treatment.
The progress of mitochondrial function and transfer in stem cell regulation and therapy.
Nucleoside therapy for thymidine kinase 2 deficiency: Long-term outcomes from a Brazilian cohort.
Mavodelpar in patients with primary mitochondrial myopathy: a phase 1 trial.
Fabrication of fusogenic and magnet-responsive cells for transplantation of an intact mitochondrial network.
How much change is meaningful in global impression anchors? Evidence from five rare diseases.
Sperm mitochondrial DNA copy number: a marker of male fertility and reproductive success.
Experimental and Computational Approaches to Identify Noncoding Pathogenic Variation in Rare Disease.
Utilizing Routine Care Data of Rare Diseases: Challenges, Chances and Call for Collaboration.
When copper turns killer: Decoding copper dyshomeostasis and cuproptosis in neurodegenerative pathogenesis and precision metal interventions.
Metformin attenuates cuprizone-induced mitochondrial dysfunction and senescence-associated changes in primary neuronal cells.
Higher-order structural organization of mitochondrial metabolism.
Living donor liver transplantation in a pediatric patient with mitochondrial DNA depletion syndrome caused by two novel POLG1 mutations: a case report and literature review.
A global survey of systems biology-based predictions of gene-rare disease associations to enhance new diagnoses.
The next paradigm in bioinformatics: a review of multi-agent systems and foundational models for end-to-end scientific discovery.
"SelO"ective NAD+ hydrolysis regulates mitochondrial NAD+ and homeostasis.
Patients offered genomic testing for rare disease and cancer: a real-world evaluation of impact and processes of care.
Hit the bull's eye: Engineered extracellular vesicles for targeted therapy.
Access to orphan drugs in adults with inherited metabolic diseases in Switzerland: a single-center retrospective cohort study.
Gut microbiota: The hidden hallmark of aging.
PROTACs for central nervous system disorders: challenges and opportunities.
A Two-Stage Questionnaire and Actigraphy Screening for iRBD in a Multicenter Retrospective Cohort.
Stress-triggered cell elimination stabilizes resource-limited cell collectives: An agent-based model.
Cerebral vasodilation and lesion patterns in stroke-like episodes of MELAS: a quantitative angiographic investigation.
Clinical Diagnosis of Rare Diseases Using Leaky Noisy-OR Bayesian Networks.
Lack of repeatability in red muscle mitochondrial function over time and across oxygen conditions in a teleost fish.
Vitrification-warming delays preimplantation development and impairs mitochondrial function and cytoplasmic lattices integrity in mouse embryos.
Treating the immune system to repair the brain.
Early-life mitochondrial impact of prenatal DL-PCB exposure: A signal from cord blood mtDNA.

Mitochondrion. 2026 May 16. pii: S1567-7249(26)00059-0. [Epub ahead of print] 102169

Electron microscopy visualization of cell-free mitochondrial DNA-associated vesicular structures in human plasma, serum, and saliva.

Alexandra Volos, Soah Grace Franklin, Jeremy Michelson, Shannon Rausser, Jonathan R Brestoff, Martin Picard.

  Human biofluids contain cell-free mitochondrial DNA (cf-mtDNA) and extracellular mitochondria (ex-Mito), creating the challenge of defining their origins, destinations, mechanisms of regulation, and purposes. To expand our understanding of vesicular structures across human biofluids, we present a descriptive electron microscopy analysis of circulating particles from cf-mtDNA-enriched plasma (citrate, heparin, and EDTA), serum (red and gold top), and saliva collected from ten healthy participants (5 females, 5 males, mean age 44.9 years). Ex-mito and extracellular vesicles (EVs) were isolated by centrifugation followed by size-exclusion chromatography, imaged by transmission electron microscopy, and morphometrically analyzed. In parallel, cf-mtDNA was quantified in each biofluid to confirm enrichment. The resulting catalog of the most common circulating particles in plasma, serum, and saliva show that circulating double-membrane extracellular particles are present across human biofluids, along with EVs and other particle types. Combining imaging with cf-mtDNA quantification, we show that individuals with higher plasma cf-mtDNA concentrations tend to contain more double-membrane, ex-Mito-like particles. These preliminary and largely qualitative results do not directly demonstrate but are consistent with the concept of mitochondria transfer and/or signaling between cells and tissues. The image inventory provided here expands our knowledge of cell-free mitochondrial biology and provides a resource to inform biofluid selection and technical considerations in future studies quantifying ex-Mito and cf-mtDNA.

Keywords:  cell-free material; circulating; human; image repository; imaging; microscopy; mitochondria; study design; vesicles

DOI:  https://doi.org/10.1016/j.mito.2026.102169
Free Radic Biol Med. 2026 May 21. pii: S0891-5849(26)00787-2. [Epub ahead of print]

Mitoredox Shifts in Mitochondrial Dysfunction.

Walter H Moos, Douglas V Faller, Ioannis P Glavas, Iphigenia Kanara, Krishna Kodukula, Julie Pernokas, Mark Pernokas, Carl A Pinkert, Whitney R Powers, Konstantina Sampani, Kosta Steliou, Demetrios G Vavvas.

  Mitochondrial dysfunction underlies a broad spectrum of primary and secondary disorders, yet current frameworks do not fully capture how diverse genetic, metabolic, and environmental stressors converge on shared pathological outcomes. Here, we propose that mitoredox shifts - bidirectional disruptions in mitochondrial redox homeostasis that alter mitochondrial quality control and genome-stability pathways - serve as a unifying axis linking oxidative stress, mitochondrial quality control failure, heteroplasmy dynamics, and regulated cell death. Both hyperactive and hypoactive mitochondrial states destabilize redox balance, altering PINK1/Parkin-dependent and receptor-mediated mitophagy, disrupting proteostasis, and reshaping mitochondrial network dynamics. These redox-driven perturbations influence the propagation of pathogenic mtDNA variants, modulate tissue-specific threshold effects, and bias cells toward apoptosis, ferroptosis, cuproptosis, and other regulated cell death pathways. We synthesize emerging evidence across mitochondrial genetics, bioenergetics, and redox signaling to outline how mitoredox shifts accelerate disease progression in both primary mitochondrial syndromes and secondary mitochondrial dysfunction. We further evaluate the expanding landscape of diagnostic biomarkers, including FGF21, GDF15, imaging-based oculomics, and high-throughput proteomic and genomic assays. In parallel, we highlight therapeutic strategies aimed at restoring redox balance, enhancing mitophagy, or shifting mitochondrial network composition by diluting dysfunctional organelles through mitochondrial transplantation. By emphasizing mitoredox imbalance as a recurrent feature of disease, this work synthesizes emerging diagnostic and therapeutic approaches across rare and common mitochondrial disorders.

Keywords:  Biomarkers; cuproptosis; ferroptosis; heteroplasmy; mitochondria; mitophagy; mitoredox medicine; oxidative stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.307
Clin Transl Sci. 2026 Jun;19(6): e70585

Collaboration as a Catalyst for Advancing Rare Disease Research: The Experience of the Rare Diseases Clinical Research Network.

Mirna Chehade, Sheridan Meyers, Talaya McCright-Gill, Rogerwene Gifford, Mustafa Sahin, Michael E Shy, Michele Manion, Dakota Campbell, Marc E Rothenberg, Maurizio Macaluso.

  The Rare Diseases Clinical Research Network (RDCRN) was established to improve diagnosis, treatment, and research collaboration across rare diseases through collaborative, multi-site, translational, and clinical research. Its governance framework promotes efficient data sharing and collaboration among research consortia, NIH representatives, and patient advocacy groups (PAGs). This infrastructure facilitates coordinated efforts to advance rare disease research through shared resources and communication. Prompted by the COVID-19 pandemic's impact on rare disease patients, the RDCRN recognized cross-consortia collaboration as a priority. Its policies promote data sharing while protecting participant confidentiality. PAGs participate in governance, study design, and regulatory discussions, helping to identify patient-relevant priorities, improve recruitment and retention, and strengthen trust between researchers and patients. Cross-consortia efforts have addressed challenges like biomarker identification and harmonization of clinical measures, leading to new methods and standardized data collection that benefit multiple rare diseases. Studies by teams focusing on different diseases have led to improved diagnostic tools by addressing overlapping disease presentations. The RDCRN offers scholars cross-consortia opportunities for presentations, competitions, and NIH training collaborations, fostering growth and networking. Network meetings promote exchange and process standardization; pilot projects facilitate independent grant submissions, forming a pipeline of skilled investigators. The RDCRN fosters trust, shared vision, and open communication by cultivating a culture of mutual respect, shared learning, and collective problem solving. By engaging a wide range of stakeholders, it has aligned its research with patient needs, advancing innovation. Its high-impact publications, effective mentoring programs, and pioneering cross-consortia initiatives underscore the value of collaboration in rare disease research.

Keywords:  collaboration; committee; consortium; network; rare disease

DOI:  https://doi.org/10.1111/cts.70585
Protein Sci. 2026 Jun;35(6): e70630

Dynamic disorder is crucial for mitochondrial protein import.

Jakob Schneider, Undina Guillerm, Caroline Simões Pereira, Paul Schanda.

  The import of proteins into mitochondria poses fundamental mechanistic challenges: aggregation-prone precursor proteins must be maintained in aqueous compartments and threaded through narrow pores without becoming stuck or mislocalized. Recent evidence from mitochondrial protein import studies and other chaperone systems underscores the critical role of dynamics in balancing sufficiently tight binding, promiscuity, specificity, and release. Dynamic binding of client precursor proteins to import machinery components arises naturally from the avidity of their interactions. Conformational entropy enhances their stability, while the multivalent nature of these interactions ensures that client transfer to downstream insertases occurs without a substantial energy barrier. Here, we discuss this emerging paradigm of dynamic protein handling, using examples where dynamic structures have been resolved and highlight outstanding questions.

Keywords:  avidity; chaperones; import machinery; intrinsic disorder; mitochondria

DOI:  https://doi.org/10.1002/pro.70630
Front Epidemiol. 2026 ;6 1765678

Detecting comorbidity patterns in rare disease patients with machine learning.

Benjamin Mark Connor, Claire Hill, Lu Bai, Amy Jayne McKnight, Anna Jurek-Loughrey.

   Introduction: Whilst individually rare, affecting only a small percentage of the population, rare diseases as a whole impact around 6% of the global population (with this number likely an underestimate). Rare diseases are often complex, with specific challenges in diagnosis, management, and treatment due to limited knowledge and research. Rare disease patients have been shown to have more comorbidities compared to those without a rare disease diagnosis. Studying comorbidities in patients with rare diseases is particularly important as these patients may exhibit unique patterns of multiple diseases which are not well understood. Understanding these comorbidity patterns can lead to insights into the etiology and progression of rare diseases, potentially identifying new therapeutic targets and improving clinical management strategies. Additionally, studying comorbidities can help in predicting complications, improving the quality of life of patients, and offering a more comprehensive approach to health care for those affected by rare diseases.
Methods: A machine learning based method known as hierarchical clustering was applied to diagnosis data from the UK Biobank to study comorbidity patterns in patients with rare diseases. The results were then compared with patterns detected for the general population.
Results: Twelve clusters were identified for the rare disease group, and 14 for the no rare disease group.
Discussion: Unique comorbidity patterns were observed for individuals with and without a rare disease diagnosis, highlighting potential priorities for intervention to improve both disease management and patient care.

Keywords:  comorbidity; machine learning; multimorbidity; pattern detection; rare disease

DOI:  https://doi.org/10.3389/fepid.2026.1765678
Pharmacol Res. 2026 May 18. pii: S1043-6618(26)00142-8. [Epub ahead of print] 108227

Review article: Improving Mitochondrial Function: Current Therapeutic Perspectives in Neurodegenerative Diseases.

Julia Brechtel, Christine Lietz, Selin Akpinar Adscheid, Kristina Friedland.

  Mitochondrial dysfunction is considered one of the key drivers of neurodegeneration and pathological aging, characterized by impaired energy production, oxidative stress, disrupted mitophagy, and biogenesis. Because mitochondria regulate bioenergetics, redox balance, and neuronal survival, therapeutic strategies that restore mitochondrial integrity are of growing interest. This review outlines mechanisms of mitochondrial function and failure, links them to Alzheimer's and Parkinson's disease, and summarizes evidence on phytochemicals and mitochondria-targeted small molecules, which enhance biogenesis, mitophagy, respiratory efficiency, and antioxidant defence in preclinical models together with life-style interventions. Although many compounds demonstrate preventive rather than restorative benefit and clinical evidence remains limited, next-generation approaches, including nanoparticles for mitochondrial delivery, mtDNA editing, and mitochondrial transfer, suggest increasing therapeutic potential. We underline that future success will rely on improved delivery, synergistic combinations, and rigorous clinical trials. Mitochondria-directed therapies may ultimately provide disease-modifying or preventive strategies for neurodegenerative disorders.

Keywords:  Alzheimer’s Disease; Mitochondria-Targeted Therapies; Mitochondrial Dynamics; Mitochondrial Dysfunction; Parkinson’s Disease; Phytochemicals; Small Molecule

DOI:  https://doi.org/10.1016/j.phrs.2026.108227
Front Hum Neurosci. 2026 ;20 1768774

Shared molecular mechanisms in aging and neurodegenerative diseases: from mechanistic insights to therapeutic strategies.

Yesim Kaya, Kevser Kübra Kırboğa.

  Aging is a complex biological process characterized by progressive functional decline and increased vulnerability to age-related diseases, particularly neurodegenerative disorders. At the biological level, aging is characterized by a range of molecular and cellular mechanisms, including genomic instability, telomere attrition, loss of proteostasis, mitochondrial dysfunction, and chronic inflammation, which collectively contribute to cognitive decline and neuronal dysfunction over time. These hallmarks do not function independently but instead interact with one another during aging and neurodegeneration. Consequently, brain aging and neurodegenerative diseases are recognized as closely interconnected processes. To better understand this relationship, it is essential to examine the shared molecular and cellular mechanisms that link brain aging to neurodegeneration. In this review, we summarize the principal mechanisms underlying aging and neurodegenerative diseases, examine their roles in these processes, and highlight how their interactions shape both aging and neurodegeneration. We also discuss potential therapeutic strategies targeting key mechanisms involved in aging and neurodegeneration.

Keywords:  brain aging; genomic instability; inflammation; loss of proteostasis; mitochondrial dysfunction; neurodegenerative diseases; telomere attrition; therapeutic strategies

DOI:  https://doi.org/10.3389/fnhum.2026.1768774
Stud Health Technol Inform. 2026 May 21. 336 2415-2419

Harnessing Patient-Generated Data for Rare Disease Knowledge Enrichment: A Pilot Study.

Selina Wai Yan Hui, Fangyi Chen, Kai Wang, Chunhua Weng.

  Patients with rare diseases often endure a 4-5-year diagnostic odyssey. Patient-generated data on social media remains an untapped resource for understanding rare diseases. This study characterizes patient descriptions of rare disease from social media and systematically compares patient-reported symptoms to literature-documented ones. 166 unique rare diseases were identified from 229 patient posts. A hybrid human-AI framework using GPT-4 with full manual verification was used to extract and standardize patient-reported symptoms, which were then compared against symptoms documented in PubMed. The most frequent patient-reported symptoms were motor impairment, ataxia, pain, and fatigue. A low average overlap was observed between patient-reported symptoms and clinical literature. Patient narratives emphasized quality-of-life impacts (e.g., fatigue, anxiety), whereas clinical literature focused on diagnostic markers (e.g., dysarthria, dysphagia). Patient-generated data reveals underreported symptoms that are particularly meaningful to patients and complement clinical findings. Harnessing these real-world insights holds immense potential to shorten the diagnostic odyssey, inform patient-centered care, and guide future research priorities for rare diseases.

Keywords:  Large Language Models; Patient-Generated Health Data; Rare Diseases

DOI:  https://doi.org/10.3233/SHTI260703
Mitochondrion. 2026 May 17. pii: S1567-7249(26)00060-7. [Epub ahead of print]90 102170

Challenging mtDNA tRNA variant guidelines: Emphasizing single-cell analysis through four novel variants.

Prosper Chloé, Zereg Elamine, Chaussenot Annabelle, Bannwarth Sylvie, Lannes Béatrice, Nathalie Streichenberger, Kaphan Elsa, Nadaj-Pakleza Aleksandra, Villa Luisa, Sacconi Sabrina, Masingue Marion, Eléonore Birgy, Francou Bruno, Ait-El-Mkadem Saadi Samira, Fragaki Konstantina, Paquis-Flucklinger Véronique, Rouzier Cécile.

  The broad clinical and genetic heterogeneity of mitochondrial diseases makes diagnosis challenging. Accurate characterization of novel variants is crucial to reduce diagnostic uncertainty, guide treatment, and enable reliable genetic counseling. In this study, we validated a single-cell NGS-based analysis approach by comparison with conventional PCR-RFLP and applied it to five mtDNA variants identified in patients evaluated at our national reference center for mitochondrial disorders (CALISSON). Variant interpretation was assessed using multiple frameworks, including Yarham's scoring, Wong's specifications, and the ClinGen guidelines. We report four novel variants (m.9998 T > C in MT-TG, m.7530A > G in MT-TD, and m.4271G > C and m.4305A > G in MT-TI), including three for which single-fiber analysis provided strong evidence supporting pathogenicity. However, these functional results alone were not sufficient to enable reclassification under the current ClinGen framework. These findings highlight differences between the various scoring systems and illustrate the limitations of current recommendations in fully integrating functional evidence and tissue segregation data. We therefore suggest that adjusted weighting of existing criteria may improve variant classification. Nevertheless, classification frameworks must preserve reproducibility across laboratories, and the criteria proposed here should be considered preliminary points for reflection requiring further validation in larger cohorts, as well as the establishment of standardized criteria for functional studies, including single-fiber analyses.

Keywords:  0m.7530A>G inMT-TD; 0m.9998T>C inMT-TG; And m.4271G>C and m.4305A>G inMT-TI; Mitochondrial DNA heteroplasmy; Next-Generation Sequencing (NGS); Single-fiber analysis; mitochondrial tRNA; mtDNA guidelines

DOI:  https://doi.org/10.1016/j.mito.2026.102170
Free Radic Biol Med. 2026 May 20. pii: S0891-5849(26)00771-9. [Epub ahead of print]

Mitochondrial Dynamics and Transfer in Mesenchymal Stromal Cells: Redox Regulation, Therapeutic Mechanisms, and Engineering Strategies.

XueXia Liu, XiaoXin Wang, FuJun Liu.

  Mesenchymal stromal cells (MSCs) are metabolically active and redox-sensitive therapeutic cells, with their therapeutic potency tightly linked to mitochondrial integrity and function. Beyond paracrine and immunomodulatory actions, MSCs can transfer functional mitochondria to damaged cells, restoring bioenergetics, maintaining redox homeostasis via ROS regulation, and facilitating tissue repair and regeneration. This review summarizes recent progress in MSC mitochondrial biology, highlighting how metabolic reprogramming, mitochondrial biogenesis, fusion-fission dynamics and mitophagy coordinately regulate MSC stemness, differentiation, senescence and therapeutic capacity. It outlines core redox regulatory networks covering mitochondrial ROS production (ETC Complexes I/III and reverse electron transport), non-mitochondrial oxidases (NADPH oxidases), and canonical antioxidant signaling (Nrf2/Keap1, thioredoxin/peroxiredoxin and glutathione/glutaredoxin). Redox-dependent post-translational modifications governing mitochondrial transfer machinery are emphasized, including cysteine oxidation of connexin 43, redox-regulated Drp1 phosphorylation, and oxidative modulation of Miro1-mediated mitochondrial trafficking. Major intercellular mitochondrial transfer routes, such as tunneling nanotubes, connexin 43-based intercellular communication and extracellular vesicles, are discussed under inflammatory, hypoxic and metabolic stress conditions. Preclinical studies across pulmonary, cardiovascular, neurological, renal, hepatic and immune-mediated diseases validate that MSC-derived mitochondrial transfer preserves ATP production, mitigates oxidative injury and remodels recipient cell immunometabolic phenotypes. Emerging engineering strategies to improve mitochondrial delivery and therapeutic outcomes are also reviewed, alongside translational bottlenecks including cell source heterogeneity, mitochondrial quality control, in vivo tracking, dosage optimization and long-term biosafety. Overall, MSC mitochondrial dynamics and intercellular transfer bridge redox biology, metabolism and regenerative medicine, offering mechanistic insights for next-generation precision regenerative therapies.

Keywords:  Extracellular vesicles; Mesenchymal stromal cells; Mitochondrial transfer; Redox homeostasis; Regenerative medicine

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.291
Semin Hematol. 2026 Apr 23. pii: S0037-1963(26)00028-4. [Epub ahead of print]

Telomere biology disorders as an example of rare disease advocacy.

Katie Barrett Stevens, Hannah A Raj, Jane K Paxton, Hilary J Longhurst.

  Patient advocacy has emerged as a transformative force within the rare disease landscape. Few rare diseases illustrate this dynamic as clearly as telomere biology disorders (TBDs). Once regarded primarily as rare pediatric bone marrow failure syndromes, TBDs are now understood as multisystem, lifelong conditions affecting individuals across the age spectrum. In this review, we examine TBDs as a case study in rare disease advocacy, highlighting how advocacy has functioned not only as a support mechanism but as an organizing architecture underpinning progress across diagnosis, management, research, and community engagement. We describe how advocacy efforts have advanced diagnostic awareness and access to validated testing, informed the development and dissemination of clinical management guidelines, enabled multidisciplinary models of care, and fostered robust research ecosystems through funding, registries, and collaborative convenings. We further explore the essential role of advocacy in addressing psychosocial needs, sustaining patient engagement, and confronting persistent inequities in access, representation, and care delivery. The TBD experience demonstrates that advocacy is not ancillary to science, but integral to its progress and impact. As the field enters a new era characterized by expanding diagnoses and emerging therapies, the TBD community offers a scalable framework for integrating advocacy as a core component of rare disease ecosystems.

Keywords:  Bone marrow failure; Dyskeratosis congenita; Genetic testing; Pulmonary fibrosis; Rare disease advocacy; Telomere biology disorders

DOI:  https://doi.org/10.1053/j.seminhematol.2026.04.002
Trends Ecol Evol. 2026 May 20. pii: S0169-5347(26)00105-9. [Epub ahead of print]

The importance of mitochondrial DNA introgression for conservation.

Jack A Brand, Michael G Bertram, Geir H Bolstad, Tomas Brodin, M Florencia Camus, Ingerid J Hagen, Justin C Havird, Geoffrey E Hill, Kjetil Hindar, Erik N K Iverson, Jade Kannangara, Sten Karlsson, Sebastian Wacker, Damian K Dowling.

  Human-mediated gene flow is increasingly altering the genetic composition of populations, yet conservation assessments typically focus on nuclear introgression alone. We synthesise evidence showing that mitochondrial DNA (mtDNA) introgression can have distinct consequences for performance, adaptation, and the viability of animal populations. Unlike most nuclear loci, mtDNA is uniparentally inherited, nonrecombining, and encodes core components of cellular energy metabolism that must function in tight coordination with nuclear genes. As a result, introgression of nonnative mtDNA can disrupt co-adapted mito-nuclear interactions, sometimes generating sex-specific or environment-dependent costs. Conversely, mtDNA introgression can also be neutral or beneficial in certain circumstances. We argue that ignoring mtDNA risks unintended maladaptation and that mitochondrial and nuclear genetics should be considered jointly in conservation planning.

Keywords:  anthropocene; conservation genetics; human-mediated gene flow; mitochondria; mito–nuclear interactions; wildlife management

DOI:  https://doi.org/10.1016/j.tree.2026.04.017
BMC Psychiatry. 2026 May 20.

Complex correlations between mitochondrial DNA variants and gut microbiome in major depressive disorder: a genome-wide association analysis.

Xuan Guan, Xiao-Ling Shen, Yan-Ni Hao, Zai-Quan Dong, Jian-Min Chen.

   BACKGROUND: Gut microbiota disturbances and impaired mitochondrial function are both linked with the development of major depressive disorder (MDD). However, little is known about how they interact in MDD.
METHODS: We used shotgun metagenomic sequencing to explore fecal microbiome based on 63 MDD patients and 30 healthy controls (HCs). Then we performed GWAS for the discriminative taxonomic features of gut microbiota to identify genetic associations between gut microbiome and mitochondrial DNA (mtDNA) in MDD.
RESULTS: Characteristic gut microbiome-based features, including significant differences in gut microbiota composition and 101 differentially enriched gut microbial species, were found in MDD group vs. HC group. 68 mitochondrial single-nucleotide polymorphisms (mtSNPs) shared between the two groups were identified through GWAS at a Bonferroni-corrected significance level of p < 0.05. The genetic variants and their associated gut microbes were mapped to mitochondrial genome, most of which were located in coding regions, including MT-ND, MT-ND4L, MT-ND5, MT-ND6; MT-CO, MT-CO3; MT-RNR, MT-RNR, and MT-TE. Manhattan plots showed 9 mtSNPs in MDD group and 10 mtSNPs in HC group were associated with 20 gut microbial species at a significance of -log10(p) >20. Furthermore, Sankey diagram was used to visualize the relationships of gut microbiota and mtDNA. 36 mtSNPs (-log10(p) >5) were shown to be associated with 54 gut microbes in crosslinked patterns.
CONCLUSIONS: The current findings provide substantial evidence that complex interactions between gut microbiota and mtDNA contribute to MDD, which enables a better understanding of MDD pathogenesis and suggests new leads for future investigations.
CLINICAL TRIAL NUMBER: ChiCTR2000029703. Registration Date: Feb. 9th, 2020. Registration Details are available at the website of Chinese Clinical Trial Registry (https://www.chictr.org.cn).

Keywords:  Genome-wide association analysis study; Gut microbiome; Major depression disorder; Mitochondrial DNA; Mitochondrial single nucleotide polymorphisms; Shotgun metagenomic sequencing

DOI:  https://doi.org/10.1186/s12888-026-08132-8
J Cell Commun Signal. 2026 Jun;20 e70080

Crosstalk between endoplasmic reticulum stress and mitochondrial homeostasis: A new perspective on ophthalmic disease treatment.

Luyang Jiang, Gongsang Cuomu, Sang Jijia, Yumei Yang, Jufen Liu, Yumin Tao.

  Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are hallmarks of many ophthalmic diseases; however, they have traditionally been examined as isolated pathological processes. Recent evidence indicates that these organelles are inextricably coupled through mitochondria-endoplasmic reticulum contact sites, also known as mitochondria-associated membranes (MAMs), which coordinate Ca2+ signaling, lipid transfer, mitochondrial dynamics, redox balance, and cell death decisions. Consequently, dysregulated ER-mitochondria communication has emerged as a key vulnerability that links the cellular stress responses among diverse ocular tissues, including lens epithelial cells, retinal ganglion cells, the retinal pigment epithelium, and corneal endothelial cells. In this review, we summarize the recent advances involving the molecular architecture and regulatory function of ER-mitochondria crosstalk. We focus on how the unfolded protein response signaling, pathological MAM remodeling, Ca2+ dysregulation, and disrupted mitochondrial quality control collectively drive disease progression. By integrating evidence from cataract, glaucoma, diabetic retinopathy, age-related macular degeneration, and Fuchs endothelial corneal dystrophy, we reveal that these disorders are not driven by a uniform mechanism of organelle failure, but rather by the dominance of pathological nodes along the ER-mitochondria axis. We propose that ophthalmic diseases should be stratified based on these distinct failure nodes, which provides a mechanistic framework for developing therapeutics. Within this context, interventions targeting maladaptive ER stress, MAM destabilization, bioenergetic failure, or defective mitophagy should be considered complementary and context-dependent strategies. By reframing ophthalmic disorders as diseases of inter-organelle stress integration, this review positions the ER-mitochondria axis as a modifiable upstream determinant of ocular cell fate, which provides a foundation for stage-specific precision therapies.

Keywords:  calcium signaling; endoplasmic reticulum–mitochondria crosstalk; mitochondrial dynamics; mitochondria‐associated membranes; mitophagy; ophthalmic diseases; unfolded protein response

DOI:  https://doi.org/10.1002/ccs3.70080
J Physiol Biochem. 2026 May 21. pii: 53. [Epub ahead of print]82(1):

The progress of mitochondrial function and transfer in stem cell regulation and therapy.

Yubing Zhang, Zhuojian Qu, Zhiliang Guo, Lijuan Zhang, Hong Li, Xiaoyun Zhang, Xiumei Guan, Xiaodong Cui, Wenxu Wang, Min Cheng.

  Mitochondria, serving as central organelles for energy metabolism, play a critical regulatory role in stem cell self-renewal and differentiation-a function increasingly supported by accumulating evidence and closely linked to various aging-related diseases. Central to their function in stem cell pluripotency are several key mechanisms, such as the control of reactive oxygen species, mitophagy, and mitochondrial-endoplasmic reticulum communication. Mitochondrial transfer, as an emerging intercellular communication mechanism, can enhance stem cell pluripotency and function by replacing damaged mitochondria or activating mitophagy in recipient cells. However, different transfer mechanisms can induce distinct effects on recipient cells. The development of artificial mitochondrial transfer technology, compared to traditional cell transplantation, reduces immune rejection and offers new strategies for stem cell therapy. This review examines the interplay between mitochondrial function and stem cell fate determination, discusses the therapeutic potential of mitochondrial transfer in stem cell-based regenerative strategies, and establishes a theoretical framework for understanding and treating mitochondrial dysfunctions and aging-associated pathologies.

Keywords:  Mitochondrial function; Mitochondrial transfer; Mitophagy; Reactive oxygen species; Stem cell regulation

DOI:  https://doi.org/10.1007/s13105-026-01192-0
J Neuromuscul Dis. 2026 May 20. 22143602261432401

Nucleoside therapy for thymidine kinase 2 deficiency: Long-term outcomes from a Brazilian cohort.

Cristiane Araujo Martins Moreno, Tatiana Ribeiro Fernandes, Clara Gontijo Camelo, Gabriel Keller, Filipe Di Pace, Gabriella Corrêa Dousseau, Alulin Tácio Quadros Santos Monteiro Fonseca, Eliene Dutra Campos, Ana Paula Dos Anjos Lança, Mariana Cunha Artilheiro, André Macedo Serafim da Silva, Michelle Abdo Paiva, Andres Nascimento, Edmar Zanoteli.

  BackgroundThymidine Kinase 2 deficiency (TK2d) is a rare, mitochondrial DNA (mtDNA) depletion/deletions syndrome leading to a severe and progressive myopathic disorder. Nucleoside supplementation (deoxythymidine and deoxycytidine) has been shown to favorably alter the disease's course, particularly in severe infantile-onset cases. Long-term data on efficacy and safety, especially in the adult patient population, remain limited.MethodsThis is a retrospective, long-term follow-up study of 14 TK2d patients (five children and nine adults with childhood-onset disease) treated with nucleosides. Patients were systematically evaluated over a period ranging from 9 to 36 months, with assessments conducted every 3 months during the first year of treatment, and every 6 months thereafter. Comprehensive functional assessments of motor, respiratory, and bulbar function were performed. Periodic measurements of liver and pancreatic function monitored safety and tolerability.ResultsAll 14 TK2d patients showed beneficial effects across motor, respiratory, and bulbar function domains. Among pediatric patients, a rapid treatment response was observed early on, with functional gains sustained and continuing beyond 12 months of therapy. Adults experienced substantial improvements in motor and respiratory capacity but most of them reported severe gastrointestinal symptoms. Liver and pancreatic enzymes abnormalities were noticed mainly in adults.ConclusionsDeoxythymidine and deoxycytidine were found to be safe and beneficial in this long-term cohort of TK2d patients, but elevation in liver and pancreatic enzymes were present and required regular monitorization. This study provided valuable evidence supporting this therapy as an effective and safe, long-term disease-modifying treatment option for both pediatric and adult patients.

Keywords:  Mitochondrial Myopahty; TK2 deficiency; deoxythymidine and deoxycytidine; mtDNA depletion syndrome; nucleosides therapy

DOI:  https://doi.org/10.1177/22143602261432401
Sci Rep. 2026 May 18.

Mavodelpar in patients with primary mitochondrial myopathy: a phase 1 trial.

Renae J Stefanetti, Chiara Pizzamiglio, Alasdair P Blain, Oliver M Russell, Lisa Alcock, Gavin Hudson, Jane Newman, Naomi Thomas, Charlotte Warren, Huizhong Su, Helen A L Tuppen, Philip Brown, David Houghton, Heather Hunter, Albert Z Lim, Yi Shiau Ng, Catherine Feeney, Iwona Skorupinska, Louise Germain, Enrico Bugiardini, Michael G Hanna, Robert McFarland, Robert D S Pitceathly, Gráinne S Gorman.

  Primary mitochondrial myopathies (PMM) are rare, genetically-defined disorders characterised by defects of oxidative phosphorylation, predominantly affecting skeletal muscle. This Phase 1b open-label trial evaluated mavodelpar, a selective peroxisome proliferator-activated receptor delta (PPARδ) agonist, over 12 weeks (Part A), with an optional 36 week extension (Part B) in adults with PMM. The primary objective was to assess safety and tolerability, with secondary assessments of pharmacokinetics, pharmacodynamics, and exploratory performance, patient-reported, and muscle biopsy outcomes. Of the 23 participants who received mavodelpar, 17 completed Part A; none completed Part B due to premature study termination during the COVID-19 pandemic. Adverse events were mild-moderate severity, with headache and constipation most common (4/23 participants; 17.4% each). Exploratory measures showed a mean increase of 104 m in the twelve minute walk test (95% CI: 53 to 156) and a mean reduction of -10.5 points in patient-reported fatigue (95% CI: -16.3 to -4.6). No consistent changes in mitochondrial function were detected in muscle biopsies (n = 10), while transcriptomic profiling (n = 6) revealed modest upregulation of fatty acid-metabolism pathways. Although findings from this Phase 1b trial supported progression to later-phase evaluation, the subsequent Phase 2b trial did not demonstrate clinical efficacy for mavodelpar. The results reported here should be interpreted as exploratory and not indicative of therapeutic benefit. Nevertheless, this Phase 1b trial provides important methodological insights to inform future PMM clinical trial design and outcome measure development.

Keywords:  Mitochondrial disease; Mitochondrial myopathy; Outcome measures; Peroxisome proliferator-activated receptor delta (PPARδ) agonist; Phase 1 trial; Rare disease

DOI:  https://doi.org/10.1038/s41598-026-43287-0
Acta Biochim Biophys Sin (Shanghai). 2026 May 11.

Fabrication of fusogenic and magnet-responsive cells for transplantation of an intact mitochondrial network.

Liqun Xu, Xiao Li, Xing Fan, Wei Yan, Wanfei Wu, Junwei Li, Ronghao Deng, Haibao Zhu, Aihua Mao, Pingnan Sun, Xin Zhang, Wencan Xu, Chi-Ju Wei.

  Mitochondrial transplantation is a promising treatment for many diseases associated with mitochondrial defects or aging; however, a reliable method for mitochondrial transfer remains urgently needed. In this study, we assemble fusogenic and magnet-responsive cells (FMRCs), which are enucleated stem cells loaded with Fe 3O 4 nanoparticles and further incorporated fusogenic vesicular stomatitis virus glycoprotein G (VSV-G). Mitochondrial transplantation from FMRCs via fusion in the presence of a magnetic force restores normal mitotic activity, mitochondrial membrane potential, ROS levels and ATP production in cells subjected to partial mtDNA depletion or in cybrids harboring mtDNA with a 4977-bp deletion. SNP tracing and qPCR analysis of the mitochondrial and nuclear genomes unequivocally demonstrate that exogenous mitochondria are able to reside stably and predominately. Mitochondrial transplantation stimulate autophagy and thus the clearance of defective endogenous counterparts, resulting in lower mtDNA heteroplasmy. These results suggest that FMRCs are excellent vehicles for mitochondrial transplantation and could be used for the treatment of aging and mitochondria-associated diseases.

Keywords:  143B cell; SNP analysis; VSV-G; autophagy; cell fusion; fusogenic and magnet-responsive cell; mitochondrial transplantation

DOI:  https://doi.org/10.3724/abbs.2026031
Value Health. 2026 May 15. pii: S1098-3015(26)02425-3. [Epub ahead of print]

How much change is meaningful in global impression anchors? Evidence from five rare diseases.

Courtney Hurt, Maja Kuharic, Somayeh Hashemi, Eloise Salmon, Sonya Eremenco, David Cella, Karen Kaiser, Chelsea Perschon, Sara Shaunfield, John Devin Peipert.

   OBJECTIVES: Rare diseases pose methodological challenges in determining meaningful change thresholds for clinical outcome assessments (COAs) due to small sample sizes and disease heterogeneity. This paper presents qualitative approaches for establishing patient-informed meaningful change thresholds on global impression anchor measures for rare diseases.
METHODS: Two FDA-funded studies employed novel cognitive debriefing methods to determine within-patient meaningful change on custom-developed anchors. NUCOAT debriefed Patient Global Impression of Severity (PGIS) and Change (PGIC) anchors referencing 5 physical function performance outcomes (PerfOs) with 34 adults with idiopathic pulmonary fibrosis, systemic sclerosis, or myositis. Prepare-NS developed swelling-related patient-reported outcome (PRO) and observer-reported outcome (ObsRO) measures for nephrotic syndrome using PGIS/PGIC and Observer Global Impression of Severity (OGIS)/Change (OGIC) anchors with 12 patients and 8 caregivers.
RESULTS: Qualitative anchor debriefing proved feasible across rare disease populations and COA types. Though many participants identified smaller (e.g., 1-category) changes as meaningful, there was strong variation by anchor type and disease group. Anchors focusing on severity (vs. impact) tended to require larger changes to be meaningful. In Prepare-NS, most PRO participants and all caregivers viewed "No change" after 3 months of hypothetical treatment negatively. In NUCOAT, some participants experienced cognitive difficulties with PerfO anchors, struggling to translate objective metrics into meaningful impact.
CONCLUSIONS: Qualitative methods can provide patient-informed meaningful change thresholds on global impression anchors, although patients may struggle to identify meaningful change for performance anchors. Nonetheless, qualitative patient-informed thresholds can inform quantitative COA interpretation and strengthen endpoint development and regulatory dialogue in rare disease clinical trials.

Keywords:  Meaningful change; anchor-based methods; clinical outcome assessments; patient-reported outcomes; qualitative methods; rare diseases

DOI:  https://doi.org/10.1016/j.jval.2026.04.012
Hum Reprod Update. 2026 May 22. pii: dmag013. [Epub ahead of print]

Sperm mitochondrial DNA copy number: a marker of male fertility and reproductive success.

Savni Sawant, Jeffrey M Mann, J Richard Pilsner.

   BACKGROUND: Sperm mitochondrial DNA copy number (mtDNAcn) has emerged as a promising biomarker of sperm health, providing molecular insight beyond what is captured by standard semen analysis. Elevated sperm mtDNAcn has been consistently associated with lower sperm motility, concentration, and morphology, as well as prolonged time-to-pregnancy in natural conception and reduced fertilization potential in ART.
OBJECTIVE AND RATIONALE: This review summarizes current evidence on the biological underpinnings of sperm mtDNAcn, including its regulation during spermatogenesis, the role of nuclear-encoded mitochondrial proteins such as TFAM (mitochondrial transcription factor A), and its potential epigenetic modulation through sperm DNA methylation. We evaluate general population and clinic-based studies linking sperm mtDNAcn to semen quality, couple fecundity, and early embryo development, while highlighting methodological considerations such as quantification techniques and somatic cell contamination.
SEARCH METHODS: A literature search was conducted to identify human studies evaluating sperm mtDNAcn in relation to male fertility, semen quality, reproductive outcomes, and embryology outcomes, as well as experimental models investigating the underlying biological mechanisms of mtDNA regulation during spermatogenesis via TFAM up to 1 April 2026. Searches were performed in PubMed, Web of Science, and Scopus using combinations of keywords and Medical Subject Headings (MeSH), including sperm mitochondrial DNA copy number, mtDNAcn, male infertility, pregnancy outcomes, ART outcomes, semen quality, sperm epigenetics, TFAM, mitochondrial transcription factor A, and sperm mtDNA regulation. Reference lists of relevant reviews and primary articles were manually screened to identify additional studies. Eligible studies included observational epidemiologic studies, clinical cohort studies, and experimental investigations that quantified sperm mtDNAcn and examined associations with semen parameters, fertility outcomes, or sperm epigenetics. No restrictions were placed on geographic location, while only articles published in English were considered.
OUTCOMES: Across 21 epidemiologic, experimental, and clinical studies, elevated sperm mtDNAcn has been consistently associated with reduced sperm quality and inconsistently associated with diminished couple-level reproductive potential. Higher mtDNAcn is associated with lower sperm concentration, total sperm count, motility, and normal morphology, as well as higher sperm DNA fragmentation and chromatin abnormalities. It has also been linked to reduced likelihood of pregnancy and poorer embryo quality. Emerging evidence indicates associations between sperm mtDNAcn and altered nuclear DNA methylation patterns, supporting a role for mitochondrial-nuclear crosstalk. Collectively, these findings position sperm mtDNAcn as a biologically informative and clinically relevant indicator of male reproductive health that may complement, or potentially enhance, traditional semen analysis in both research and clinical settings.
WIDER IMPLICATIONS: Sperm mtDNAcn holds promise as a biomarker for male fertility assessment, yet its full clinical potential has not been yet to be realized. Establishing standardized measurement protocols across sperm fractions and laboratory platforms will be essential for enabling cross-study comparability and facilitating clinical translation. Large prospective studies are needed to define clinically meaningful thresholds and better characterize the relationship between mtDNAcn alterations and spermatogenic impairment. Intervention strategies targeting mtDNA biogenesis and depletion, including antioxidant strategies and mitochondria-directed pharmacotherapy, warrant further investigation in the context of male fertility and fecundity. Collectively, sperm mtDNAcn may serve as an adjunctive marker in the assessment of male reproductive health and may inform future precision medicine approaches.
REGISTRATION NUMBER: N/A.

Keywords:  TFAM; male infertility; mtDNA dysfunction; sperm mitochondrial DNA copy number; spermatogenesis

DOI:  https://doi.org/10.1093/humupd/dmag013
Annu Rev Genomics Hum Genet. 2026 May 21.

Experimental and Computational Approaches to Identify Noncoding Pathogenic Variation in Rare Disease.

Laura E Covill, Lindsay Romo, Anne O'Donnell-Luria.

Noncoding variants occur within noncoding genes as well as within the regulatory nontranslated regions of protein-coding genes. It is important to be aware that these variants have been increasingly implicated in developmental disease through a variety of mechanisms. However, they remain difficult to interpret clinically due to their unclear effect on transcript or protein abundance compared with coding variants. Here, we review methods to identify pathogenic noncoding variants in rare disease, which can present challenges due to the inaccessibility of disease-relevant tissue for many conditions. We explore experimental approaches such as high-throughput functional assays, omic data integration, and long-read sequencing. We also review computational methods for annotating and filtering variants, as well as machine learning methods for predicting variant effect and pathogenicity. We discuss the recent discovery of several developmental syndromes caused by noncoding variants and propose an integrated approach to identifying pathogenic noncoding variants within this patient cohort.

DOI: https://doi.org/10.1146/annurev-genom-111124-024627
Stud Health Technol Inform. 2026 May 21. 336 2489-2490

Utilizing Routine Care Data of Rare Diseases: Challenges, Chances and Call for Collaboration.

Miriam Hübner, Marco Schaarschmidt, Harisa Muratovic, Claudia Finis, Elisabeth Nyoungui, Dagmar Krefting, Jana Zschüntzsch, Josef Schepers, Richard Röttger.

  Approximately 300 million people are living with a rare disease (RD) worldwide. Despite this significant health burden, the prevalence of many RDs is underestimated due to the limited specificity of standard coding systems such as the International Classification of Diseases, 10th Revision (ICD-10), which assigns broad codes to many RDs, hindering precise epidemiological analyses. The precise naming and coding of RDs using terms and identification numbers from the Orphanet Rare Disease Ontology (ORDO) is increasingly being used in Germany and across Europe. This poster highlights ongoing efforts in identifying the challenges and chances in enhancing routine care data for secondary use with the purpose of improving RD visibility and epidemiological understanding, helping to pave the way for the European Health Data Space in the field of RD.

Keywords:  Epidemiology; Rare disease studies; Rare diseases; Routine care data

DOI:  https://doi.org/10.3233/SHTI260722
Neural Regen Res. 2026 Sep 01. 21(9): 3964-3976

When copper turns killer: Decoding copper dyshomeostasis and cuproptosis in neurodegenerative pathogenesis and precision metal interventions.

Wei Du, Tingyao Wu, Yonggang Fan, Min Zhao.

  Copper is an essential cofactor for neuronal metabolism, enzymatic functions, and neurotransmission. However, copper dyshomeostasis-induced redox activity makes the brain vulnerable to oxidative and proteostatic stress. Cuproptosis, a recently characterized form of programmed cell death, is triggered by copper binding to lipoylated enzymes of the tricarboxylic acid cycle, resulting in proteotoxic stress, mitochondrial dysfunction, and cell death. Given that mitochondria are central to copper handling and the primary site of cuproptosis, we examine mitochondrial pathways and key cuproptosis-related genes. We also assess disease-specific signatures of copper imbalance. In Alzheimer's disease, excess copper binds to amyloid-β, promoting aggregation and neurotoxicity. In Parkinson's disease, copper-bound α-synuclein fosters aggregation, while copper-driven redox cycling elevates reactive oxygen species. Cuproptosis worsens mitochondrial vulnerability in Parkinson's disease and impairs cellular stress responses in Huntington's disease. In amyotrophic lateral sclerosis, superoxide dismutase 1-related defects compromise antioxidant defenses alongside copper-dependent mitochondrial dysfunction. In prion diseases, copper facilitates prion protein misfolding and toxicity. Across these disorders, common features include mitochondrial dysfunction and cuproptosis hallmarks-such as enhanced protein lipoylation, elevated reactive oxygen species, impaired electron transport chain activity, fragile Fe-S clusters, and increased reliance on the tricarboxylic acid cycle-which collectively increase neuronal susceptibility to copper dyshomeostasis. Clarifying and understanding the critical roles of copper metabolism not only elucidates the pathogenesis of neurodegenerative diseases but also offers alternative therapeutic strategies. This review uniquely integrates the mitochondria-centered cuproptosis axis with copper dyshomeostasis across Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases, mapping convergent vulnerabilities to mechanism-grounded interventions and outlining testable translational routes.

Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; copper homeostasis; cuproptosis; mitochondrial dysfunction; neurodegenerative disease; prion diseases

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00808
Cell Struct Funct. 2026 May 15.

Metformin attenuates cuprizone-induced mitochondrial dysfunction and senescence-associated changes in primary neuronal cells.

Yeojin Kim, Hyunbum Jeon, Sunyoung Kwon, Sehyun Chae, Ji Young Mun.

  Mitochondrial dysfunction and cellular senescence are key features of brain aging and neurodegenerative diseases. Cuprizone (CPZ), a mitochondrial toxin, induces oxidative stress, abnormal lipid metabolism, and iron accumulation in neurons and oligodendrocytes. Here, we investigated whether metformin (MFN), an AMPK activator with a known safety profile, can protect against CPZ-induced mitochondrial and senescence-like changes. Using confocal and transmission electron microscopy, we observed mitochondrial enlargement, increased reactive oxygen species (ROS) production, iron accumulation, and lipofuscin formation in CPZ-treated primary neuronal cultures. Next, we assessed the impact of MFN on mitochondrial changes and increase of lipid-radicals in cells exposed to CPZ. The treatment of MFN resulted in a decrease of abnormal mega-mitochondrial morphology, levels of mitochondrial reactive oxygen species (mitoROS), and accumulation of iron within the mitochondria. Moreover, MFN treatment prevented the typically observed increases in lipofuscin and lipid radicals in CPZ-affected cells. Analysis of gene expression in primary neuronal cells treated with CPZ showed differences in mitochondria-related genes linked to lipid peroxidation, oxidative stress, and cellular senescence. These findings suggest that MFN mitigates mitochondrial dysfunction and senescence-associated alterations, highlighting its therapeutic potential in aging-related neurodegeneration.Key words: mitochondria, CPZ, MFN, oxidative stress, lipofuscin.

Keywords:  CPZ; MFN; lipofuscin; mitochondria; oxidative stress

DOI:  https://doi.org/10.1247/csf.26019
J Biol Chem. 2026 May 20. pii: S0021-9258(26)02046-6. [Epub ahead of print] 113174

Higher-order structural organization of mitochondrial metabolism.

Greg Kafetzopoulos, Jonas Döbler, Panagiotis L Kastritis.

  The mitochondrion embeds numerous metabolic, biosynthetic, and signaling pathways occurring within its specialized compartments that collectively define eukaryotic biology. To visualize these, cryogenic electron microscopy (cryo-EM) is now utilized, particularly for resolving biomolecular complexes that were notoriously hard to study with other structural methods. Our review synthesizes recent cryo-EM-based discoveries, analyzes structures related to mitochondrial metabolism and explains related functional aspects of core energy metabolism, biosynthetic processes, transport and regulatory systems. We report on recent data on mitochondrial enzyme filamentation, higher-order metabolons, enzyme gating mechanisms, and contact-site nanostructures. In addition to single-particle cryo-EM results, we discuss emerging in situ cryo-tomography data, the integration of traditional structural biology approaches, and the use of in silico models for less-studied pathways. By mapping hundreds of recent mitochondrial structures, we provide a roadmap that connects structural biochemistry with cell physiology disclosing the molecular basis of mitochondrial disease. Our collected resource may guide future integrative research aiming to elucidate mitochondrial architecture and function across organisms and conditions.

Keywords:  conformational landscape; dynamic protein complexes; filamentous enzyme regulation; integrative structural modeling; lipid-protein interactions; metabolic modularity; mitochondrial metabolons; scaffolding; structural and molecular biology; supramolecular assemblies

DOI:  https://doi.org/10.1016/j.jbc.2026.113174
Transl Pediatr. 2026 Apr 30. 15(4): 161

Living donor liver transplantation in a pediatric patient with mitochondrial DNA depletion syndrome caused by two novel POLG1 mutations: a case report and literature review.

Yanhao Li, Fuxiao Xie, Lin Wei, Zhijun Zhu.

   Background: Mitochondrial DNA depletion syndrome (mtDDS) is a rare genetic disorder caused by mutations in nuclear genes responsible for mitochondrial DNA maintenance, most notably POLG1. The disease is characterized by diverse clinical manifestations, including myopathy, hepatopathy, and neurological deficits. Due to its phenotypic heterogeneity, diagnosing mtDDS in pediatric populations remains a significant clinical challenge, often leading to delays in life-saving interventions.
Case Description: We report the case of an 11-month-old male infant presenting with acute liver failure and recurrent hypoglycemia. Laboratory findings revealed elevated liver enzymes, jaundice, and persistent metabolic distress. Notably, the patient lacked the neurological symptoms typically associated with POLG1 mutations, complicating the initial clinical picture. Genetic analysis via whole exome sequencing (WES) identified two novel compound heterozygous mutations in the POLG1 gene (695G>A and 1735C>T), confirming the diagnosis of mtDDS. Following the diagnosis, the patient underwent a successful liver transplantation, which resulted in significant clinical stabilization and improved quality of life.
Conclusions: This case expands the known mutational spectrum of the POLG1 gene and highlights an atypical presentation of mtDDS isolated to hepatic dysfunction. Our findings underscore the critical importance of early genetic testing, such as WES, in infants with unexplained liver failure or metabolic crises. Timely diagnosis is essential to guide surgical interventions like liver transplantation, which can effectively improve outcomes. Clinicians should maintain a high index of suspicion for underlying mitochondrial genetic defects in pediatric hepatopathy to facilitate early intervention and long-term management.

Keywords:  Mitochondrial DNA depletion syndrome (mtDDS); POLG1 gene mutation; case report; liver dysfunction; living donor liver transplantation (LDLT)

DOI:  https://doi.org/10.21037/tp-2025-1-883
Sci Rep. 2026 May 21.

A global survey of systems biology-based predictions of gene-rare disease associations to enhance new diagnoses.

Yolanda Benítez, Graciela Uría-Regojo, Pablo Mínguez.

  In rare disease diagnosis, described genotype-phenotype associations are evaluated first. In the absence of strong evidence, WES and WGS provide hundred to million other genetic variants, most poorly annotated, that need to be prioritized. While several in silico approaches leverage existing gene-disease knowledge to predict novel associations, doing so in isolation can hide how different genes are represented across other predictions. We hypothesize that a global perspective, accounting for differences in the knowledge accumulated in the gene collections, can refine predictions. Using a network-based algorithm, we explored functional neighborhoods of known disease-associated genes to predict novel candidates for over 200 rare and other Mendelian diseases. A global analysis of gene and protein family behavior across predictions identified genes and functions broadly associated with multiple conditions, 192 genes linked to a single disease and 251 genes functionally associated with specific classes of genetic diseases. These findings are integrated into a gene-disease specificity score, aimed at enhancing variant prioritization and guiding geneticists in advancing candidate genes toward functional validation.

Keywords:  Candidate gene prediction; Genetic diagnosis; Network biology; Rare diseases; Sequencing; Variant prioritization

DOI:  https://doi.org/10.1038/s41598-026-54510-3
Brief Bioinform. 2026 May 04. pii: bbag245. [Epub ahead of print]27(3):

The next paradigm in bioinformatics: a review of multi-agent systems and foundational models for end-to-end scientific discovery.

Francesco Branda, Mohamed M Ahmed, Massimo Ciccozzi, Pietro Hiram Guzzi, Fabio Scarpa.

  Bioinformatics is entering a new phase characterized by the integration of universal biological models and multi-agent systems to enable end-to-end scientific discoveries. This review argues that the next paradigm shift will go beyond traditional predictive models and generative artificial intelligence (AI) toward agentic AI: systems capable of planning, acting through tools, reflecting on results, and iterating until a goal is achieved. We first examine recent foundational models that produce transferable representations across omic modalities, such as scGPT, Nicheformer, and EpiAgent, and discuss their architectural choices, training regimes, and interpretability constraints. We then analyze biomedical agent frameworks through their main components (planning, action, reflection, and memory), highlighting representative systems such as ClinicalAgent and Biomni that operationalize these ideas in controlled environments. Next, we focus on hypothesis validation mechanisms, including retrieval-augmented generation for evidence grounding, sequential statistical testing, and benchmarking methodologies designed to quantify robustness and reproducibility. Finally, we summarize emerging applications in drug discovery and personalized medicine, from molecular literature analysis and protocol automation to drug repurposing for rare diseases and closed-loop synthesis. We conclude by outlining the main challenges ahead, namely hallucinations, interpretability, systemic biases, integration with clinical infrastructures, and regulatory and ethical requirements, and propose a roadmap for the development of scientific agents that are not only high-performing but also reliable, verifiable, and implementable in real biomedical contexts.

Keywords:  agentic AI; drug discovery; foundation models; multi-agent systems; personalized medicine; retrieval-augmented generation (RAG)

DOI:  https://doi.org/10.1093/bib/bbag245
Cell Chem Biol. 2026 May 21. pii: S2451-9456(26)00147-9. [Epub ahead of print]33(5): 591-593

"SelO"ective NAD+ hydrolysis regulates mitochondrial NAD+ and homeostasis.

Qing Zhang, Trina Chia Min Tan, Vincenzo Sorrentino.

Nicotinamide adenine dinucleotide (NAD+) is a metabolic redox cofactor whose compartmentalization in mitochondria is crucial for cellular function; however, its regulation mechanisms are largely unknown. In a recent Cell publication, Jia et al.1 uncover that the enzyme SelO catalyzes mitochondrial NAD+ hydrolysis to regulate β-oxidation and maintain mitochondrial and liver homeostasis.

DOI: https://doi.org/10.1016/j.chembiol.2026.04.012
Eur J Hum Genet. 2026 May 19.

Patients offered genomic testing for rare disease and cancer: a real-world evaluation of impact and processes of care.

Melissa Martyn, Ling Lee, Emily Forbes, Anaita Kanga-Parabia, Callum McEwan, Rigan Tytherleigh, Alli Jan, Ella Lynch, Ivan Macciocca, Clara Gaff.

Robust evidence is required to support decision-making about incorporating genomics into healthcare; patient perspectives are crucial. Prior studies centre on people giving research consent for testing, yet significant differences between research and clinical cohorts are well established. We investigated 1690 patients offered genomic testing during clinical care by a range of medical specialists, for rare diseases and cancer. Ninety per cent (1515) accepted testing. Of 74 decliners providing their reasons, 20 gave genomic-specific concerns. Impact and experiences of care were captured using surveys after consent (S1:RR 73%) and return of results (S2:RR 53%). We actively included those often missing from research, e.g. 8% of S2 respondents accepted telephone assistance - typically with interpreters - to complete surveys. Those who spoke English as an additional language were less likely to have received enough information at pre-test counselling (88% v 96%) and less likely to correctly answer questions about potential genomic test results. After receiving results, 10% (52/534) of respondents had moderate-high decision regret; predictors included English as an additional language and not receiving enough information at consent. Value from testing was quantified and compared: those with informative results valued their medical and personal utility; those with uninformative results derived social utility. Perceived personal control increased post-result for those with diagnostic results and decreased for those with uninformative results. Our results expand the evidence base available for genomic health technology assessment. On balance, genomic test results provide more value than harm, but equity issues need to be addressed to ensure all patients can benefit.

DOI: https://doi.org/10.1038/s41431-026-02138-2
Bioact Mater. 2026 Oct;64 324-358

Hit the bull's eye: Engineered extracellular vesicles for targeted therapy.

Yijin Cai, Hengjing Zhang, Xinao Fan, Haojie Fu, Haiyan Li, Xiaoling Fu, Xudong Wang, Changyong Yuan, Kaili Lin, Yu Zhuang.

  Extracellular vesicles (EVs) are nanoscale vesicles secreted by most cell types and have a similar composition to their parent cells. By delivering effector molecules, EVs serve as mediators of intercellular communication and hold significant therapeutic potential. However, challenges such as uncertain in vivo biodistribution and the risk of adverse reactions in non-target tissues still limit their broader clinical translation. Recent studies increasingly demonstrate that EVs can be engineered to target pathological tissues, thereby enhancing their specificity and therapeutic efficacy across various diseases. This review first outlines the biogenesis, composition, trafficking, cellular uptake, and biological functions of EVs, followed by a description of their natural biodistribution patterns, emphasizing how molecular heterogeneity contributes to natural targeting. We then discuss engineering strategies for EV targeting, comparing their advantages, limitations, and industrial feasibility. Subsequently, we examine how organ-specific microenvironment influences targeting efficiency of engineered EVs and summarize their applications in targeted therapy across various organs and tissues. Finally, the major challenges and future directions for the clinical translation of engineered EVs in targeted therapy are highlighted.

Keywords:  Clinical translation; Engineering strategies; Extracellular vesicles; Targeted therapy

DOI:  https://doi.org/10.1016/j.bioactmat.2026.04.035
Orphanet J Rare Dis. 2026 May 18. pii: 202. [Epub ahead of print]21(1):

Access to orphan drugs in adults with inherited metabolic diseases in Switzerland: a single-center retrospective cohort study.

Giovanni De Antoni, Camille Kumps, Jérôme Berger, Jasmin Barman-Aksözen, Christel Tran.

   BACKGROUND: Orphan drugs (ODs) are increasingly used to treat rare diseases, including inherited metabolic diseases (IMDs), but real-world access remains insufficiently characterized. This study aimed to evaluate access to ODs in adults with IMDs treated at a Swiss reference center and to analyze the associated regulatory and reimbursement frameworks.
METHODS: In this retrospective, single-center study conducted between 2017 and 2022, we included all adult patients with a confirmed biochemical and/or genetic diagnosis of an IMD who received an OD. The primary outcome was the proportion of patients receiving OD therapy. Secondary outcomes included the types of ODs used, reimbursement procedures, time from treatment indication to treatment initiation, timelines in Swiss marketing authorization (MA) and reimbursement compared with international benchmarks.
RESULTS: Of 190 patients followed, 41 (21.6%) had an indication for OD therapy and 39 (20.5%) received treatment (median age 30.3 years, range 19-65). Seventeen different ODs were prescribed. The median time from treatment indication to treatment initiation was 1.0 month [IQR 0.6-2.6] but was longer for drugs without Swiss MA (Art. 71c OAMal: 6.5 months [IQR 2.5-11.9]). Swissmedic MA occurred a median of 1.9 years [IQR 1.5-2.7] after approval by other international regulators. Three patients were the first adults in Switzerland to access novel substances (olipudase alfa, pegvaliase, metreleptin), and one received the newly approved formulation of nitisinone.
CONCLUSION: In this cohort from a specialized adult metabolic clinic, most patients with an indication for OD therapy accessed treatment. However, administrative burden, fragmented reimbursement procedures, and regulatory delays may still affect timely treatment initiation in certain situations. These findings highlight the need for continued efforts to streamline regulatory and reimbursement pathways and to ensure equitable access to innovative therapies for rare diseases.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT05818566, registered 18 April 2023.

Keywords:  Inherited metabolic diseases; Orphan drugs; Therapies

DOI:  https://doi.org/10.1186/s13023-026-04367-6
Acta Microbiol Immunol Hung. 2026 May 21. pii: 030.2026.02808. [Epub ahead of print]

Gut microbiota: The hidden hallmark of aging.

Kimaya Kaushik, Mihir Sharma, Ritik Sharma, Asif Reza, Geetansh Sharma, Saetukrit Panwar, Rupak Nagraik, Poonam Negi, Avinash Sharma.

  Aging is the natural process of changes that are accumulated over time and are responsible for the ever-increasing susceptibility to diseases and death. Extensive research has been done to understand the role of gut microbiota in aging, however, limited progress has been made. Thus, considering the need of the hour we have tried to give a new perspective to this body of research by delving deep into all major factors that are associated with gut microbiome and aging. This review presents a holistic view of the relation between gut microbiome and aging starting from hallmarks of aging and evolution of gut microbiome over lifespan to intricate mechanisms like inflammaging, immunosenescence, gut-brain axis, mitochondrial dysfunction, nutrient imbalance and cardiac implications. In addition, it highlights different therapies like fecal microbiota transplantation, omics and metabolomics studies, and gut modulation therapies that show a promising future towards regulation of gut microbiota for aging interventions. More importantly, this review is an addition to the existing literature which advocates gut microbiome as an additional hallmark of aging, summarising the known status of the research in this field, contributing to developing gut microbiota targeted healthy aging.

Keywords:  aging; gut microbiome; gut microbiota-associated aging; hallmarks of aging; senescence

DOI:  https://doi.org/10.1556/030.2026.02808
Bioorg Med Chem. 2026 May 13. pii: S0968-0896(26)00159-8. [Epub ahead of print]139 118703

PROTACs for central nervous system disorders: challenges and opportunities.

Na Zheng, Jikuan Shao, Baichen Xiong, Yuqing Wei, Xiaolong Wang, Yang Zhou, Zuoaoyun Song, Ao Zhang, Chunlei Xu, Qun Zhao, Yulan Wu, Zongliang Liu, Yao Chen, Haopeng Sun.

  Central nervous system (CNS) disorders, particularly neurodegenerative diseases and brain tumors, pose substantial and long-standing challenges to the global public health system. Current therapeutic approaches for CNS disorders are primarily confined to symptomatic relief and generally fail to halt or reverse disease progression. However, proteolysis-targeting chimeras (PROTACs), as an emerging therapeutic strategy, have introduced new prospects for effective intervention in this domain. Although several studies have demonstrated the use of PROTACs in degrading pathogenic proteins associated with CNS disorders, their clinical translation remains hindered by multiple challenges, including insufficient degradation efficiency, potential off-target toxicity, and limited blood-brain barrier (BBB) permeability. In response to the above challenges, researchers are actively pursuing various strategies-ranging from structural optimization of PROTACs to enhance their degradative activity, to the implementation of novel nano-delivery systems and targeted delivery approaches to improve BBB permeability and tissue selectivity. These strategic advancements have demonstrated significant potential in preclinical research for the treatment of CNS disorders. This review provides a comprehensive overview of the research and development of various PROTACs targeting CNS disorders, and highlights potential application strategies for advancing protein degrader therapeutics in the CNS field. By synthesizing current advances and challenges, it offers researchers in related disciplines a well-defined theoretical framework and forward-looking strategic guidance, thereby facilitating in-depth investigation and transformative applications in this rapidly evolving domain.

Keywords:  BBB permeability; Central nervous system disorders; New technologies; Proteolysis-targeting chimeras; Targeted protein degradation

DOI:  https://doi.org/10.1016/j.bmc.2026.118703
Ann Clin Transl Neurol. 2026 May 22.

A Two-Stage Questionnaire and Actigraphy Screening for iRBD in a Multicenter Retrospective Cohort.

Caleb A Massimi, Giorgio Ricciardiello Mejia, Andre Metzger, Kang Hyun Ryu, Salonee Marwaha, Eva Grzegorczyk, Li Zhou, Eliana Jacobs, Boris Gilyadov, Claudia Kunney, Liqhwa Ncube, Ankit Parekh, Emmanuel Mignot, Fanny M Elahi, Joseph Winer, Kathleen Poston, Andreas Brink-Kjaer, Emmanuel H During.

   OBJECTIVE: Isolated rapid-eye-movement sleep behavior disorder is a prodromal marker of synucleinopathies. However, most cases remain undiagnosed due to the insufficient predictive value of questionnaires and limited access to confirmatory video-polysomnography. We assessed a two-stage screening strategy combining a brief questionnaire on rapid-eye-movement sleep behavior disorder symptoms and other prodromes with wrist actigraphy across multiple case-control cohorts.
METHODS: Participants aged 40-80 without neurodegenerative disease were recruited from five cohorts; all cases were confirmed by video-polysomnography. The questionnaire was administered to 289 participants, and 236 underwent ≥ 14 nights of home wrist actigraphy. The wearable-based algorithm was built on four movement features (mean motor activity, activity index, short or long immobile bouts, twitch activity). Models were trained with nested cross-validation using XGBoost.
RESULTS: The full retrospective cohort included 396 participants (99 cases, 297 controls; mean age 64 ± 11; 55% male). The dream enactment question alone achieved an area under the curve of 0.85, which improved to 0.86 using the four-item questionnaire. Actigraphy alone achieved 82% sensitivity and 84% specificity. In the subgroup completing both assessments (75 cases, 54 controls), the two-stage protocol-questionnaire followed by actigraphy-yielded 68% sensitivity and 100% specificity using the dream enactment question alone, and 73% sensitivity and 100% specificity using the four-item questionnaire.
INTERPRETATION: A two-stage protocol combining questionnaire and actigraphy demonstrated high specificity and good sensitivity for detecting isolated rapid-eye-movement sleep behavior disorder in this multicenter cohort. This low-cost, scalable strategy is compatible with widely used wearable devices and warrants validation in community-based populations.

Keywords:  actigraphy; machine‐learning; questionnaire; rapid‐eye‐movement sleep behavior disorder; screening; wearable devices

DOI:  https://doi.org/10.1002/acn3.70439
Biosystems. 2026 May 20. pii: S0303-2647(26)00128-0. [Epub ahead of print]265 105818

Stress-triggered cell elimination stabilizes resource-limited cell collectives: An agent-based model.

Bertan Korkmaz.

  Mitochondria, long regarded as the cell's "powerhouses", also serve as intracellular quality-control modules that promote the elimination of damaged or proliferatively dysregulated cells. Alongside their energetic benefits, mitochondrial apoptosis regulation may have helped shape the earliest steps toward stable multicellular organization. An agent-based modeling framework is developed to isolate and quantify the evolutionary impact of a mitochondrial death-surveillance system under nutrient stress, independently of its energetic contribution. The model tracks two cell types - normal prokaryotic cells (NPCs) and dysfunctional prokaryotic cells (DPCs) - each characterized by three dynamic state variables: damage load, proliferation drive and energy deficit. Mitochondrial surveillance is formalized as a simplified rule that detects stress and eliminates dysfunctional cells when a critical dysregulation boundary is crossed. Across 1200 stochastic simulations spanning variable nutrient regimes and inoculum sizes, mitochondrial surveillance prolonged median colony-collapse time by approximately 17%-18% across both nutrient regimes. The results indicate that a mitochondria-linked, intrinsic apoptosis-like gate can stabilize simple microbial groups independently of bioenergetic benefit, and is consistent with the view that such quality-control mechanisms provided a selective advantage toward robust multicellular organization. The framework also provides a conceptual basis for viewing mitochondrial transplantation as a means to restore intracellular fate-decision control, rather than solely to augment energy supply, in settings such as aging and cancer.

Keywords:  Agent-based modeling; Apoptosis; Endosymbiosis; Mitochondria; Multicellularity

DOI:  https://doi.org/10.1016/j.biosystems.2026.105818
Quant Imaging Med Surg. 2026 May 01. 16(5): 361

Cerebral vasodilation and lesion patterns in stroke-like episodes of MELAS: a quantitative angiographic investigation.

Kwanju Song, Myung Ki Yoon, Wookjin Yang, Jun Young Chang, Dong-Wha Kang, Sun U Kwon, Bum Joon Kim.

   Background: The pathophysiology of stroke-like episodes in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome remains incompletely understood, despite the syndrome's distinctive clinical and radiological characteristics. This study aimed to gain insight into the underlying mechanisms of stroke-like episodes by analyzing vascular and perfusion changes during acute stroke-like episodes.
Methods: We conducted a retrospective observational study of genetically confirmed MELAS patients who experienced stroke-like episodes between January 2010 and December 2023. All patients underwent magnetic resonance imaging (MRI) and angiography during the acute phase. Vessel diameters were quantitatively measured at predefined anatomical locations on both the affected and contralateral sides, and were compared using the Wilcoxon signed-rank test. Follow-up imaging was reviewed when available to assess the reversibility of vascular changes.
Results: Among the 17 patients, 15 (88.2%) exhibited lesions characterized by cortical cytotoxic edema and subcortical vasogenic edema. Angiographic analysis revealed significant vasodilation of major vessels in 10 patients (58.8%), primarily affecting the middle cerebral artery (MCA) on the symptomatic side. Hyperperfusion was observed in all patients who underwent perfusion-weighted MRI, which spatially corresponded to stroke-like lesions. Quantitative analysis indicated a significant difference in vessel diameter between the affected [1.92 (interquartile range, 1.76-2.42)] and unaffected sides [1.84 (interquartile range, 1.74-2.22), Z=-2.250, P=0.024]. Follow-up angiography was conducted for three patients, all of whom demonstrated complete resolution of vasodilation.
Conclusions: Our findings of cortical cytotoxic edema, subcortical vasogenic edema, and reversible major vessel vasodilation during stroke-like episodes contribute to the pathophysiological understanding of MELAS based on mitochondrial energy failure.

Keywords:  Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); mitochondrial diseases; stroke-like episodes; vasodilation

DOI:  https://doi.org/10.21037/qims-2025-1-2735
Stud Health Technol Inform. 2026 May 21. 336 368-372

Clinical Diagnosis of Rare Diseases Using Leaky Noisy-OR Bayesian Networks.

François Roucoux, Sébastien Jodogne.

  This study presents a probabilistic method for the clinical diagnosis of rare diseases using leaky noisy-OR Bayesian networks automatically constructed from Orphanet and Human Phenotype Ontology data. The resulting model represents diseases and phenotypes as binary variables linked by causal probabilities derived from standardized annotations. Loopy belief propagation enables efficient approximate inference of disease posterior probabilities in large networks containing over 8,000 diseases and 9,000 finding variables. Evaluation on real clinical cases achieves 56.2% Top-3 diagnostic accuracy, in line with the reported performance of leading phenotype-based systems. The proposed framework demonstrates that interpretable and knowledge-grounded probabilistic reasoning can achieve state-of-the-art diagnostic performance for rare diseases while maintaining transparency and reproducibility. Unlike deep learning or ensemble models, it provides explicit causal explanations for each diagnostic hypothesis, enhancing interpretability and trust-worthiness.

Keywords:  Clinical diagnosis; Human Phenotype Ontology; Leaky noisy-OR Bayesian networks; Orphanet; Rare diseases

DOI:  https://doi.org/10.3233/SHTI260179
Comp Biochem Physiol A Mol Integr Physiol. 2026 May 15. pii: S1095-6433(26)00055-3. [Epub ahead of print] 112020

Lack of repeatability in red muscle mitochondrial function over time and across oxygen conditions in a teleost fish.

Jean-Baptiste Quéméneur, José-Luis Zambonino-Infante, Karine Salin.

  Mitochondrial aerobic metabolism varies among individuals and has been linked to components of animal performance and fitness. However, because assessments of mitochondrial function have often required terminal sampling, most studies rely on single measurements, leaving the temporal and environmental consistency of mitochondrial traits within individuals largely unknown. Here, we investigated the repeatability of mitochondrial function measurements over time and across environmental conditions using repeated measurements in permeabilized red muscle of individual European sea bass (Dicentrarchus labrax). Mitochondrial metabolic traits were measured at monthly intervals under stable normoxic conditions and following exposure to hypoxia. At the population level, mean mitochondrial function was largely stable over time, with the exception of an increase in cytochrome c oxidase activity under hypoxia. However, mitochondrial respiratory rates, ATP production, and efficiency showed no repeatability within individuals over a one-month period across either stable or changing oxygen conditions. These results indicate that, although individuals differ markedly in mitochondrial function at any given time, mitochondrial phenotypes permeabilized red muscle are highly dynamic and context-dependent. Our findings highlight important limitations in the interpretation of single time-point measurements of mitochondrial metabolism and have implications for studies linking mitochondrial function to performance, ecological responses, and fitness.

Keywords:  Biopsy; Individual variation; Red muscle; Sea bass; Temporal repeatability

DOI:  https://doi.org/10.1016/j.cbpa.2026.112020
iScience. 2026 Jun 19. 29(6): 115859

Vitrification-warming delays preimplantation development and impairs mitochondrial function and cytoplasmic lattices integrity in mouse embryos.

Mariana T Barroso, Jose A Rodriguez Muñoz, Viola Sjöström, Konstantina Dindini, Jian Zhao, Kenny A Rodriguez-Wallberg, Arturo Reyes Palomares.

  Vitrification and warming of human embryos have become standard procedures in assisted reproduction over the past two decades. Although generally considered safe, their full impact on embryo development remains unclear. Epidemiological studies have raised concerns about differences in birth weight and long-term health outcomes between newborns from fresh versus frozen embryo transfers. Here, we present a descriptive study using mouse embryos to investigate the impact of vitrification and warming on developmental kinetics, mitochondrial function, and cytoplasmic lattice integrity. Time-lapse imaging revealed significant developmental delays across all preimplantation stages in vitrified embryos. Additionally, mitochondrial distribution, volume, and membrane potential exhibited signs of impairment. Ultrastructural analysis identified ruptured mitochondrial membranes, disrupted cytoplasmic lattices during early cell divisions, and underdeveloped mitochondrial cristae at the blastocyst stage. We hypothesize that embryo vitrification and warming disrupt mitochondrial function and compromise cytoplasmic lattices integrity, ultimately contributing to developmental delays in preimplantation mouse embryos.

Keywords:  Cell biology; Cryopreservation; Developmental biology

DOI:  https://doi.org/10.1016/j.isci.2026.115859
Sci Transl Med. 2026 May 20. 18(850): eaeb1677

Treating the immune system to repair the brain.

Michal Schwartz, Tommaso Croese.

Non-neuronal brain cells and systemic immunity play a central role in Alzheimer's disease (AD) and other brain disorders. The immune system, initially protective, becomes dysfunctional as the disease progresses. Here, we discuss next-generation therapeutic approaches aimed at treating the immune system rather than the brain to combat AD and other neurodegenerative diseases.

DOI: https://doi.org/10.1126/scitranslmed.aeb1677
Ecotoxicol Environ Saf. 2026 May 20. pii: S0147-6513(26)00536-1. [Epub ahead of print]319 120207

Early-life mitochondrial impact of prenatal DL-PCB exposure: A signal from cord blood mtDNA.

Chen Yang, Xiang Li, Xiaohui Zhang, Hua Chang, Hui Li, Lulu Liu, Bingnan Liu, Zaili Zhang.

  Mitochondrial DNA (mtDNA) copy number in umbilical cord blood is increasingly recognized as a sensitive indicator of mitochondrial health and vulnerability to environmental exposures during early development. Although persistent organic pollutants (POPs), such as dioxin-like polychlorinated biphenyls (DL-PCBs), have been associated with mitochondrial disturbances, the relationship between prenatal exposure to DL-PCBs and neonatal mtDNA levels remains insufficiently characterized. This study set out to assess the relationship between maternal DL-PCB concentrations during gestation and mtDNA content in cord blood at birth. We recruited 1620 pregnant women from China between 2022 and 2023. Cord blood levels of 12 WHO-identified DL-PCB congeners were quantified using validated Gas Chromatography-Mass Spectrometry methods. Umbilical cord blood samples were collected at birth, and relative mtDNA copy number was measured by quantitative real-time PCR. Associations between individual and mixture DL-PCB exposures and mtDNA copy number were evaluated using multivariable linear regression, quantile g-computation (g-comp), generalized weighted quantile sum (gWQS) regression, and Bayesian kernel machine regression (BKMR). After adjusting for potential confounders, a significant inverse relationship was observed between mtDNA copy number and several specific DL-PCB congeners, notably PCB77, PCB81, PCB126, and PCB169. The g-comp models supported a robust negative association between cumulative DL-PCB exposure and mtDNA levels (β = -0.264, 95% CI: -0.415 to -0.113; p < 0.001). Additionally, the BKMR analysis revealed a non-linear dose-response relationship, with more pronounced changes in mtDNA copy number occurring at low-to-moderate DL-PCB exposure levels. Our findings suggest that prenatal exposure to DL-PCBs is associated with reduced mtDNA copy number in cord blood, which may reflect potential mitochondrial disturbances in the developing fetus. These results underscore the need for further mechanistic studies to clarify the role of mitochondrial pathways in the developmental effects of DL-PCBs.

Keywords:  Environmental Exposure; Mitochondrial DNA; Polychlorinated Biphenyls (PCBs); Pregnancy; Umbilical Cord Blood

DOI:  https://doi.org/10.1016/j.ecoenv.2026.120207